The goal of this study is to identify the pathological findings and expression of immune checkpoint marker (PD-1, PD-L1, and CTLA-4) in the tumor microenvironment of both primary and chemoreduced retinoblastoma and correlate with clinicopathological parameters and patient outcome.
Total of 262 prospective cases was included prospectively in which 144 cases underwent primary enucleation and 118 cases received chemotherapy/radiotherapy before enucleation (chemoreduced retinoblastoma). Immunohistochemistry, qRT-PCR and western blotting were performed to evaluate the expression pattern of immune checkpoint markers in primary and chemoreduced retinoblastoma.
Tumor microenvironment was different for both primary and chemoreduced retinoblastoma. Expression of PD-1 was found in 29/144 (20.13%) and 48/118 (40.67%) in primary and chemoreduced retinoblastoma respectively, whereas PD-L1 was expressed in 46/144 (31.94%) and 22/118 (18.64%) in cases of primary and chemoreduced retinoblastoma respectively. Expression pattern of CTLA-4 protein was similar in both groups of retinoblastoma. On multivariate analysis, massive choroidal invasion, bilaterality and PD-L1 expression (p = 0.034) were found to be statistically significant factors in primary retinoblastoma whereas PD-1 expression (p = 0.015) and foamy macrophages were significant factors in chemoreduced retinoblastoma. Overall survival reduced in cases of PD-L1 (80.76%) expressed primary retinoblastoma, and PD-1 (63.28%) expressed chemoreduced retinoblastoma.
This is the first of its kind study predicting a relevant role of the immune checkpoint markers in primary and chemoreduced retinoblastoma with prognostic significance. Differential expression of these markers in both group of retinoblastoma is a novel finding and might be an interesting and beneficial target for chemoresistant tumors.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Pancreatic cancer remains a leading cause of cancer-related mortality worldwide. Tumor-infiltrating lymphocytes (TILs) play an important role in mediating tumor progression and treatment resistance in pancreatic cancer. However, the prognostic value of TILs in pancreatic cancer remains uncertain. This meta-analysis evaluated the prognostic significance of TIL subsets (CD3+, CD4+, CD8+, FoxP3+ T cells) on overall survival (OS) and disease-free survival (DFS) of patients with resected pancreatic ductal adenocarcinoma.
Pertinent studies were gathered through systematic search of PubMed, Google Scholar and Cochrane Library databases up to August 1, 2019. Using Review Manager version 5.3, pooled hazard ratios and 95% confidence intervals were calculated using random or fixed effects models, depending on the heterogeneity of studies.
A total of 11 studies comprising 1760 patients were included. Pooled analysis revealed that high levels of CD8+ TILs were associated with improved OS (HR = 0.59, 95% CI = 0.51-0.69, p < 0.00001) and DFS (HR = 0.60, 95% CI = 0.50-0.73, p < 0.00001). Similarly, high levels of CD3+ TILs correlated with better OS (HR = 0.64, 95% CI = 0.54-0.75, p < 0.00001) and DFS (HR = 0.53, 95% CI = 0.31-0.92, p < 0.0001). In contrast, high FoxP3+ TILs associated with worse OS (HR = 1.37, 95% CI = 1.00-1.87, p = 0.05), with no significant difference in DFS (HR = 1.21, 95% CI = 0.88-1.67, p = 0.23). While high CD4+ TILs showed significant improvement in OS (HR = 0.74, 95% CI = 0.63-0.86, p = 0.0001), there was no significant disparity in DFS (HR = 0.79, 95% CI = 0.47-1.35, p = 0.39).
TILs are a promising prognostic biomarker in pancreatic cancer. High levels of CD8+ TILs correlated with favorable OS and DFS, while high levels of FoxP3+ TILs associated with poor OS. Nonetheless, results of this meta-analysis should be approached with caution due to the lack of established standards in assessment of TILs and the small number of available studies. Prospective studies that assess TILs in a more comprehensive and standardized manner are needed.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Gastric cancer (GC) is the 3rd commonest cause of cancer mortality. T cells infiltrates are prognostic in other cancer types (Pagès 2018) but most studies in GC have used manual counting, lacked a validation cohort and were performed in Asian patients with often better outcomes than Western patients. The prognostic role of T cells hence remains poorly established in Western GCs.
Tissue microarrays from 474 therapy naïve GCs resected in Leeds, UK, were split into discovery and validation cohorts and stained using multispectral immunofluorescence for CD8 (cytotoxic-), CD45RO (memory-), FOXP3 (regulatory-T cells), cytokeratin and DAPI. T cell densities were measured by computational image analysis. GCs were assigned to 5 equal sized density classes (C1 low to C5 high) for each marker and cancer specific survival (CSS) was assessed.
CD45RO (p = 0.000) and FOXP3 (p = 0.001) densities were significantly associated with CSS in the discovery cohort (n = 327). For both markers, C1 (low) and C5 (high) were associated with the shortest and longest CSS, respectively, C2 to C4 all showed similar CSS and were consolidated into an intermediate group. Reanalysis using low, intermediate and high groups showed significant associations of CD45RO (p = 0.024) and FOXP3 (p = 0.003) densities with CSS in the validation cohort (n = 147). TNM stage, CD45RO and FOXP3 densities were independent predictors of CSS in multivariate analysis of both cohorts. EBV positive (EBV+) and MMR deficient (dMMR) GCs are considered highly immunogenic GC subtypes. 20/475 GCs were EBV+ and 70% of these showed high CD45RO or FOXP3 densities. 51/488 were dMMR but only 38% were CD45RO or FOXP3 high, perhaps indicating the frequent acquisition of immune evasion mechanisms by dMMR GCs (von Loga 2019).
This study identified and validated CD45RO and FOXP3 T cell infiltrates as independent prognostic markers in Western GC patients. This may enable personalized follow up or (neo)adjuvant treatment strategies. Whether high infiltrates are predictive of immunotherapy benefit should be assessed. Unexpectedly, high FOXP3 densities were associated with longer CSS, warranting studies into the role regulatory T cells in GC.
Marco Gerlinger.
National Institute for Health Research and Biomedical Research Council - Royal Marsden Hospital, Cancer Research UK, Schottlander Foundation.
All authors have declared no conflicts of interest.
Pancreatic cancer (PC) contributes to over 7 % of all cancer related deaths worldwide with a relative 5-year survival of less than 8 %. High levels of tumor-infiltrating lymphocytes (TILs) are associated with improved survival in many cancer types. Examining the impact of TILs on survival in PC could provide better prognostication and help clinicians tailor therapy for patients.
A systematic search based on the PICO-process was conducted on PubMed, Embase, The Cochrane Library and Web of Science. Outcome of interest was overall survival (OS). Studies examining high vs. low levels of TILs in pancreatic tumor tissue and its impact on OS was included. Following data extraction a random-effects model meta-analysis was conducted on the reported outcome with corresponding lymphocyte subset. The Newcastle-Ottowa Scale was used for study quality assessment.
In total, 43 studies were included in the systematic review and 40 were eligible for meta-analysis. A time-to-event meta-analysis on the different lymphocyte subtypes revealed, that high vs. low infiltration of CD3+ T and CD8+ T cells was significantly associated with improved OS (HR = 0.59, 95 % CI: 0.51 - 0.68, I2: 0 % and HR = 0.61, 95 % CI: 0.57 – 0.67, I2: 0 %, respectively). High infiltration of FoxP3+ T cells was associated with decreased OS (HR = 1.41, 95 % CI: 1.15 – 1.73, I2: 85 %). The prevalence of CD4+ and CD20+ lymphocytes in pancreatic tumor tissue was not significantly associated with increased OS (HR = 0.87, 95 % CI: 0.65 - 1.17, I2: 80 % and HR = 0.86, 95 % CI: 0.54 – 1.35, I2: 66 %, correspondingly).
High infiltration of CD3+ and CD8+ lymphocytes is associated with improved OS among patients with resected PC, whereas high infiltration of FoxP3+ T cells is associated with decreased OS. CD4+ and CD20+ lymphocytes did not have a significant impact on OS. Based on these findings, staining for TILs, especially CD3+, CD8+ and FoxP3+ T cells, might be an important tool for future assessment of patient survival and prognosis, as well as for tailored oncological therapy.
CRD42019134744.
The authors.
Center for Surgical Science.
All authors have declared no conflicts of interest.
Nasopharyngeal carcinoma (NPC) has distinct histopathology and associated with high mortality rate. Identification of NPC cases that have aggressive behavior at an early-stage can aid in improvement of the survival. Assessment of tumor-infiltrating lymphocytes (TILs) has shown a promising prognostic value in many epithelial cancers.
This study included a multicenter cohort of 44 cases treated for early-stage (I-II) NPC at the five Finnish university hospitals (Helsinki, Turku, Tampere, Kuopio and Oulu). Hematoxylin and eosin-stained cancer sections were used to evaluate TILs. We followed the guidelines that recently introduced by International Immuno-Oncology Biomarkers Working Group for assessment of TILs in different tumors including head and neck cancer.
The score of intra-tumoral TILs showed a promising prognostic value for predicting survival in early NPC. A hazard ratio of 2.45 and 95% confidence interval of 1.07 to 5.62 (P = 0.03) was reported, indicates that tumors with low TILs have a higher risk of mortality.
In early-stage of NPC, assessment of TILs has a significant prognostic value that can be useful to identify cases with aggressive behavior. Further studies are necessary to validate the importance of TILs in larger cohorts of early NPC.
Alhadi Almangush.
Has not received any funding.
The author has declared no conflicts of interest.
Predictive biomarkers of immune checkpoint inhibitors (ICIs) efficacy in NSCLC are still an unmet goal. PD-L1 expression at tissue level (tPD-L1) is not steadily assessable in metastatic setting and, although routinely recommended, its dynamic nature hinders an accurate estimation. Thus, the aim of our study was to determine whether embodying genetic, tissue and circulating PD-L1 status may predict ICI response in NSCLC patients. To encompass PD-L1/PD-1 axis, we investigated the incidence of PD-1 receptor on circulating T-lymphocytes.
Peripheral blood (PB) samples from 80 consecutive ICI-treated NSCLC patients were collected at baseline. Soluble PD-L1 (sPD-L1) was measured by Human/Cynomolgus Monkey PD-L1/B7-H1 Immunoassay (R&D Systems). PD-L1 polymorphisms (rs2282055, rs4143815) were determined by RT PCR using TaqMan® method. FACS analysis was performed to detect PD-1 expression on T cells. Available tissue sections were immunohistochemically stained for tPD-L1 scoring. All these parameters were correlated with patient characteristics, survival outcome and response to treatment.
sPD-L1 values ranged from 14.8 to 189.8 pg/ml (median 62.8 pg/ml). High sPD-L1 and low number of PB CD8+PD-1+ lymphocytes were detected in NSCLC cases displaying ECOG PS = 2, >3 metastatic sites, liver and pleural involvement (p < 0.05). PD-L1 polymorphisms or tPD-L1 did not appear to affect sPD-L1 levels neither correlated with clinicopathological features. Kaplan Meier curves displayed significantly reduced PFS and OS (P < 0.01) in cases with high sPD-L1, while no difference emerged according to tPD-L1 levels. PD-L1 rs4143815 allelic variant conditioned a trend of improved PFS, although without reaching statistical significance. Moreover, cases with high PB CD8+PD1+ T cells showed 12 and 22 months gain in PFS and OS (P < 0.001 vs low), respectively. Finally, a remarkable impact of sPD-L1 and CD8+PD1+ cells on Disease Control Rate was apparent (P < 0.01).
Our preliminary results support sPD-L1 as a promising biomarker of ICI benefit. The simultaneous assessment of the pool size of PB PD1+ effector cells might implement the strategy to predict NSCLC survival and response to treatment.
University Hospital of Parma.
Has not received any funding.
All authors have declared no conflicts of interest.
Selection of Checkpoint Inhibitor therapies in several cancers are based on PD-L1 expression in tumor tissue determined by IHC. Invasive biopsy to obtain tumor tissue is associated with procedural risks, sequelae and expenses. Though PD-L1 profiling of Circulating Tumor Cells (CTCs) has been attempted previously, limitations arise due to low yields of CTCs in conventional methods. We describe a novel approach for harvesting sufficient CTCs that can be used for PD-L1 profiling by Immunocytochemistry (ICC).
15 ml peripheral blood was collected from 95 patients with histopathologically confirmed diagnosis of lung cancer. PBMCs were isolated by centrifugation. CTCs were enriched from PBMCs via an epigenetically acting stabilization process which induces apoptosis in normal (non-cancerous) cells while simultaneously conferring survival privilege on apoptosis-resistant cells of tumorigenic origin (CTCs). Surviving CTCs were confirmed by immunostaining for EpCAM and pan-CK. CTCs were further profiled for Napsin and TTF-1 (Lung-Adenocarcinoma specific), p40 (Squamous Cell Carcinoma specific), CK7 (Adenocarcinoma specific), Synaptophysin and Chromogranin (Neuroendocrine carcinoma specific) and PD-L1 (22c3).
Viable CTCs could be enriched and harvested in all 95 samples regardless of treatment status and extent of disease (metastatic status). Deep ICC profiling including all organ- and subtype-specific markers as well as PD-L1 could be conducted in 71 out of the 95 samples (74.7%). Among the 71 samples which were evaluable, PD-L1 positivity was observed in 33 samples (46.5%). PD-L1 expression in these 33 samples was quantitatively estimated and assigned as ‘Low’, ‘Moderate’ or ‘High’. Among the 33 PD-L1 positive samples, 25 (75.8%) had low PD-L1 expression, 7 (21.2%) had moderate expression, and 1 (3%) had high expression.
ICC profiling of CTCs is a viable approach for determining suitability of patients for checkpoint inhibitor therapies. This method permits quantitative determination of PD-L1 expression which appears to have clinical relevance in determining the probability of favourable response to checkpoint inhibitor therapies.
The authors.
Datar Cancer Genetics Limited.
R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. P. Devhare: Full / Part-time employment: Datar Cancer Genetics Limited. S. Patel: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Shareholder / Stockholder / Stock options: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest.
Multiple myeloma (MM) is a lymphoid neoplasm characterized by the accumulation of malignant clones of plasma cells, usually within the bone marrow (BM). Despite the increase of T cells expressing inhibitory signal molecules (ISMs) — PD-1, TIM-3 etc. — having been described in MM, the first results of anti-PD-1 therapy for MM remain modest. ISMs are expressed on T cells and modulate the functional activity. A stable expression of ISMs on T cells is associated with T cell exhaustion, the condition of severe decrease of both cytotoxicity and cytokine secretion. At the same time, ISMs are also expressed by activated T cells. We studied the expression of PD-1 and TIM-3 by circulating and bone marrow (BM) T cells as a manifestation of T cell exhaustion treated MM patients.
Peripheral blood (PB) and BM samples of 45 MM patients were obtained during routine diagnostic procedures. The expression of PD-1 and TIM-3 by CD4+ and CD8+ T cells, intracellular production of IFNγ and intracellular expression of Ki-67 by T cells and Granzyme B production by CD8+ T cells were assessed using flow cytometry.
Relative counts of PD-1+ subset of CD8+ T cells and both PD-1+ and TIM-3+ subsets of CD4+ T cells were higher in BM compared with PB. BM samples also contained higher amounts of double-positive PD-1+TIM-3+ subsets of CD8+ and CD4+ T cells compared with PB. Percentage of PB CD8+PD-1+, CD4+PD-1+, CD4+TIM-3+, CD8+PD-1+TIM-3+ and CD4+PD-1+TIM-3+ T cells correlated with the content of respective subsets in BM. Both PB and BM CD8+PD-1+ and CD4+PD-1+ T cells of MM patients retain a cytotoxic, proliferative and cytokine-producing potential appropriate to PD-1-negative subsets. On the contrary, the functional activity of CD8+PD-1+TIM-3+ and CD4+PD-1+TIM-3+ T cells was significantly reduced compared with PD-1- and TIM-3-negative subsets.
PD-1+ T cells in MM patients are related to activated rather than exhausted populations. T cell exhaustion is associated with cells co-expressing PD-1 and TIM-3. It is recommended to evaluate T cell subsets co-expressing PD-1, TIM-3 and other ISMs, and to study their functional properties.
The authors.
The Russian Science Foundation (grant no. 18-75-00050).
All authors have declared no conflicts of interest.
Immune checkpoint inhibitors have been reported to be ineffective in patients with high levels of MDSC (myeloid-derived suppressor cells) and MDSC has been proven to be stimulated by inflammation involving VEGF and IL-17. We have reported that MDSC, IL-17 and VEGF are closely associated with immunosuppression and poor prognosis.
Stimulation index (SI) obtained by PHA-blastogenic response of lymphocyte was used as a marker of cell-mediated immunity and was tested in 658 patients with unresectable diseases including 260 esophageal, 110 gastric and 288 colorectal cancers. These patients received chemotherapy and SI were analyzed in correlation with nutritional status, treatment outcome (RECIST) and prognosis. These patients were divided into 2 groups with a median level of SI and, chemotherapy outcome and overall survival were compared between these groups (Study 1). To characterize the mechanisms of immunosuppression, PBMC (peripheral blood cells) were separated from the patients and the production of IL-17 (ELISA) by PBMC. Circulating levels of MDSC (CD14-CD11b+CD33+/flow cytometry), serum levels of VEGF (ELISA) were measured and analyzed in 43 patients with gastric cancer and 64 with colorectal cancer (Study 2).
(Study 1) The overall survival was significantly worse in patients with lower SI than in those with higher SI in each disease, and the responses (RECIST) to chemotherapy were significantly better in patients with higher SI than those with lower SI. SI were significantly inversely correlated with NLR (neutrophil/lymphocyte ratio: inflammatory parameter) and nutritional factors including prealbumin, retinol-binding protein and transferrin. (Study 2) SI were significantly and inversely correlated with the levels of MDSC, the production of IL-17, and the levels of VEGF. The levels of MDSC, VEGF, IL-17 were significantly correlated with each other and inversely with nutritional parameters.
The key mechanisms of immunosuppression in these patients are systemic inflammation involving MDSC, VEGF and IL-17. Immune checkpoint inhibitors might be more effective with a decreased MDSC by controlling VEGF and IL-17.
Masahiko Shibata.
Has not received any funding.
All authors have declared no conflicts of interest.
Kadmon has generated an anti-PDL1/IL-15 fusion protein (KD033) by combining a proprietary, fully human, high affinity anti-human/mouse PD-L1 antibody with human IL-15. Initial assessment of KD033 showed enhanced tolerability relative to a non-targeted IL-15 fusion protein, in addition to its potent anti-tumor activity and immune memory generation. KD033 increased CD8+ T and NK cells in peripheral blood of humans, cynomolgus monkeys and mice as expected from on target engagement of IL-15. In this study, we evaluated additional immune cell population changes in mice and cynomolgus monkeys treated with KD033.
Tumor size, measured at day 7 in syngeneic subcutaneous CT26 colorectal cancer mouse model after a single KD033 surrogate treatment, was used to define mice as either KD033 responders (decreasing tumor volumes) or non-responders (no change or increasing tumor volumes). Peripheral blood from KD033 responders and non-responders as well as from cynomolgus monkeys treated with KD033 at predose, 24 and 168 hours after dosing was analyzed by flow cytometry for various immune cell populations.
Granzyme B+ CD8+ T and gamma delta T cells in peripheral blood were specifically increased in KD033 surrogate responder mice. These increases were not observed in non-responder mice. Greater increases in NKT-like cells were also observed in KD033 surrogate best responders. This is in contrast to other immune populations, such as CD8+ T and B cells, which were similarly impacted, in both KD033 surrogate responder and non-responder mice. In cynomolgus monkeys, CD3+CD4-CD8- cells, which includes gamma delta T cells, were one of the immune populations with the highest increases at 168 hours post dose.
KD033 administration increases CD8+ T and NK cells, consistent with IL-15 pharmacodynamics. In addition, analysis of peripheral blood from KD033 surrogate best and non-responder mice demonstrated increases in different immune populations, which can facilitate their use as in-treatment biomarkers of KD033 activity in tumors. Importantly, KD033 administration resulted in increases in rare cytotoxic cells such as NKT and gamma delta T cells in peripheral blood which may contribute to its anti-tumor activity and immunity.
Kadmon Corporation LLC.
Kadmon Corporation LLC.
S. Martomo: Full / Part-time employment: Kadmon Corporation. D. Lu: Full / Part-time employment: Kadmon Corporation. Z. Polonskaya: Full / Part-time employment: Kadmon Corporation. X. Luna: Full / Part-time employment: Kadmon Corporation. F. Miyara: Full / Part-time employment: Kadmon Corporation. J. Patel: Full / Part-time employment: Kadmon Corporation.
Many different mechanisms allowing for immune escape have been described in solid tumors, but their relevance for hematological malignancies is underexplored. We analyzed possible involvement of selected processes in the acute myeloid leukemia (AML), with regard to the mutational status of NPM1 and Flt3 genes, which are important prognostic markers in AML.
The expression of HLA class I, CLIP, and of different inhibitory receptors was analyzed by flow-cytometry on fresh or cryopreserved primary mononuclear cells, which were isolated from the peripheral blood of AML patients at diagnosis (N = 38). The amount of regulatory T-cells (CD25+FoxP3+) was measured in fresh whole blood samples (N = 81). Some markers were assessed in parallel on the transcript level. AML blast lysis by NK cells was tested by flow-cytometry using donor-derived expanded NK cells.
A decrease in HLA class I expression on AML blasts to about 20 % of normal levels was detected in 26 % of cases. This decrease did not significantly enhanced AML cell lysis by NK cells. High CLIP expression was found on leukemia blasts in 61 % of cases. High PD-L1 expression, which was determined by PCR, was associated with significantly worse overall survival (OS), specifically in patients with internal tandem duplication in Flt3 (Flt3-ITD; published finding, Brodská et al. IJMS 2019). We noted no mark of lymphocyte exhaustion (Tim3, LAG3, CTLA-4) in AML samples. On the other hand, Tim-3 was frequently found on blast cells (53 % of cases), in close correlation with higher levels of Tim-3 transcript. Tim-3 negativity was associated with better OS in patients without Flt3-ITD (p = 0.07). Increased count of regulatory T-cells was detected in 17.5 % of AML patients at diagnosis.
The majority of AML patients display at least one marker of immune escape at diagnosis. These include decreased HLA class I expression, reduced antigen processing, increased PDL1 expression, secretion of Tim3 by leukemia blasts, or increased Treg counts. The mechanisms of immune suppression in AML are likely heterogenous, similarly to the disease itself. Both PD-L1 and Tim-3 might have prognostic value in selected AML subgroups.
The authors.
Ministry of Health of the Czech Republic (Grant no 16-30268A).
All authors have declared no conflicts of interest.
There exists a need for a prognostic marker apart from PDL1 expression for patients being treated with immunotherapy. Neutrophil lymphocyte ratio (NLR) has been shown to correlate with outcomes in certain malignancies treated with immune checkpoint inhibitors (ICI).
A retrospective analysis was carried out of a total of 70 patients who received ICI for metastatic renal cell carcinoma (mRCC) and metastatic non-small cell lung cancer (mNSCLC) from 2016-2019. Peripheral blood NLR of 5 at baseline was used as cut off to divide patients into two groups. Objective response rate (ORR) and overall survival (OS) were calculated in the two groups.
37 patients of mRCC and 33 patients of mNSCLC were treated with ICI. Among the 37 with mRCC , 24 patients (64.9%) had a NLR less than 5. Those with NLR<5 had a significantly better response rate with a ORR of 70.8% as compared to ORR of 15.4% in NLR>5 group (p = 0.01).There was also a marked significant difference in the survival between the two groups with median OS not reached in NLR<5 group v/s 5 months in NLR>5 group( HR = 0.12 , 95% CI : 0.04-0.40, p = 0.00). Three patients with NLR< 5 have a ongoing complete response of 40, 38, and 30 months respectively. Among the 33 patients of mNSCLC, 19 patients (57.5%) had NLR of < 5 . Those with NLR<5 had a better response with ORR of 57.9% as compared to 28.5% in NLR>5 . Those with NLR<5 also had a better survival with median OS of 24 months as compared to only 6 months in those with NLR >5 (HR = 0.59).
Patients with low NLR had a significantly better response rate and overall survival. In a resource and cost constraint setting, a simple inexpensive test such as NLR would not only be prognostic, but can help in choosing treatment strategies in scenarios where PDL-1 expression does not carry any implication such as in 2nd line mRCC and 2nd line mNSCLC. Also with the advent of combination regimens in 1st line setting (chemo+ ICI in mNSCLC and oral TKI+ICI in mRCC), large scale studies need to be done on whether those with low NLR can benefit with only single agent ICI which would have an impact in not only lowering the cost burden in a developing country such as India but also maintain a better quality of life.
Nitin Yashas Murthy.
Has not received any funding.
All authors have declared no conflicts of interest.
The Lung Immune Prognostic Index (LIPI), combining the derived neutrophils/[leucocytes minus neutrophils] ratio (dNLR) and lactate dehydrogenase (LDH), has been associated with survival for ICI-single agent in large cohorts of refractory advanced NSCLC. However the role of LIPI in untreated NSCLC patients has not been explored yet. We assessed the value of LIPI in the front-line setting of advanced NSCLC patients (pts) treated with ICI-single agent or in combination with chemotherapy and compared to a cohort of pts treated exclusively with chemotherapy (CT).
Retrospective multicenter study of pts treated in first-line ICI single agent if PD-L1 ≥50% (ICI-cohort), or in combination with chemotherapy (Combo-cohort) from 15 centers worldwide. A control cohort with pts treated with platinum-based CT (CT-cohort) was extracted from the prospective MSN study. LIPI was calculated as previously reported. We correlated pretreatment LIPI with overall survival (OS) in the 3 cohorts.
A total of 470 pts were enrolled in the three cohorts between 2011 and 2019. Median follow-up is 13.9 months. In the ICI-cohort (N = 252), 165 (65%) were male, with median age of 67, 195 (77%) with PS ≤ 1. Based on LIPI (available for 195 pts): 81 (42%) were considered good, 86 (44%) intermediate and 28 (14%) poor group. In the combo-cohort (N = 98), 71 (72%) were male, with median age of 66, and 84 (86%) with PS ≤ 1. Based on LIPI (available for 69): 23 (33%) were good group, 34 (49%) intermediate and 12 (17%) poor group. In the CT-cohort (N = 120), no differences were observed by LIPI groups. The impact of LIPI groups in the 3 cohorts is summarized in the table. Table: 17P OS and PFS in the 3 cohorts; OS according to the LIPI groups NR: not reached; OS: overall survival; PFS: progression-free survival.OS ICI-cohort Combo-Cohort Chemo-cohort Median PFS 8.5m. [6.6-11.8] 9.6m. [6.7-11] 5.7m. [5.1-6.6] Median OS 21.3 m. 12.8-NR] 24.7m. [14.9-25.7] 13.8m. [9.6-15.3] LIPI good Median OS NR [17.36-NR] 25.7m. [25.6-NR] 14.4 m. [9.6-18.1] LIPI intermediate Median OS NR [9.2-NR] 16.9 m. [12.8-NR] 13.8 m. [8.5-15.8] LIPI poor Median OS 7.9m. [2.3-NR] 6.2m. [5.7-NR] 6.5 m. [6-NR] P value P = 0.01 P = 0.02 P = 0.19
Pretreatment LIPI correlates with ICI survival in monotherapy and in combination with chemotherapy in front-line in advanced NSCLC pts. The correlation is not statistically significant in the chemotherapy alone group. The value of LIPI for ICI upfront should be explored in prospective clinical trials.
The authors.
Has not received any funding.
E. Auclin: Travel / Accommodation / Expenses: Mundipharma; Speaker Bureau / Expert testimony: Sanofi Genzyme. D. Planchard: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Boehringer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Celgene; Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Merck; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: prIME Oncology; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Peer CME; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. L. Hendriks: Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (self): Boehringer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Lilly; Honoraria (self): Quadia. B. Besse: Honoraria (institution): AbbVie; Honoraria (institution): Amgen; Honoraria (institution): AstraZeneca; Honoraria (institution): Biogen; Honoraria (institution): Blueprint Medicines; Honoraria (institution): Bristol-Myers Squibb; Honoraria (institution): Celgene; Honoraria (institution): Eli Lilly; Honoraria (institution): GSK; Honoraria (institution): Ingnyta; Honoraria (institution): Ipsen; Honoraria (institution): Merck KGaA; Honoraria (institution): MSD; Honoraria (institution): Nektar; Honoraria (institution): Onxeo; Honoraria (institution): Pfizer; Honoraria (institution): Pharma Mar; Honoraria (institution): Sanofi; Honoraria (institution): Spectrum Pharmaceuticals; Honoraria (institution): Takeda. L. Mezquita: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche diagnostics; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Tecnofarma; Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses: Chugai. All other authors have declared no conflicts of interest.
The role of neoangiogenesis in progression of solid tumors is crucial [Han J.M., 2017]. Activated neutrophils (Nph) can synthesize vascular endothelial growth factor (VEGF) and interleukine-8 (IL-8) [Merritt W.M., 2008], regulated by nuclear factor-kappa B (NF-κB) [Annunziata C.M., 2010]. The aim of the study was to assess the role of pro-angiogenic factors of circulating Nph in the progression of ovarian cancer (OC).
We isolated circulating Nph from the peripheral blood of 97 OC patients (stage I-IV FIGO) 36-76 years old on a double layer of ficoll-urographin. Using ELISA, the VEGF-A (RayBiotech, USA) and IL-8 (Vector-Best-Volga CJSC, Russia) levels were determined in the Nph lysate, and the expression of NF-kB (eBioscience, USA) was determined in the Nph nuclear fraction. The control group included 30 healthy women 23-65 years old. The study was conducted in accordance with the requirements of the IMEPC ULSU ethics commission (protocol №3 from 15.03.2015). The correlation between the parameters was evaluated using the Spearman coefficient, the statistical significance of the differences was evaluated using the nonparametric Mann-Whitney U-test (p ≤ 0.05).
We detected a statistically significant increase in the level of VEGF in Nph already at the initial stage of the OC compared to the control (469.764±185.028 pg/ml vs 50.483±9.505 pg/ml, p = 0.0053). With more advanced OC stage, the VEGF level in Nph decreased by 2 times, but remained statistically significantly high compared to control. An average correlation was revealed between the level of VEGF in Nph and the stage of OC (p = 0.5196). The level of NF-kB in the nuclear fraction of Nph was statistically significantly increased in I stage OC (0.589±0.129 mg/ml vs 0.166±0.028 mg/ml in the control, p = 0.0253) and decreased statistically significantly with the OC spread. A weak correlation between the level of NF-kB in Nph lyzate and the OC stage was revealed. The level of IL-8 in Nph did not significantly change in OC. An average correlation was found between the NF-kB level and IL-8 level in Nph (p = 0.6914).
The results obtained indicate an increase in the pro-angiogenic activity of circulating Nph with the progression of OC.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) had shown to increase progression-free survival (PFS) and overall survival (OS). The prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) are biomarkers easy to measure by blood tests and they had been studied as possible prognostic predictors in patients (pts) with various types of cancer treated with ICI. This study intends to analyze the impact of the NLR and PNI in pts with NSCLC treated with ICI.
Thirty-four pts with stage IV NSCLC that had started ICI in 1st and subsequent lines between 03/2016 and 06/2019 were retrospectively analyzed. The pre-treatment NLR and PNI were calculated and the cut-off 5 and 50 were respectively considered. The Kaplan-Meier method and Log Rank test and the Cox regression were used in survival analysis.
Twenty-seven (79%) were male, with a median age of 67 (34-79) years; ECOG 0-1 (n = 30; 88%); stage IVA (n = 14; 41%); PD-L1 ≥50% (n = 18; 53%); NLR ≥5 (n = 13; 38%); PNI ≥50 (n = 14; 41%). Eleven pts (32%) were submitted to ICI in 1st line. The median follow-up time was 19,3 months (mo.). The median PFS was 6,1 mo. (95%CI 1,94-10,26) and median OS was 9,3 mo. (95%CI 0,31-18,29) - 16,5 mo. in 1st line vs 8,6 mo. in subsequent lines. The median PFS was superior in patients with PNI ≥50 (7,0 vs 2,1 mo., p = 0,039), but there weren’t differences considering the NLR. The median OS was also superior when PNI ≥50 (16,8 vs 6,7 mo., p = 0,019). In multivariate analysis (sex, age, 1st line, PD-L1, stage, ECOG, NLR and PNI), the mortality probability was superior in pts with ≥70 years [HR 6,14 (95%CI 1,49-25,39)]. Moreover, PD-L1 ≥50% [HR 0,09 (95%CI 0,01-0,52)], male sex [HR 0,03 (95%CI 0,004-0,24)], stage IVA [HR 0,26 (95%CI 0,07-0,997)] and PNI ≥50 [HR 0,15 (95%CI 0,03-0,69)] were associated to a reduced mortality risk.
PNI ≥50 was predictive of a better PFS and OS and the NLR wasńt a predictor of survival. Regarding OS, PNI ≥50 was an independent survival prognostic factor. In order to understand the impact of this biomarker in NSCLC treated with ICI, it is important to evaluate it in more studies with a larger population and prolonged follow-up time.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The incidence of colorectal cancer cases is high and increases each year. Colorectal cancer is the 3rd most common cancer in both sexes. The five-year survival rate has not increased significantly for several decades. Usually our patients come to the hospital already in advanced stage and the elderly patients seem to have a better clinical outcome than young and adult patients. One factor that could be suggest for those cases is different immune profiles between them. We evaluated the difference of immune profiles between those groups in advanced stage colorectal cancer.
This was a cross sectional analytic study on colorectal cancer patients in advanced stage, to evaluate whether any difference in immunity profiles between 3 age groups (young: <40 y.o; adult: 40 – 60 y.o; elderly: >60 y.o). We evaluated the level of CRP, IL-1β, IL-6, IL-10 IFNγ, TNFα, CD-8, IG G and IG M from blood specimens of those colorectal cancer patients. MANOVA test was done to evaluate the level of significance of those differences between each age group.
62 colorectal cancer patients were evaluated on this study. We found significant differences in the levels of CRP, IL-6, IFNγ, CB-8, IG G and IG M between the young, adult and elderly patients, rp < 0.05. Whereas the difference between the young and adult patients, in the levels of IL-6, IFNγ, CD-8, IG G and IG M were found to be significant (p < 0.05), while between the young and elderly group, the signifant differences were in the levels of CRP, IL-6, IFNγ, CB-8, IG G and IG M (p < 0.05). The level of IL-6 was only significantly different between the adult and elderly group (p < 0.05)
There were significant differences in immune profile between young, adult and elderly colorectal cancer patients.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immunotherapy modified advanced lung cancer treatment. Unfortunately, not all patients respond to it and little is known about predictive markers of response. Recently, a lung immune prognostic index (LIPI) was developed to predict outcomes. Neutrophil-lymphocyte ratio (NLR) has also been shown as possible marker of response to immune checkpoint inhibitors. The aim of this study is to evaluate the prognostic value of both LIPI and NLR in patients with advanced lung cancer treated with anti-PD1 drugs, pembrolizumab and nivolumab.
Data from patients diagnosed with lung cancer (stage III-IV) treated with pembrolizumab and nivolumab, from a Portuguese tertiary cancer centre were reviewed retrospectively (July’15 to July’19). LIPI and NLR were calculated before the beginning of immune checkpoints inhibitors. NLR was calculated as the ratio between neutrophils and lymphocytes. NLR was categorized into low (≤ median NLR in our cohort) and high NLR (>median). LIPI score results from NLR and LDH level and has 3 different risk categories: low, intermediate and high. Univariate analysis and multivariable analysis (Cox model adjusted for age, EGFR status, PD-L1 expression and previous treatment) were done to evaluate the association between LIPI and NLR with time to progression (TTP) and overall survival (OS).
In our cohort, 120 patients were treated, according to PD-L1 expression, with pembrolizumab (83) and nivolumab (37). Median follow-up in living patients was 13 months, having occurred 60 deaths and 54 disease progression. In both univariate (p = 0.019) and multivariable (p = 0.001) analysis, LIPI score was an independent prognostic factor for OS but not for TTP. HR for intermediate vs low LIPI score was 3.1 (95%CI 1.1-8.8) and HR for high vs low LIPI score was 7.5 (95% CI = 2.5-22.8). Similarly, in univariate (p = 0.007) and multivariable (p = 0.006) analysis, NLR was an independent prognostic factor for OS but not for TTP. HR for high NLR was 2.9 (95% CI = 1.3-6.4).
In our cohort of patients, both LIPI score and NLR are prognostic factors for overall survival in advanced lung cancer patients treated with pembrolizumab and nivolumab. Prospective studies are needed to validate the value of these biomarkers in immunotherapy.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The role of cfDNA-based analyses in the management of patients (pts) receiving ICIs is still poorly understood. We have implemented a translational program to systematically obtain blood samples of pts receiving ICIs in phase I clinical trials for cfDNA monitoring.
Since August 2018, 92 pts were prospectively included and baseline blood samples and prior to every cycle were collected. Plasma cfDNA was isolated using QIAamp Circulating Nucleic Acid Kit and measured using Qubit fluorometer. DNA fragments length and profile were assessed using Agilent 2100 Bioanalyzer. Pts with baseline and prior to cycle 2(preC2) blood samples and at least 1 tumor assessment have been included in the analysis. We established 2 groups based on variations of cfDNA levels on preC2 related to baseline: 1) cfDNA progression group as increase (>0% cfDNA change) 2) cfDNA response group as decrease (<0% cfDNA change). We analysed the correlation between longitudinal changes in cfDNA with progression free survival (PFS) and clinical benefit (partial response or stable disease as best response). PFS was calculated using Kaplan-Meier method, long rank test was used for statistical comparison and chi-square for categorical variables.
92 pts with different advanced tumor types were included. Median number of previous lines was 2.38. Median time from baseline cfDNA to preC2 was 22.82 days and from preC2 to first tumor assessment was 32.18 days. PFS in the cfDNA response group (38 pts) was higher compared with cfDNA progression group (54 pts); median 4.87 m (3.11 – 6.62) and 3.0 m (2.24-3.76), respectively (HR = 0.49 [0.28-0.86] p < 0.001). Clinical benefit was higher in the cfDNA response group (66%) as compared to cfDNA progression group (44%), chi‐square p < 0.04 No difference was observed in median baseline cfDNA levels between pts with PD as best response (28.12 ng/ml) and pts with clinical benefit (19.76 ng/ml) p = 0.28.
The monitoring of early changes of cfDNA levels is a fast approach to predict response to ICI therapy in our cohort. Further validation of these results and correlation with circulating tumor DNA is ongoing.
The authors.
This research has been partially funded by the Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI), supported by the Banco Bilbao Vizcaya Argentaria Foundation (BBVA Foundation) - Grant 9/2017.
C. Hierro Carbo: Research grant / Funding (self): Bayer; Honoraria (self): Ignyta; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Travel / Accommodation / Expenses: Roche. J. Martin-Liberal: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self): Bristol-Myers Squibb; Travel / Accommodation / Expenses: Astellas. I. Braña: Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Regeneron; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Incyte; Speaker Bureau / Expert testimony, Research grant / Funding (self): Orion Pharma; Research grant / Funding (institution): Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Janssen; Research grant / Funding (self): Kura; Research grant / Funding (institution): Pfizer. M. Vieito Villar: Travel / Accommodation / Expenses: Roche. E. Elez: Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck Serono; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Speaker Bureau / Expert testimony: Servier. E. Felip: Speaker Bureau / Expert testimony: ABBVIE; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Blueprint; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: Guardant; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: Janssen. R. Dienstmann: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Research grant / Funding (self): Merck Serono; Advisory / Consultancy: Symphogen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: IPSEN; Advisory / Consultancy: Astellas. A. Gros: Research grant / Funding (institution): Novartis. J. Tabernero: Advisory / Consultancy: Array; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Beigene; Advisory / Consultancy: Boehringer; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genetech; Advisory / Consultancy: Genmab; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Roche; Advisory / Consultancy: Inflection Bioscience; Advisory / Consultancy: IPSEN; Advisory / Consultancy: Kura; Advisory / Consultancy: Lilly; Advisory / Consultancy: Menarini; Advisory / Consultancy: MSD; Advisory / Consultancy: Merck; Advisory / Consultancy: Merrimarck; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners. E. Garralda: Advisory / Consultancy: ROCHE; Advisory / Consultancy: Ellipses; Advisory / Consultancy: Neomed; Advisory / Consultancy: Janssen; Advisory / Consultancy: Boehringer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): MSD; Advisory / Consultancy: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
With the approval of anti-PD1 blocking antibodies in a growing number of indications, understanding the mechanisms responsible for potentiating response to these agents has been a critical avenue of research. However, most studies rely on the use of single cohorts and are relatively limited in their scope, thus limited their utility.
We created a consortium of investigators who share clinical and accompanying transcriptional data collected on the NanoString® nCounter® platform from patients treated with single agent immunotherapy to facilitate biomarker research. In this study, we apply a meta-analysis to a combined cohort of 4 lung cancer studies (n = 150) to identify transcriptional correlates of response to identify patients who are likely to experience clinical benefit.
RNA was profiled with the NanoString IO360 and IO360 beta gene expression panels, and 43 signatures that describe facets of the immune response, tumor biology, and the tumor microenvironment were calculated. Included in these signatures is the Tumor Inflammation Signature (TIS), an investigational 18 gene signature of a suppressed adaptive immune response which enriches for clinical response to pembrolizumab. These signatures, as well as genes of interest identified in a given cohort, were compared to objective response, overall survival, or progression free survival across the cohorts. We confirm previously reported association of TIS with patient outcome and identify immune cell subsets that are also associated with response. In addition, we examine differences between patients with distinct mutational backgrounds, smoking histories, or histological classifications, as well as differences attributable to biopsy location.
This multi-cohort study allows for the development of multi-variate predictors of response to anti-PD1 monotherapy using a single research assay to transcriptionally profile the tumors. We can generate robust predictions from real-world cohorts, which may lead to the development of improved diagnostic assays to guide treatment decisions.
NanoString Technologies.
NanoString Technologies.
N. Radosevic-Robin: Research grant / Funding (institution): NanoString Technologies. J. Reeves: Full / Part-time employment: NanoString Technologies. K. Leroy: Research grant / Funding (self): NanoString Technologies. M. Duruisseaux: Research grant / Funding (self): NanoString Technologies. P. Morel: Full / Part-time employment: NanoString Technologies. M. Bhagat: Research grant / Funding (institution): NanoString Technologies. F. Penault-Llorca: Advisory / Consultancy, Research grant / Funding (institution): NanoString Technologies. D. Damotte: Research grant / Funding (institution): NanoString Technologies. F. Goldwasser: Research grant / Funding (institution): NanoString Technologies. A. Brindel: Research grant / Funding (institution): NanoString Technologies. M. Cumberbatch: Research grant / Funding (institution): NanoString Technologies. S. Ong: Full / Part-time employment: NanoString Technologies. J. Lopez: Research grant / Funding (institution): NanoString Technologies. S. Warren: Full / Part-time employment: NanoString Technologies.
TG01/GM-CSF is an injectable antigen-specific cancer immunotherapy targeted to treat patients (pts) with KRAS mutations, found in > 90% of pancreatic adenocarcinomas (PAC). TG01 consists of a mixture of 7 synthetic peptides representing 7 of the most common codon 12 and 13 mutations associated with PAC. Pancreatic cancer is a heterogeneous and genetically unstable disease, meaning that more than one KRAS mutation may be present in a single tumor. We investigated if cancer-related DNA from pts with resected PAC had more than one KRAS mutation and if the mutation status changed during treatment with TG01/GM-CSF.
Pts were eligible after an R0 or R1 PAC resection. TG01 (0.7 mg intradermal injection id) together with GM-CSF (0.03 mg id) was given on day 1, 3, 5, 8, 15, 22 and 2-weekly until end of chemotherapy, 4-weekly up to 1 year and 12-weekly up to 2 yrs. Within 12 weeks after resection, pts were expected to receive gemcitabine for 6 cycles. Plasma samples (up to 9) from 21 pts were collected and cancer related KRAS DNA were analyzed using ARMS (real time qPCR) for the 6 most common mutations: 12D, 12V, 12A, 12R, 12S and 12C.
21 pts from UK, median age 65 (46-77) enrolled between Jan-2014 and Apr-2016. Previous results from tumor specimen showed that 16 out of 21 pts had a KRAS mutation (single mutation). However, when analyzing mutations using ARMS 20 out of 21 pts had ≥1 KRAS mutations; 19 out of 21 pts (90%) had between 1-6 mutations throughout the study. 12D and 12V mutations co-occurred in 17 out of 21 (81%) of the pts. In one pt all 6 assessed KRAS mutations were detected throughout the study. In 5 pts mutations disappeared during the treatment while in 10 pts the mutations changed either revealing new mutations or shift of mutations over time, possibly indicating selection pressure.
The great majority of patients with PAC have multiple KRAS mutations; in addition, mutations changed during the course of the study. Single mutation vaccines and small molecules targeting single mutations are therefore unlikely to be effective while therapies targeting a mix of KRAS mutations (TG01) may be more beneficial.
CT TG01-01; EudraCT: 2012-002400-40.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Colorectal Cancer (CRC) is the second leading cause of cancer mortality worldwide. Effective and non-invasive biomarkers are needed to improve early diagnosis and disease management. Immune cells play a key role in tumor progression. Circulating immune cell count is a potential cancer biomarker, as indicated by the association of high blood neutrophil-to-lymphocyte ratio with poor prognosis in patients with cancer. The study goal was to determine the correlation between circulating immune cell counts and immune cell-specific RNA signatures and to evaluate the signature potential for CRC detection.
The transcriptome profiles of peripheral blood mononuclear cells from 561 Asian and Caucasian subjects (189 CRC, 115 advanced adenomas, 39 other cancers, 218 controls without colorectal lesions (CON)) were generated by RNA-seq on the Illumina platform. Neutrophils, lymphocytes and monocytes counts were obtained by standard hematology testing. Specific RNA signatures for neutrophils, monocyte/macrophages, T cells, CD4, CD8, B cells, NK cells were compiled from literature. The mean expression level of all genes in each Immune cell signature was calculated and used for statistical analyses.
The main immune cell type RNA signatures showed correlation with the relative cell counts (r: 0.4-0.6), indicating the validity of the RNA signatures. Myeloid cell (monocyte/macrophage and neutrophil) RNA signatures were the most significantly upregulated in CRC compared to CON (p < 0.01), whereas the T-cell signature was the most significantly downregulated. Interestingly, the NK cell RNA signature was strongly upregulated in the Asian compared to Caucasian patients, which was mirrored by a higher lymphocyte cell count, in line with a previous study.
This study shows that measuring specific immune cell type by RNA signatures correlate with traditional cell counting methods, enabling the extraction of valuable clinical information from blood transcriptomic data. This data suggests that both blood myeloid and T cells RNA signatures are promising biomarkers for CRC detection. Further biomarker development would require the optimization of the RNA signatures to validate and increase their diagnostic power.
Novigenix.
Novigenix.
S. Morgenthaler: Advisory / Consultancy: Novigenix. L. Ciarloni: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novigenix. G. Dorta: Advisory / Consultancy: Novigenix. S. Hosseinian Ehrensberger: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novigenix. All other authors have declared no conflicts of interest.
Invasive growth of glioblastoma multiforme (GBM) is associated with CD133 + cancer stem cells (CSCs) and differentiated CD133- glioblastoma cells (DGCs) formed under the influence of transforming growth factor (TGF-β). The aim of the study was a comparison of CD133+ CSCs and CD133- DGCs proteomes stimulated by TGFβ.
The human GBM U87MG cell line was cultured with a set of growth factors to obtain CSCs. CSCs were extracted through magnetic-activated cell sorting based on the expression of 133 cluster of differentiation; CD133- DGCs were used as a control. Differentiated glioblastoma cells (CD133- DGCs) were stimulated of TGF-β1. Highperformance liquid chromatography-mass spectrometry (HPLC-MS) was used for proteome analysis.
589 proteins that significantly changed expression in CD133+ CSCs compared to (P < 0.05) CD133- DGCs were identified. Bioinformatics analysis revealed that 134 proteins belong to 15 signaling pathways. 14 proteins involved in signaling cascades associated with the interaction between CSCs and the ECM have been upregulated more than 2 times. 4 proteins responsible for activating this signaling cascades have also been upregulated more than 2 times. COL6A1 and LAMB1 in CD133+ CSCs have increased more than 8 times, and metalloprotease LOXL2 more than 9 times compared to CD133- DGCs. Stimulation with TGF-β have increased motility, inhibited proliferation and caused the transformation of the CD133- DGCs proteome through inhibition of the synthesis of adhesive E-cadherin, occludin and claudine-1, increasing production of migratory N-cadherin, vimentin, vitronectin, proteins of the actin-myosin complex, matrix metalloproteinases MMP2, MMP9, MMP14, ADAMTS1. At the same time, 13 proteins of the signaling pathway of the receptor interaction with the ECM: CD44, HMMR, COL1A2, COL6A1, COL6A3, FN1, LAMB1, LAMC1, ITGA2, ITGA5, ITGAV, ITGB1, ITGB3 and 3 proteins FERMT2, HDAC2, FBN1 activating this signaling pathway in CD133- DGCs have reached values comparable to CD133+ CSCs.
TGF-β enhances expression of the ECM-receptor interaction signaling pathway proteins in CD133- DGCs differentiated GBM cells to the level of cancer CD133+ stem cells.
Far Eastern Federal University.
Ministry of Science and Higher Education of the Russian Federation (grant no. 14.584.21.0027; ID: RFMEFI58417X0027).
All authors have declared no conflicts of interest.
Treating CMM patients with ICI have significantly increased PFS and overall survival (OS) for this patient population. In order to further improve ICI efficacy we need to identify predictive biomarkers to foresee which patient would benefit from treatment. Extensive research is being performed globally but with very little focus on host genotype variations. The aim of this study was to identify host genetic markers that can predict treatment outcome in patients with metastatic CMM.
We have genotyped 49 patients with metastatic CMM treated with ICI at Karolinska University Hospital in Sweden. Blood samples were collected before treatment start. As platform we have used the Axiom Precision Medicine Research Arrays (Affymetrix ®). We have conducted genome-wide and targeted analysis of approximately 488,000 and 4000 single nucleotide variants respectively, using Partek Genomic Suite Software®.
49 patients were included between July 2015 and August 2017, 22 females and 27 males. The median age was 68 years old (range 31 – 84). All patients had metastatic disease (33 M1C, 5 M1B, 11 M1A). ICI was first line treatment in most of the patients (n:40). Patients were treated with either nivolumab or pembrolizumab. Twenty-eight patients achieved disease control (with 8 complete responses) whereas 19 had progressive disease. Eleven patients were still responding at the cut-off date in 2018 November 30th, 1 missed follow-up and 2 were not included in the response analysis due to premature death. Median PFS was 6,9 months (range 0 – 40 months). The median OS was 19 months (range 0 – 40 months, 22 patients still alive at cut-off). We have in the targeted analysis identified one candidate significantly associated with both response and PFS. We are expanding the cohort and genotyping 40 additional patients.
Host genotype variations could identify novel predictive biomarkers candidates to ICI. Validation of our results with a bigger cohort is warranted.
Karolinska Institute.
Cancer Research Funds of Radiumhemmet, The Swedish Cancer Society and Knut and Alice Wallenberg Foundation.
All authors have declared no conflicts of interest.
Gastric cancer (GC), ranking fifth among cancers, is the third most common cause of cancer related mortality in the world. The symptoms of GC occur rather in the late stages, making early diagnosis a challenging task to clinicians compromising disease management. Therefore, efforts are underway to develop effective biomarkers for early diagnosis of the disease and to identify potential targets for drug development.
Illumina RNA-Seq based transcriptome profiles of six tumor and normal tissue pairs at different stages (stage I, II and III) of GC were generated to identify differentially expressed genes (DEGs) and single nucleotide polymorphisms (SNPs) implicated in gastric tumorigenesis. The major clusters of candidate genes at different stages of GC and associated enriched gene ontology terms were analysed. Transcription factors involved in GC were also identified and the protein-protein interaction networks were constructed.
A total of 2207 differentially expressed genes including 972 upregulated genes and 1235 downregulated genes were identified covering stage I, II and III of disease progression. The SNP profiles revealed gene enrichment in cancer related pathways including apoptosis, mTOR and MAPK signalling. The DEGs were accommodated in various ontology categories primarily with digestion system and digestive tract development processes. Functional enrichment of SNPs showed GO categories such as immune system process, regulation of signalling, response to stress, transport, etc. Furthermore, 18 upregulated and 21 downregulated transcription factors were identified during cancer progression.
Stage-specific identification of DEGs and transcription factors may help in the better understanding of the molecular pathogenesis of gastric cancer. Our findings will also provide useful leads for developing future strategies for the management of gastric cancer.
The author.
Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organisation (DRDO).
The author has declared no conflicts of interest.
Long non-coding RNAs (lncRNAs) appear to be one of the key regulators of cellular signaling processes. According to several authors, they play a crucial role in the regulation of the antitumor immune response. Dysregulation of lncRNA profile is associated with carcinogenesis. Alteration of the lncRNA profile in ovarian cancer (OC) tumor tissue was shown. The aim of our study was to identify serum lncRNAs as potential biomarkers in ovarian cancer.
The study included 34 patients with verified ovarian cancer II-IV FIGO stage. Blood sampling was performed before treatment and after 3 courses of standard neoadjuvant (paclitaxel 175 mg/m² + carboplatin AUC 6 every 3 weeks) chemotherapy. To isolate free-circulating RNA from serum, the SileksMagNA-Direct magnetic particle kit was used. Analysis of the normalized expression of lncRNA MALAT, HOTAIR and PVT1 was carried out using qPCR method with normalization by 18S. We assessed the correlations between lncRNA levels and the patient age, tumor stage and CA-125 level. For statistical analysis, the ANOVA criterion (Statistika 13.0) was used.
We have established strong correlations between the HOTAIR plasma level and age (p = 0.120) and CA-125 level (p = 0.082), and weak correlation with a relapse-free period duration (p = 0.167). The level of MALAT strongly correlated with age (p = 0.050) and with a relapse-free period duration (p = 0.014) and weakly correlated with the stage of ovarian cancer (p = 0.140). PVT1 expression did not reliably correlate with any of the studied clinical and biological parameters.
The revealed relationships between the levels of circulating MALAT and HOTAIR in the blood plasma of patients with OC require further study of these epigenetic regulators in OC carcinogenesis and chemoresistance. Free circulating lncRNA MALAT and HOTAIR, as an element of a liquid biopsy, are potential prognostic and predictive biomarkers for OC.
The authors.
RFBR (project number 19-315-50012).
All authors have declared no conflicts of interest.
The study of crosstalks between cancer cells and T cells in the tumour microenvironment (TME) can inform on tumour immune escape and help in predicting responses to immunotherapy. By reproducing in vitro how tumour infiltrating lymphocytes (TILs) interact with cancer cells, novel methodologies may allow a thorough characterization of the transcriptomic changes induced in tumours undergoing a T cell attack (TuTACK).
Thirteen pairs of highly tumour-reactive TILs and autologous cancer cell lines, covering four distinct tumour types, were selected and co-cultured to induce a cytostatic effect in tumour cultures. The global TuTACK transcriptome was characterized, and a TuTACK gene signature was extracted to be tested for prediction of response to anti-PD-1/anti-PD-L1.
We showed that an autologous T cell attack induced large transcriptomic changes in tumours, that were independent of IFN-g signaling. Transcriptomic changes were tumour-type independent and allowed the identification of a gene-set (TuTACK gene-set) containing 256 genes covering 55 defined biological processes, that included several potential actionable adaptive immune resistance pathways. We extracted a 14-gene signature (TuTACK signature) that allowed a novel scoring of the TME. The TuTACK score correlated well to the estimated immunological activity in the TME (measured by the T cell-inflamed gene expression profile or GEP), and was predictive of response to anti-PD-1/PD-L1 therapy across 26 tumour types (Spearman R = 0.54, Pearson R = 0.57) outperforming the T cell-inflamed GEP score (Spearman R = 0.25, Pearson R = 0.34) and with a comparable predictive power to the tumour mutational burden (TMB; Spearman R = 0.65, Pearson R = 0.56). The TuTACK score was only moderately correlated to the TMB (Spearman R = 0.36; Pearson R = 0.53), indicating that these biomarkers may be independent.
TuTACK measured the effects of an immune response rather than its activity and it represents an innovative method to identify immunologically hot tumours. Our findings suggested that TuTACK may allow better patient selection in immunotherapy clinical trials and provide hints to improve the treatment of “hot” tumours resistant to current immunotherapies.
The authors.
The Danish Cancer Society (grant number R148-A9862); The Lundbeck Foundation (grant number R233-2016-3728); The Capital Region of Denmark Research Foundation (grant number R146-A5693); The National Research, Development and Innovation Fund of Hungary (FIEK_16-1-2016-0005).
All authors have declared no conflicts of interest.
The PURE01 study (NCT02736266) evaluates preoperative pembrolizumab before radical cystectomy (RC). Here, the possibility to predict the pathologic complete response (pT0) after neoadjuvant immunotherapy could have paradigm-shifting implications for the management of patients with MIBC.
The reported analyses include comprehensive genomic profiling with FoundationONE CDx assay and programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS, Dako 22C3 antibody) on baseline TURB samples. Multivariable logistic regression analyses (MVA) evaluated clinical T-stage and biomarkers (tumor mutational burden [TMB], and CPS) in association with pT0 response. Multivariable-derived coefficients were used to develop a novel risk calculator. Decision-curve analysis was used to evaluate the net benefit of the predictive model.
From 02/2017 to 06/2019, 112 patients with full biomarker data were enrolled. At MVA, only CPS showed a significant association with pT0 (p = 0.005). Increasing TMB and CPS values featured a linear association with logistic pT0 probabilities (p = 0.02 and p = 0.004). Very high TMB values, associated with a predicted probability of pT0 > = 55%, were independent from CPS contribution. The coefficients of the predictive model were used to develop a risk calculator. The c-index of the model was 0.77. At decision-curve analysis, the net-benefit of the model was higher than the “treat-all” option from more than 10% threshold probabilities.
We presented the first biomarker-based risk stratification tool that can be used to recommend use of neoadjuvant pembrolizumab in those patients who have equal or greater chances to achieve a pT0 status compared to the literature on neoadjuvant chemotherapy or to RC alone, depending on cisplatin eligibility.
PURE01 study (NCT02736266).
The authors.
Merck & Co., Inc., Kenilworth, NJ, USA; Associazione Italiana per la Ricerca sul Cancro (AIRC).
R. Madison: Shareholder / Stockholder / Stock options, Full / Part-time employment, employee and stock owner of Foundation Medicine Inc: Foundation Medicine Inc. M. Colecchia: Speaker Bureau / Expert testimony: Roche Diagnostics. S.M. Ali: Full / Part-time employment: Foundation Medicine. J.H. Chung: Full / Part-time employment: Foundation Medicine. J. Ross: Leadership role, Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. A. Salonia: Speaker Bureau / Expert testimony: Astellas Pharma; Travel / Accommodation / Expenses: Konpharma. A. Briganti: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Hanssen-Cilag; Advisory / Consultancy: OPKO Health; Advisory / Consultancy: MDxHealth; Advisory / Consultancy: Ferring; Research grant / Funding (institution): Novartis. A. Necchi: Advisory / Consultancy: Merck, Incyte, AstraZeneca, Roche, Rainier Therapeutics, Clovis Oncology, Bristol-Myers Squibb, Bayer, Basilea Pharmaceutica; Research grant / Funding (institution): AstraZeneca, Ipsen, Merck and Incyte; Spouse / Financial dependant: Bayer. All other authors have declared no conflicts of interest.
Immunogenomic profiling of the tumour and the TME is critical for identifying biomarkers of immunotherapy response and understanding resistance. However, running many assays for each sample is impractical given limited sample quantity, processing complexity, and prohibitive cost. To address this, we developed a novel, augmented exome-/transcriptome-based tumour immunogenomics platform.
We optimized the design of our sequencing assays and analytics for improved somatic SNV, indel, CNA, and fusion detection across ∼20,000 genes, and for the evaluation of neoantigens, expression signatures, HLA typing and LOH, TCR/BCR repertoires, oncoviruses, TILs, clinically-actionable mutations, TMB, and MSI status.
With 25ng of DNA per FFPE sample and co-extracted RNA, this platform completely covers between 17-40% more genes compared to a non-augmented exome; increasing sensitivity to somatic mutations and neoantigens. For neoantigen detection, we generated immunopeptidomic data from monoallelic HLA transfected cell lines and trained neural networks to predict neoepitope binding to MHC; demonstrating higher precision (0.88) across alleles than publicly-available tools (0.9 and >0.94, respectively). For TILs, we developed signatures for immune cells, demonstrating concordance with CyTOF-derived validation sets. We achieve HLA typing accuracy of 99.1% for Class I and 95% for Class II calls, and have developed a novel tool for HLA LOH evaluation. We achieve sensitive detection of oncoviruses, as well as accurate MSI and TMB assessment. For diagnostic reporting, we report high sensitivity and specificity for clinically-reportable mutations comparable with diagnostic cancer panels.
We have developed a novel tumour immunogenomics platform that simultaneously profiles the tumour and TME from a single sample.
Personalis, Inc.
Personalis, Inc.
R. Power: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. G. Bartha: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. J. Harris: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. S.M. Boyle: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. E. Levy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. P. Milani: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. P. Tandon: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. R. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. M. Chinnappa: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. A. Haddad: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. P. McNitt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. R. McClory: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. M. Morra: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. S. Saldivar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. M. Clark: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. C. Haudenschild: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. E. Newburn: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. C. Johnson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Personalis, Inc. R. Chen: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Personalis, In J. West: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Personalis, Inc.
Tumour mutational burden (TMB) is a measurement of DNA variants in a tumour and is a potential biomarker of response to Immune Checkpoint Inhibitor (ICI) therapy. Patients with non-small cell lung cancer (NSCLC) whose tumours have a high TMB (≥10 mutations/Mb) might benefit from upfront ICI combination therapy. Clinical trials have measured TMB using Whole Exome Sequencing (WES) and/or the FoundationOne CDx (F1CDx) assay. In parallel, several commercial next-generation sequencing (NGS) assays have become available. Before implementation of TMB testing in clinical practice, technical and clinical validation are needed. Hence, a multi-center study was organised to establish concordance between several TMB assays.
Fifteen resection NSCLC formalin-fixed paraffin-embedded (FFPE) samples with broad TMB range were selected. Each participant received extracted DNA and was asked to report TMB values using their own protocol. In parallel, FFPE slides were analysed with F1CDx. Eight labs participated using five different methods: Oncomine TML assay (Thermofisher; n = 4), TSO500 assay (Illumina; n = 1), NEOplus assay (NEO New Oncology; n = 1), a 0,4 Mb targeted resequencing lab-developed assay (LDT; n = 1) and WES using three different TMB calculation methods (n = 1). Correlations between each platform and F1CDx were calculated. Also, the reported TMB category (high vs low) of the different platforms in comparison to F1CDx was evaluated for the fifteen samples.
Assessment of TMB values obtained by the platforms and F1CDx demonstrated a high correlation (R2 between 0.81 and 0.94), except for the smaller LDT (R2 = 0.53). The TMB category (high vs low) reported by each platform showed concordance with the F1CDx category for eleven (73%) to thirteen (93%) of the fifteen samples. From the fifteen samples, the same category was reported by all different platforms for seven (47%) samples.
Our data show that assays from different providers can be used to predict TMB. However, samples with a TMB value around the cut-off of 10 mut/Mb are challenging and interpretation should occur with caution. Further studies are required before implementing these assays in routine clinical diagnosis.
The authors.
Bristol-Myers Squibb.
S. Lambin: Research grant / Funding (institution): Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Immune checkpoint blockade revolutionized anti-cancer therapy but unfortunately not all patients can benefit from it. The development of innovative and efficacious diagnostic methods that can guide treatment decisions is warranted. Nanobodies (Nbs) are small antigen-binding moieties that efficiently penetrate cell-cell interfaces in tumors and generate high contrast in noninvasive imaging, making them prime candidates for development of novel imaging tracers. In this study, we generated and characterized Nbs as tools for nuclear imaging of the immune checkpoint LAG-3.
Nanobody generation was initiated by immunization of llamas with recombinant LAG-3. Periplasmic extracts were generated and analyzed for their binding to mouse LAG-3 using ELISA and flow cytometry. Selected Nbs were cloned in a vector for high yield production and purified in order to analyze their affinity using SPR. A total of 9 high affinity Nbs were subsequently evaluated for their labeling efficiency with Technetium-99m (99mTc), after which the biodistribution of 99mTc labeled Nbs was assessed in mice. Additionally, we evaluated the noninvasive detection of LAG-3 expressed by immune cells in the tumor environment of murine colon adenocarcinoma (MC38) using 99mTc-Nb3132.
Nine high affinity Nbs were selected to evaluate their potential as noninvasive imaging tracers. Subsequently, Nb3132 was reported as the most potent tracer for noninvasive imaging of the immune checkpoint LAG-3 (1). SPECT/CT of MC38 tumor-bearing mice 1h after injection of 99mTc-Nb3132 presented specific uptake in spleen, thymus, lymph nodes as well as at the tumor site. This uptake pattern coincided with the presence of LAG-3 expressed on immune cells in these organs, as determined by flow cytometry and immunohistochemistry. No specific uptake was observed when injecting mice with a radiolabeled control Nb.
Nb3132 showed excellent in vivo imaging capacities to specifically identify LAG-3 expressing immune cells within the tumor site. These findings support the predictive potential of Nb3132 to noninvasively detect LAG-3 by nuclear imaging and to guide treatment decisions in future, improving the shortcomings of using full-sized antibody formats as diagnostic tracers.
Geert Raes.
Kom op tegen kanker and FWO flanders.
All authors have declared no conflicts of interest.
CAR-T cells therapies turn out to be a breakthrough, particularly for B-cell malignancies. However, its application in solid tumor remains a challenge. The main limitations are: few highly specific tumor associated antigen (TAA), low T cell penetration and an immune-suppressive tumor microenvironment (TME). Thus, our aim was to develop a new immunotherapeutic strategy against HLA-G, an immune-tolerogenic molecule involved in tumor immune escape, frequently upregulated on tumor cells. HLA-G is a CMH-Ib molecule and exerts its immuno-inhibitory activity through specific binding with two inhibitory receptors, ILT2 and ILT4, leading to the inhibition of all immune cell subsets and the induction of suppressive immune cells. HLA-G was recently identified as an ICP molecule, could be highly neo-expressed in cancer, i.e.: ccRCC (98%) and associated with malignant transformation. HLA-G is found on tumor cells and is rarely observed in healthy tissues defining it as a remarkable TAA. RNAseq analyses show that HLA-G is a far better tumor specific antigen than PD-L1. However, no immunotherapy against HLA-G-expressing tumors has been developed. Indeed, neither stimulatory functions nor cellular responses directed against allogeneic HLA-G have been reported.
Highly specific antibodies against HLA-G, generated by our team, strongly bind to multiple HLA-G isoforms and their scFv were used to develop 3rd generation chimeric antigen receptors (CARs).
Anti-HLA-G CAR-T were specifically cytotoxic for HLA-G expressing target cells (K562-HLA-G1 and Jeg-3 cell lines), with resulting IFNg secretion and activation phenotype and also inducing a long-term T effector memory phenotype. Finally, in vivo assays demonstrated that anti-HLA-G CAR-T cells had strong anti-tumor activity controlling tumor progression up-to 50 days of experiment.
We report here for the first time CAR-T cells specifically targeting HLA-G expected to disrupt the tumor micro-environment related to HLA-G and solid tumors.
Invectys (Paris, France).
Invectys (Paris, France).
The author has declared no conflicts of interest.
Enhanced anti-tumour activity is required for eradication of solid tumours by CART cells. One possibility of enhancing anti-tumour activity is by programming CART cells to express chemokine receptors that match chemokines produced either by the tumours or tumour-associated cells, thereby improving the infiltrating capacity of the CART cells. In this study, we engineered CCR2b expressing anti-Tn-MUC1 CAR T cells for the treatment of breast cancer.
Anti-Tn-MUC1-CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. CCR2b expressing anti-Tn-MUC1 CAR T cells were prepared using PLV-CAR-5E5-CCR2b lentivirus. The susceptibility of MCF-7 cells to either anti-MUC1 CART or CCR2b expressing anti-MUC1 CART cell-mediated lysis was assessed using in vitro killing assays. For cytolytic analysis, CART-cells were cocultured 10:1 (effector:target) ratio with MCF-7 cells. The effects of CCR2b expressing CART cells on anti-tumour activity and infiltration were also assessed in an in vivo murine xenograft model.
Activated T cells co-modified with both CCR2b and anti-MUC1-CAR had greater anti-tumour activity both in vivo and in vitro. When the effector / target cell ratio was 10, the killing rates of CART and CART-CCR2b were 56.9% and 83.9%, respectively. Tumour size was significantly smaller (P < 0.001) in the CAR-CCR2b group compared to the CAR alone group. At day 7 post-injection of CART cells, the infiltrated T cells was significantly increased (∼2 folds) in the CAR-CCR2b group compared with the CART only group.
Our data demonstrated that the anti-tumour activity of the CCR2b expressing anti-Tn-MUC1 CART cells is 1.5 times more potent than CART cells without CCR2b. Augmentation of tumour suppression was also demonstrated in vivo in a murine xenograft model. These pre-clinical results show translational potential to the clinic for treatment of solid breast tumours.
Not Applicable.
Guangzhou Anjie Biomedical Technology Co. Ltd.
Guangzhou Anjie Biomedical Technology Co. Ltd.
All authors have declared no conflicts of interest.
One of most promising strategies for cancer immunotherapy is adoptive T cell therapy (ACT). In the frame of this approach, tumor-specific lymphocytes (TSL) are infused into patients to recognize and destroy tumor cells. The key step of ACT is identification of TSL within the tumor-infiltrating lymphocytes (TILs). However, current procedures of obtaining TSL are very labor-intensive and expensive or have not demonstrated the sufficient clinical benefits. The purpose of this study was to develop an effective and simple method for TSL identification in a mouse melanoma model.
The experiments were carried out on C57BL/6 mice bearing B16F0 mouse melanoma model. TILs were obtained by disaggregation of tumor nodules, and mouse spleen T-cells were harvested by magnetic separation. Tumor reactivity of T-lymphocytes was assessed by IFNγ secretion assay or intracellular staining. IFNγ+ T-cells were collected by BD FACSAria III cell sorter (BD Biosciences, USA).
To obtain melanoma specific T-cells we isolated TILs from tumor nodules and sorted live activated IFNγ+ T-cells. We identified 1-6% CD4+ and 3-8% CD8+ IFNγ+ activated T-lymphocytes. With bioinformatic analysis of T-cell receptor repertoires we detected the clusters of cells that recognize the same antigens and are enriched in IFNγ+ cell fraction compared to IFNγ- cells. This fact is an additional evidence of tumor specify of these cells. To check tumor specificity of bioinformatically identified T-cells we have used one of the common approaches for TSL identification – in vitro stimulation of T-cells by APCs loaded with tumor antigen. First, we established mice with stable immunity against B16F0 and harvested T-cells from spleen. Then T-cells were cocultured with B16F0-loaded APCs. To improve the efficiency, we have optimized several parameters, such as additional immunization of the mice and co-cultivation conditions. As a result, we registered 1% of B16F0-specific CD4+ T-lymphocytes against the background of non specifically activated cells.
We have developed a new method to obtain potential TSL from tumor nodules. Future experiments will be directed to compare their repertoires with B16F0-specific T-cells.
The authors.
Ministry of Education and Science of the Russian Federation (grant No 14.W03.31.0005).
All authors have declared no conflicts of interest.
Precise targeting of patient’s tumor can be facilitated through T cells recognizing specific pMHC complexes on these tumors. Once such antigen landscape is defined, an additional challenge relates to the ability to mount a functional T cell response specific to such antigens. Current T Cell expansion techniques provide no efficient strategy for antigen-specific stimulation and results largely in exhausted T cells. Here we present a new technology for ex-vivo peptide-MHC directed expansion and functional enhancement of T cells, using artificial antigen-presenting scaffolds (Ag-scaffolds).
Dextran backbone conjugated with streptavidin was used for Ag-scaffold assembly. Such backbone was incubated together with biotinylated MHC class I molecules holding a given peptide (pMHC) and biotinylated human cytokines in various ratios. PBMCs from healthy donors with known virus epitopes and from melanoma patients with known epitopes were expanded for 2 weeks with Ag-scaffold, added when the cell cultures were initiated and twice per week for two weeks. The expansion of antigen-specific CD8 T cells was monitored and analyzed by flow cytometry.
Here we demonstrate the value of the antigen-scaffold based expansion, by the expansion of virus-CD8 T cells from peripheral blood, and tumor-specific T cells from both peripheral blood and tumor site. We can favorably expand both neo- and shared antigen specific T cell populations. The resulting T cell product exhibit a multifunctional cytokine profile upon antigen challenge, high levels of CD28 expression, and reduced levels of PD-1 expression. Importantly, numerous different pMHC-specific T-cell populations can be stimulated in a single culture, and we can obtain better tumor killing properties than conventional TIL-ACT products.
This study presents a new technology for expanding functionally enhanced antigen-specific CD8 T cells suited for implementation to ACT strategies. T cell phenotype and functionality are known to be important parameters in successful adoptive T cell transfer, and hence it´s plausible that antigen scaffold based expanded T cell product may improve treatment outcome compared to conventional expansion strategies.
The authors.
Innovation Fund Denmark.
All authors have declared no conflicts of interest.
Adoptive cell therapy is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity. We report the successful treatment for the patients with recurrent Gastrointestinal Stromal Tumors (GIST) with adoptive cellular immunotherapy and personalized vaccine.
A total of 8 patients (aged from 29 to 54 years) with GIST. The patients with recurrent progressive disease refractory to aggressive multi-modality therapy including repetitive surgical resection, radiation, and chemotherapy and all lines targeted therapy. They received multiple courses of systemic intravenous administration of allogenous phytohemagglutinin (PHA) activated T-lymphocytes in combination with a low dose of interleukin-2 (IL-2) and personalized vaccine, which was adopted in laboratory from donors B-lymphocytes and Patient’s Circulated Tumor Cells.
The side-effects of this treatment were limited and manageable. Among 8 patients, 5 achieved a complete remission (p < 0,001 as compared to the 3 noncomplete response patients) , as demonstrated by MRI after 2 months from initiation of immune therapy and confirmed by glucose-positron emission tomography (PET) imaging 7 months after initiation of immune therapy. After 14 months of follow-up, the 5 patients are still in remission with improving performance status. 2 patients showed disease progression during the treatment in the liver and both lungs too as multiple metastases and only one patient had disease stabilization.
Adoptive cellular immunotherapy utilizing allogenous phytohemagglutinin (PHA) activated T-lymphocytes and personalized vaccine with low dose IL-2 appears to be a safe and effective therapy for a subset of patients with primary, recurrent or progressive Gastrointestinal Stromal Tumors following conventional therapy.
Paris Descartes University
Paris Sorbonne University
Tbilisi State Medical University
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Refractory and relapsing sarcoma and high-risk neuroblastoma show poor prognoses. Monocyte-derived dendritic cell anticancer vaccine could extend the treatment modalities in these patients. Pharmacotherapy prior to mononuclear cell harvest may influence the quality of manufactured dendritic cell product.
In approved pediatric academic phase I/II clinical trial EudraCT 2014-003388-39 with primary safety endpoint an impact of preceding and concomitant therapy sixty days prior to mononuclear cell harvest on the manufactured anticancer vaccine quality characteristics in enrolled neuroblastoma and sarcoma subjects was statistically evaluated. The chemotherapeutic drugs, kinase inhibitors, biological therapeutics and growth factors were analysed.
Potency and quality control characteristic of thawed DCs included DC phenotype and 2-day cultivation DC phenotype, the production of IL-12 and IL-10 during 24-hour cultivation, allo-MLR and auto-MLR. Out of 47 enrolled subjects, pre-monocyte harvest treatment was evaluated in 23 (19 sarcoma, 4 neuroblastoma) subjects, of which 6 manufactured DC anticancer vaccines (5 sarcoma, 1 neuroblastoma) failed to pass quality control criteria. Dendritic cells from subjects pretreated with MTD-based dose of the alkylating agent (cyclophosphamide), topoisomerase I inhibitor (topotecan) and tyrosin kinase inhibitor (pazopanib) displayed impaired IL-12 production, depressed IL-12/IL-10 ratio, increased CD14 expression and poor T-cell stimulation in auto-MLR. Alkylating agent temozolomide (TMZ) together with topoisomerase I inhibitor (irinotecan) enabled the monocyte differentiation marked by decreased CD14 expression, however failed to display immunostimulatory properties with low CD80 expression and markedly decreased IL-12 production and IL-12/IL-10 ratio.
Pharmacotherapy should be understood as concomitant factor influencing the DC vaccine product quality outcome. Certain monocyte-interfering anti-cancer pharmacotherapy combinations prior to monocyte harvest were associated with impaired quality and potency of DC-based immunotherapy.
EudraCT: 2014-003388-39.
State Institute for Drug Control Czech Republic.
Has not received any funding.
All authors have declared no conflicts of interest.
The Quantum® hollow fiber bioreactor system represents a platform integrating GMP-compliant manufacturing steps in a closed system for automated cultivation of cellular products. A previous report to generate monocyte-derived DCs (Mo-DCs) for cancer immunotherapy involved fibronectin-coating of the hollow-fibers and trypsin digestion to harvest cells and proved unsatisfactory as only one tenth of an apheresis product could be processed. Thus, optimization of this approach is needed.
Monocytes were enriched by using the Elutra® cell separation system and were differentiated over 6 days into immature DC in the presence of GM-CSF + IL-4, and then exposed to a maturation cocktail to generate mature Mo-DCs. This was performed in parallel either by using the Quantum® or by our in-house established standard protocol in cell culture bags. Phenotype, antigen presentation, and functionality of these Mo-DCs were then analyzed and compared.
Intitial tests with the Quantum® were performed to avoid the initial fribronectin coating and trypsin digestion for harvesting of cells, which required optimization of media exchange rate, cytokine concentration and cytokine addition. Under optimized conditions, cells cultured in the Quantum® resulted in a yield of 27.8% mature DCs (related to input monocytes) with CD83 expression in 92.0% of these cells. Total yield of mature Mo-DCs was slightly higher when the in-house established standard protocol was used. Survival of Mo-DCs analyzed in the washout test (24 hour culture in medium without cytokines) was comparable with both methods. Cell surface CD80, CD83, CD86, and HLA-DR expression was in general higher in DCs generated by our standard protocol. GFP-electroporated Mo-DCs generated by Quantum®, however, showed a trend towards higher GFP- expression as well as towards higher T-cell stimulation and proliferation in the primary allogeneic MLR-assay.
We have adapted the Quantum® system to process one complete apheresis product to yield a large number of mature and functional GMP-compliant monocyte-derived DCs for the use in cancer immunotherapy without any need for fibronectin coating or trypsin digestions.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Dendritic Cell (DC) therapy is considered as a promising immunotherapeutic approach for treatment of advanced cancer. However, the tumor microenvironment is highly immunosuppressive that leads to DC dysfunction. Therefore, in clinical trials DC therapy has generally failed to fulfill its expectations. Oncolytic adenoviruses are well tolerated and have shown to preferentially target and kill cancer cells. Therefore, to improve the therapeutic efficacy of DC therapy, we armed oncolytic adenovirus with CD40 ligand (CD40L). CD40L is well known to regulate immune responses through its capacity to stimulate dendritic cells that lead to the activation of cytotoxic T-cells.
In this study, we generated a novel virus Ad3-hTERT-CMV-hCD40L (Ad3-hCD40L), which is fully serotype 3 adenovirus. It features a human telomerase reverse transcriptase promoter for tumor specificity and expresses human CD40L (hCD40L) under a cytomegalovirus promoter for induction of antitumor immune responses. Animal experiments were implanted in immunocompetent and in humanized mice model. To further deeply dissect if Ad3-hCD40L can modulate tumor microenvironment, tumor histocultures derived from prostate patients were used.
In syngeneic studies in animal models, DC therapy with Ad3-hCD40L showed significant antitumor immune response. This enhanced therapeutic effect is associated with increased tumor specific T-cells and induction of T-helper type 1 immune response. Moreover, Ad3-hCD40L and human DCs showed 100 percent survival in conjunction with tumor control. Tumor histocultures treated with Ad3-hCD40L showed that virally expressed hCD40L in the tumor microenvironment leads to significant activation of dendritic cells and induction of Th1 immune response.
To conclude, CD40L armed oncolytic adenovirus 3 improves DC therapy by favorable alteration of tumor microenvironment. These findings support clinical trials where DC therapy is enhanced with oncolytic adenovirus.
Cancer Gene Therapy Group, University of Helsinki.
University of Helsinki.
V. Cervera-Carrascon: Full / Part-time employment: TILT Biotherapeutics Ltd. J.M. Santos: Full / Part-time employment: TILT Biotherapeutics Ltd. A. Hemminki: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.
Individually prepared immunotherapy (ITx) based on autologous dendritic cells (DCs) represents a new possibility in modern advanced anti-cancer treatment. As an extended evaluation of DC-based medicinal product in an academic phase I/II clinical trial for children, adolescents and young adults with progressive, recurrent or primarily metastatic high-risk tumors (EudraCT 2014-003388-39), we performed the examination of T-cell stimulatory properties and detailed peripheral blood immunomonitoring.
Ten patients (6 female, 4 male, median age 19 years) with relapsing sarcomas disease were treated with DCs pulsed with self-tumor antigens. DC ITx was administered intradermally in 2-4 week intervals. Peripheral blood was collected at baseline, after 5th, 9th and 13th dose. Nine circulating immune markers were quantified by flow cytometry: absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), effector CD8+T-cells, activated CD8+ T-cells, γδ T-cells (GD), monocytic MDSC, regulatory T-cells, NK, and NKT-like cells. DC stimulatory properties were examined by autologous mixed lymphocyte reaction using patient T-cells obtained before DC vaccination (pre-DC) and after min 5th doses of DCs (post-DC). The stimulation was expressed as % of the division after DC stimulation.
ALC was baseline low in 9 of 10 cases and 6 of 10 cases were connected to high (>3) NLR with no significant changes during DC ITx. We observed decrease of NKT-like (p = 0.04) and elevation of GD (p = 0.008) after 13th dose compared to baseline. Post-DC auto-MLR was higher compared to pre-DC in all sarcoma study patients. The median patient T-cell stimulation increased from 8.8% with pre-DC T-cells to 14.6% division with post-DC T-cells.
Circulating cell-based immune markers revealed dose-dependent changes in subtle T-cell subsets during the course of DC treatment. Personalized anti-cancer DC-based ITx stimulates a pre-existing immune response against self-tumor antigens.
EudraCT: 2014-003388-39.
Czech Ministry of Health.
Czech Ministry of Health (Projects LO1413, LM2015090, academic clinical trial).
All authors have declared no conflicts of interest.
Lung cancer is a major threat to the world and 80% of the reported cases belong to non-small cell lung cancers. Epigenetic modifications are common in lung cancers but can be reversible by using demethylating agents such as 5-AZA. Through our present study, we hypothesized that treatment with 5-AZA may induce the apoptosis and expression of immunogenic NY-ESO-1 antigen in NCI-H1975 cells. Apoptotic cell death would help to release the induced NY-ESO-1 protein which in turn could trigger T cells mediated immune responses.
NCI-H1975 cells were treated with incrementing concentrations (1 to 10µM) of 5-AZA. Cytotoxicity was measured using real-time cell analyzer assay (RTCA). Apoptosis and cell cycle analysis were measured by flow cytometry and western blot. A proteomic profiling was carried out using label-free mass spectrometry. Bisulfite sequencing was performed for NY-ESO-1 gene and expression at mRNA and protein level was analyzed using qRT-PCR, cellular ELISA.
RTCA data revealed that 5-AZA treatment reduced cell proliferation at 120 h which was opted for comparative study. Flow cytometry showed an induction of apoptosis and a cell-cycle arrest at Sub-G0 phase. Western blot analysis confirmed the induction of apoptotic marker proteins such as cleaved Caspase3, Caspase8, PARP and BAX. We also observed that 31 proteins responsible for the induction of apoptosis were upregulated and 18 proteins linked to cell proliferation and metastasis were down-regulated. Bisulfite sequencing revealed demethylation of the promoter of NY-ESO-1 gene and showed an induced expression of NY-ESO-1 protein and mRNA levels.
Our study shows that 5-AZA cytotoxic effect would induce the expression of the immunogenic NY-ESO-1 antigen leading to activation of T cells mediated immune response. Our data infers the potential use of 5-AZA for lung cancer treatment.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Telomerase is an active enzyme that produces and maintains telomeres which are located at the end of chromosomes. In general, telomeres become shorter as the number of cell divisions increases, leading to apoptosis. However, telomerase prolongs and maintains the length of the telomere so that tumor cells continue proliferation without cell death. When the telomerase is reduced, the telomere DNA is not produced and maintained and the chromosomes become shorter and shorter. Telomerase is not well observed in normal cells and are known to act as a specific antigen by over-expression in various cencer cell types. The riavex(GV1001) which is 16-amino acid sequence from the telomere combines with HLA class I to induce an immune response through activation of CD4 T cells.
We analyzed 50 patients who were injected with riavex. The riavex was provided through the application for emergency medication from the Korea Food and Drug Administration. Most patients who were given riavex failed several standard chemotherapies. The administration methods was injection of riavex 0.2ml intradermally three times at the first week and one time at 2 weeks, 3 weeks, 4 weeks, 6 weeks and then once per 28 days. A total of 12 doses were given to each patient. After the end of the administration, we evaluated anti-tumor response by RECIST 1.1 and quality of life by EORTC QLO-C30 and EQ-5D.
Partial response was found in one patient with renal cell carcinoma. The rest of the patients showed a stable or progressive response. However, quality of life was significantly improved in 19 patients, and 15 of them have applied for re-treatment. Only three patients had a fever of more than 38oC, and no significant side effects were observed in other patients
In conclusion, riavex as an anti-cancer vaccine is relatively safe in heavily pre-treated solid cancer patients and is assessed to improve quality of life, although the treatment response is not promising.
The author.
Has not received any funding.
The author has declared no conflicts of interest.
Patients (pts) living with cancer are exposed to higher risk for thrombotic event (TE). The thrombotic risk (TR) is related to cancer disease and could also be associated with anti-cancer drugs such as antiangiogenic (AA). AA are currently being used more and more widely, alone or in combination (combo) with anti-PD(L)1 immunotherapies. It isn’t known whether combining anti-PD1 or PD-L1 with AA drug could increase the risk of TE. This study aimed at evaluating the TR in patients receiving a combo of AA and anti-PD1 or PD-L1.
Observational study conducted from January 2017 to September 2019 and retrospectively investigated all consecutive adults pts with cancer treated with a combo of AA plus anti-PD(L)1. All TE (venous and arterial) occurring following investigated treatment(s) and Khorana scores (KS) were analyzed. The TR was assessed in pts receiving the combo and compared with pts treated with single anti-PD(L)1. For the single anti-PD(L)1 cohort, data were collected from the pharmacovigilance Register of Severe Adverse Effects of Immunomodulatory Monoclonal Antibody in Cancer (REISAMIC). Data were compared between the combo and REISAMIC cohort using the Fisher’s exact and CHI2 tests (α = 5%).
Overall, 83 pts receiving a combo of anti-PD(L)1 plus AA and 484 pts treated with anti-PD(L)1 were included. Both cohorts were similar for baseline characteristics: sex ratio, age, weight. Main tumor types in single anti-PD(L)1 vs combo were (in %): renal cell carcinoma, 5 vs 37; urothelial carcinoma, 3 vs 4; thoracic (lung or mesothelioma), 45 vs 32; gynecologic, 1 vs 8. The KS score was heterogeneous. It found 334/484 (69%) pts at intermediary or high risk of TE in the REISAMIC cohort and 70/83 (84%) in combo cohort (p = 0.006). In REISAMIC cohort, TE incidence was 7% compared to 18% in the combo cohort (p value=0.0006).
These results suggest that pts treated with combo AA plus anti-PD(L)1 seem to be more at risk of developing TE compare to single therapy anti-PD(L)1, according to a KS higher in this cohort. Further prospective study're warranted to investigate the risk of TE in pts receiving AA plus anti-PD(L)1 and to investigate the benefit of preventive anticoagulants therapy.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
In recent years, ICI therapies have become standard-of-care treatments in several malignancies. ICIs introduced novel toxicities, which can arise from various organ systems or at any time point even after treatment discontinuation. The toxicities can be life threatening, but most are reversible if detected and treated early and therefore, early detection could result in improved safety profile of treatment and better Health related Quality-of-Life. Electronic collection of patient reported symptoms (ePRO) could be used in development of machine learning (ML) based prediction models to enable earlier detection of toxicities compared to traditional follow-up.
The training dataset consists of ePRO data of ICI-treated patients collected using Kaiku Health platform, including 21 744 reported symptoms from 72 ICI patients. The ML models were built with an established classification algorithm extreme gradient boosting and trained for 14 symptoms related to ICI toxicities. The validation dataset consisted of 16 884 reported symptoms from 67 cancer patients receiving ICIs and followed with the ePRO tool.
ML models were able to predict the onset and continuation of 14 symptoms that may indicate the development of ICI toxicities. The model performance assessed using area under curve (AUC), a common performance metric for ML models, is best for dyspnea (0.96) and lowest for headache (0.77). Generally, the models are performing well with an average AUC of 0.86, as shown in the table. Table: 50P AUC values for symptoms related to ICI toxicities from the validation datasetSymptoms AUC Dizziness 0,88 Itching 0,84 Fever 0,90 Diarrhoea 0,78 Stomach pain 0,86 Nausea 0,82 Fatigue 0,90 Rash 0,84 Decreased appetite 0,84 Cough 0,90 Dyspnea 0,96 Joint pain 0,92 Headache 0,77 Chest pain 0,88
ML based modeling of ePRO data on ICI treated cancer patients is feasible in predicting onset and continuation of symptoms related to ICI toxicities. The study suggest that ML based approaches could be used in early detection of toxicities. The results should be validated with a dataset collected in a prospective clinical trial.
Kaiku Health Oy.
Oulu University and Finnish Cancer Society.
J. Ekström: Full / Part-time employment: Kaiku Health Oy. H. Virtanen: Full / Part-time employment: Kaiku Health Oy; Shareholder / Stockholder / Stock options: Kaiku Health Oy. J.P. Koivunen: Advisory / Consultancy: Kaiku Health Oy. All other authors have declared no conflicts of interest.
Immune-Checkpoint Inhibitors (ICI) treatments have specific Health Related Quality of Life (HRQoL) profiles. While HRQoL is central in the oncology patient experience, its integration into current practice remains poorly documented. The study objective was to describe patients' experience and expectations regarding HRQoL, in particular in their relationship with oncologists.
This research was a cross-sectional study within a French online patients’ community. Patients treated with ICI for cancer were recruited between Sep-18 and Jan-19. They answered to a questionnaire developed to assess health care practitioners (HCP) involvement in HRQoL, times of discussion and dimensions discussed. Importance of nine HRQoL dimensions were measured with a visual analog scale (VAS; 0–10 [low–high]).
Over 82 patients included (median age: 59 years; 56% male, 41% with lung cancer), two third (53) mentioned a HRQoL discussion at least once with an oncologist. Half of them (39) discussed of HRQoL with oncologists and were mostly satisfied of this interaction. When occurred, discussions were mainly occasional during follow-up visits (64%), adverse event occurrence (57%), treatment initiation (43%) and were mostly on patients’ initiative (64%). The most discussed HRQoL dimensions were symptoms (85%) and physical well-being (74%). In terms of expectations, two thirds of patients (54) considered oncologists were one of the most important HCP to discuss HRQoL with. Among them, 85% to 98% considered that HRQoL discussion was important at all times of care considered in the study from diagnosis to palliative care. The most important discussion for patients were symptoms (8.7 SD ± 2.0), physical well-being (8.6 ±1.8) daily activities (8.1 ±2.2), family and social life (8.0 ± 1.8), work and leisure (7.9 ±2.1), cognition (7.8 ±2.5) and emotional state (7.7 ±2.7).
According to patients, HRQoL consideration mostly relies on oncologists. Integration of HRQoL in clinical practice could be optimized by increasing frequency of dedicated interactions and by extending discussions to the less often addressed dimensions.
Carenity.
Bristol-Myers Squibb.
O. Wilczynski: Honoraria (institution): Bristol-Myers Squibb. A. Boisbouvier: Honoraria (institution), Full / Part-time employment: Bristol-Myers Squibb. L. Radoszycki: Honoraria (institution): Bristol-Myers Squibb. F-E. Cotté: Full / Part-time employment: Bristol-Myers Squibb. A-F. Gaudin: Full / Part-time employment: Bristol-Myers Squibb. H. Lemasson: Full / Part-time employment: Bristol-Myers Squibb.
Immune checkpoints inhibitors (ICIs) are receiving approval for a growing number of indications. Even if generally well-tolerated, ICIs can cause rare but severe immune-related adverse events (irAEs) with late onset and long-term impact. Aim of this analysis was to evaluate the completeness of irAEs description, with particular attention to irAEs duration and occurrence of late toxicities, in ICIs pivotal trials.
We analysed the publications corresponding to the studies leading to ICIs approval by US Food and Drug Administration (FDA) and/or European Medicines Agency from March 2011 up to August 2019. We searched for duration of follow-up, proportion of patients still on treatment at data cut-off, duration of irAEs and proportion of patients with unresolved toxicities at data cut-off.
Overall, we found 58 publications, corresponding to 49 trials (table). Among all studies, median follow-up was 13,5 months (interquartile range [IQR] 5,8–14,9), and it was 10,2 months (IQR 5 -11,9) for the ones which led to ICIs approval with FDA fast-track procedure versus 15,2 months (IQR 12-16,2) for those leading to ICIs approval through regular procedure (p < 0.001). In 40/58 publications (68,9%), a mean of 22,4% of patients (range 1%-63%) were still ongoing at data cut-off; in 10/58 (17,2%) data were not reported. Duration of irAEs and proportion of patients with unresolved toxicities at data cut-off were not specified in 52 publications (89,6%). In 6 publications with available data, 3% to 66% of patients had still ongoing irAEs. Secondary publications were available in 15/58 cases (25,8%) and showed that even at longer follow-up (median 24.2 months), the proportion of patients still on treatment at data cut-off was not negligible (7.3%-32%) and only 3/15 studies (20%) presented an update regarding duration of irAEs. Table: 52P n.a.: not available dataPublications n (%) Studies with patients ongoing at data cut-off n (%) Median follow-up months Studies reporting duration of irAEs n (%) Whole series 58 40 (81) 13.5 6 (10.3) Year of publication 2010 2015 2016 2017 2018 2019 1 (1.7) 11 (18.9) 5 (8.6) 21 (36.2) 15 (25.8) 5 (8.6) n.a. 3 (27.2) 5 (100) 17 (80.9) 13 (86.6) 3 (60) 27.8 13.1 10.4 14 12.9 11.1 1 (100) 3 (27.2) 0 1 (4.7) 1 (7.6) 0 Drug Pembrolizumab Nivolumab Atezolizumab Avelumab Durvalumab Ipilimumab Nivolumab + Ipilimumab 29 (50) 12 (20.6) 7 (12) 3 (5.2) 2 (3.5) 2 (3.5) 3 (5.2) 18 (62) 9 (75) 6 (85.7) 3 (100) 2 (100) n.a. 3 (100) 10.6 9.5 14.5 13.4 10.1 30.3 18.7 0 3 (20) 0 0 0 2 (100) 1 (33.3) Studies leading to FDA fast-track approval 24 (41.4) 23 (95,8) 10.2 2 (6)
Description of toxicity in publications of clinical trials of ICIs is often suboptimal especially in terms of duration and long-term sequelae. Future efforts should focus on capturing the real impact of irAEs on patients’ QoL to better define treatments value.
The authors.
Has not received any funding.
G. Valabrega: Honoraria (self): Roche; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): PharmaMar; Honoraria (self): Tesaro. M. Aglietta: Honoraria (self): Tesaro; Honoraria (self): Roche; Honoraria (institution): AstraZeneca. M. Di Maio: Honoraria (institution): Tesaro; Honoraria (self): Bristol Meyers Squibb; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Takeda; Honoraria (self): Janssen. All other authors have declared no conflicts of interest.
Clinical trials have demonstrated the benefit of immune-checkpoint inhibitors (ICIs) for many cancer types. With the widespread use of ICIs, we are facing challenges in the management of immune-related adverse events(irAEs). It is extremely important for physicians to be aware of early recognition and immediate treatment of irAEs. In this study, we aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs.
Between January 2015 and December 2018, patients who were treated with at least one ICIs in clinical trials, expanded access programs or in routine practice in Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine were included in this study. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. All irAEs were graded using the CTCAE v4.0.
A total of 255 patients were retrospectively evaluated. Of these 71 (27.8%) patients developed irAEs. 52(73.2%) of the patients were male, 19 (26.8%) were female. All patients have ECOG performance status 0 -1. More than 2 irAEs were detected in 16 (6.2%) patients. A total of 3177 doses were given with 93 episodes of any grade irAEs. There were 22 irAEs (23.7%) reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most common among them were pneumonitis (n:15), hepatitis (n:13), hypothyroidism (n:13) and dermatitis (n:12). 3 patients were reported to develop grade 4 pneumonitis, toxic epidermal necrolysis and thrombocytopenia. There were 9 immune related deaths in our study. In 4 patients same irAEs recurred upon rechallenge of the ICIs. 39 of irAEs (41.9%) occurred after anti PD1, 47 (50.5 %) occurred after anti PDL1, 7 (7.5%) occurred after combination of anti CTLA4+ anti PDL1.
With the increased use of immunotherapeutic agents in oncology clinics, increased awareness and early recognition are required for effective management of irAEs and improved treatment outcomes. We believe that this study will have a significant impact on current and future service delivery in oncology units.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Microsatellite instability high (MSI-H) is an approved tissue-agnostic predictive biomarker of benefit to immune checkpoint inhibitors (ICI). However not all patients (pts) respond to ICI and additional biomarker of response in this population is still required. The Lung-Immune Prognostic Index (LIPI), combining derived NLR (dNLR=neutrophils/[leucocytes-neutrophils]) and lactate dehydrogenase (LDH) demonstrated a strong correlation with ICI outcomes in NSCLC and other tumor types. We aimed to evaluate the value of pretreatment LIPI for predicting benefit to ICI in MSI-H population.
We performed a multicenter retrospective study of pts with metastatic MSI-H tumors treated with ICI from Apr 2014 to May 2019. Biological and clinical data were retrospectively collected and LIPI was calculated based as previously reported. LIPI groups were: good (dNLR≤3 + LDH≤upper limit of normality [ULN]), intermediate (dNLR>3 or LDH>ULN and poor (dNLR>3+LDH>ULN). The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS), overall response rate (ORR).
Preliminary data is available for 111 pts, with the following characteristics: 43 (39%) male; median age of 62 (24-93), median number of previous lines 1 (range 0 – 6); most common tumor types were colorectal (43%) and endometrial cancer (15%). MSI was defined by immunochemistry and/or polymerase chain reaction (PCR) in 88% and 37 pts (38%) had a confirmed Lynch Syndrome. 98 pts (88%) were treated with a single agent-PD(L)1 inhibitor. The median (m) PFS was 14.1 months (m.) [95%CI, 8.38-not reached (NR)] and the mOS was NR [95%CI, 30-xx] with 44% of ORR. LIPI stratified the population in: good (51, 46%), intermediate (50, 45%) and poor groups (10, 9%). The good group had mPFS of 20.9m. vs. 32m. for intermediate vs. 1.8m. for poor groups (P = 0.0006). In the good group, the ORR was 55% vs. 38% for intermediate vs. 13% in poor group (P = 0.05). OS data are not mature yet.
Poor LIPI is correlated with worse ICI outcomes (PFS, ORR) in MSI-H pts, identifying potentially a MSI-H subset of pts with no benefit from ICI. This study is still ongoing for assessing the value of LIPI in a larger cohort.
The authors.
Has not received any funding.
P. Vuagnat: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). E. Auclin: Travel / Accommodation / Expenses: MundiPharma; Speaker Bureau / Expert testimony: Sanofi Genzyme. L. Mezquita: Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Tecnofarma, Roche, AstraZeneca; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Roche, Chugai. M.R. Vidal Tocino: Advisory / Consultancy: Amgen, Celgene, Merck, Sanofi; Travel / Accommodation / Expenses: Amgen, Roche. P. Martin Romano: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). C. Baldini: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). A. Varga: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). B. Besse: Research grant / Funding (institution): Bristol-Myers Squibb, Roche, Chugai. C. Massard: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, Novartis, Pfizer, Roche, Sanofi, Orion: Consultant/Advisory fees. A. Hollebecque: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP). All other authors have declared no conflicts of interest.
Immunotherapy has become a standard of care for an increasing number of tumors. Patients have a chance of developing immune-related adverse events (irAEs). In general, irAEs occur quite early, mostly within weeks to 3 months after initiation of treatment. Being drugs relatively innovative, “late” irAEs are still unknown.
We conducted a multicenter retrospective study of advanced cancer patients (any histology, regardless of treatment line) treated with anti-PD-1/PD-L1 (mono)immunotherapy, with a minimum time to treatment failure (TTF) of 12 months. IrAEs were categorized into “early” (<12 months of treatment) and “late”. An explorative analysis of clinical outcomes (TTF and Overall Survival – OS) was performed.
We evaluated 318 consecutive patients treated with immunotherapy from September 2013 to August 2018. Median age was 68.6 years (32-90). 175 patients (55.5%) experienced any grade early-irAEs, while 110 (34.6%) experienced any grade late-irAEs (p = 0.0013); 13 patients (4.1%) experienced G3/G4 early-irAEs, while 12 (3.8%) G3/G4 late-irAEs (p = 0.8446). There was a significant association between the occurrence of any grade early-irAEs and late-irAEs (p = 0.0452), as well as between G3/G4 early-irAEs and late-irAEs (p = 0.0251). Among patients who experienced early-irAEs, 63 (36%) experienced “multiple-site” irAEs (multiple sites/organs), while 17 patients (15.4%) experienced multiple-site late-irAEs (p = 0.0040). The median period of follow-up was 22.2 months. The median time to irAEs onset were 3.1 and 16.1 months for early- and late-irAEs, respectively. Late irAEs were not significantly related to TTF; on the other hand, were significantly related to a prolonged OS. When adjusted for primary tumor, late-irAEs were confirmed to be significantly related to a prolonged OS (HR = 0.25 [95%CI:0.11-0.55]; p = 0.0006).
Late-irAEs among long responders seem to have a mild/moderate incidence. They are mostly non-serious and clinical manageable, with a low rate of treatment discontinuation. In this positive-selected population, the occurrence of any grade late-irAEs seems to be furtherly related to a prolonged OS.
Being a retrospective study, this collection was not considered a clinical trial. Therefore, approval by institutional review boards was not required, although a notification was sent (normative ref Gazzetta Ufficiale della Repubblica Italiana n. 76 of 31-3-2008). All patients provided written, informed consent to the proposed treatment option. The procedures followed were in accordance with the precepts of Good Clinical Practice and the ethical standards of the local responsible committee on human experimentation (Comitato Etico dell'Insubria).
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
There are fewer adverse events with immune checkpoint inhibitors (ICPI) than with chemotherapy, however, some patients receiving ICPI may require intensive care treatment in case of severe immune-related adverse events (IRAE’s), which should be immediately recognized to permit an appropriate treatment. We present data of patients admitted to The Royal Marsden Cancer Critical Care Unit (CCU) with IRAE’s. Our objective was also to determine if baseline inflammatory biomarkers (IB), such as LDH, neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR) and systemic inflammatory response index (SIRI) at admission could correlate with patient outcomes.
17 patients were identified between January 2012 and July 2019. Survival analysis was performed using Kaplan-Meier curves and Cox regression, using SPSS v24. All ratios were calculated with absolute counts of neutrophils, lymphocytes and monocytes. Best cut-off ratios were obtained using ROC curves.
Most patients (88.2%; n = 15) had the diagnosis of metastatic melanoma. 6 patients were treated with ipilimumab, 3 with nivolumab, 7 with the combination of both and 1 patient with pembrolizumab. Median length of stay in the CCU was 4 days. The most common reason for admission was colitis in 47.1% (n = 8) of patients. Median overall survival (OS) from date of admission was 8.7 months. Outcome from CCU (stable discharge or long-term rehab) correlates with survival (R2=0.61). In the group of patients with LDH ≥ 189, OS was 1.4 months and in the group with LDH<189, OS was not yet reached (HR 0.28; p = 0.05). In the group with NLR ≥ 6.8, OS was 1.5 months and in the group of NLR<6.8, the median OS was 27.6 months (HR 0.34; p = 0.11).
It is likely that the number of critical care admissions may increase with more patients receiving ICPI. These events can be responsible for great morbidity which might be associated with increased mortality. IB such as high LDH, high NLR and high SIRI might correlate to poor outcome and worse survival and could be used to develop awareness of these events and a more effective approach. However, some of these results were not statistically significant and further studies are needed with a larger data to validate them.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Treatment with immune checkpoint inhibitors (ICPi) has revolutionized cancer treatment over the past few years. Despite the clinical benefits, there is a wide range of toxicities related to the mechanism of action of such group of therapies. Almost every system of organs may be affected. Although rare, fulminant and even fatal toxicities may occur and so, high level of suspicion is the key element to detect and treat them. The purpose of this analysis was to present real world data of programmed death-1 receptor (PD-1) and its ligand (PD-L1) blockade immune-related toxicities in a population of patients treated in a Community Hospital.
A descriptive retrospective analysis of 65 consecutive patients with advanced non-small cell lung cancer (NSCLC), thymoma, head and neck cancer, urothelial and clear cell kidney cancer treated between February 2016 and December 2018 with anti-PD-1/PD-L1 checkpoint inhibitors, was performed. The variables analyzed were the prevalence of toxicities, evaluated according to the system of organs affected and the drug used, their severity according to the Common Terminology Criteria for Adverse Events (CTCAE) classification (v 5.0) and timing of onset. Analyses were performed with use of SPSS v.18 software.
On our population, 94% received treatment with anti-PD-1 checkpoint inhibitor and 89% had NSCLC. Treatment-related adverse events (AE) were observed in 40% of the patients, for any AE. Grade 3-4 toxicities were reported in 6,2% of the patients. Rheumatologic and cutaneous AE were the most frequent ones. They were all reported amongst patients treated with anti-PD-1 checkpoint inhibitors. The reported treatment-related AEs for the nivolumab and pembrolizumab-treated groups were 42,9% and 30,4% (any AE) and grade 3-4 AEs were 7,1% and 4,3%, respectively. No deaths related to toxicity were documented. Rheumatologic and cutaneous AEs were the earliest ones to appear, median time of onset 4 and 6 weeks respectively. Pneumonitis was the latest toxicity, with a median time to appearance of 45 weeks.
The data we present here represents an heterogeneous population in real world settings and it similar to the literature. Implementing careful follow-up for immune related events contributes to promptly diagnose and treat.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immunotherapy with checkpoint inhibition has gained high importance for oncological treatments with benefits in overall survival (OS). However these drugs are not harmless, and immune related adverse events (irAE) have been reported. We pretend to evaluate which patients (pts) are in risk for developing these.
Retrospective evaluation of all pts treated with PD-1 and PD-L1 inhibitors for solid tumors in our center, during January 2015 and October 2018. A multivariate regression was made to determine potential risk factors for irAE. Significance was stablished at p < 0,05. Statistical analysis was made with STATA.
75 pts were included. Median age as 66 years (28-88y). 47 pts (62%) were male. 67 pts (90%) had metastatic disease. 48 pts (64%) were treated with nivolumab, 17 (22%) with pembrolizumab, 8 (10%) with durvalumab and 2 pts with atezolizumab. The most common diagnosis was non small cell lung cancer, with 53 pts (70%), of which 38 were adenocarcinomas. Urothelial cancer, hepatocellular carcinoma e renal cell cancer had 12%, 6% and 5% of the sample respectively. 31 (42%) pts had irAE. 20 (65%) had grade 2 or lower events, and 5pts had multiple irAE. The most common irAE were endocrine dysfunction, skin toxicity and pneumonitis, with 29%, 25% and 19% respectively. Of the 11 serious irAE (grade 3 or higher), the most common cause was pneumonitis with 5 cases. Median time of occurence was 3 weeks after the first treatment (0-52w). The multivariate regression showed higher likelihood of irAE in patients that were female, odds ratio (OR) of 3,72 (p = 0,037, 95% confidence interval (CI95%) 1,15 - 12,83); Lung adenocarcinoma, OR 3,94 (p = 0,032, CI95% 1,12 - 13,79), history of allergies, OR 17,04 (p = 0,022; CI95%) 1,57 - 191,55); history of autoimmune disease, OR 16,88 (p = 0,002; CI95% 2,75 - 103,48). There was no correlation between drug used, previous thoracic radiotherapy or previous steroid treatment.
This study helped distinguish potential risk factors for irAE, like the female gender and history of allergies. Autoimmune disorders are already reported as risk factores. However the small sample isn't enough for us to draw accurate conclusions. More prospective trials are waranted in this setting.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Primary (PCNSL) and secondary (SCNSL) central nervous system lymphoma still carry a poor prognosis. Treatment of relapsed/refractory (r/r) CNS lymphoma remains a challenge. Biological features of CNS lymphoma determine the opportunity to use checkpoint inhibitors in r/r CNS lymphoma.
Analysis included 35 patients with CNS lymphoma treated at the First Pavlov Saint Petersburg state medical University between 2010 and 2019. SCNSL comprised 54% of patients (n = 19), PCNSL - 40% (n = 14), and 6% (n = 2) had CNS involvement in primary testicular lymphoma (PTL). Latter would further be analysed together with PCNSL. Median age at a diagnosis was 56 (30-65) in pts with PCNSL and 48 (20-65) in pts with SCNSL. Tumor histology was diffuse large B-cell lymphoma in 83% of cases. Relapsed or refractory CNS lymphoma was the case in 21 pts (60%): PCNSL – 81% (n = 13/16), SCNSL – 42% (n = 8/19). Nivolumab (nivo) was used in 12 pts: PCNSL – 44% (n = 7/16), SCNSL – 26% (n = 5/19). Median follow-up was 16 months (mo) (0-99): 24,5 mo (0-99) for PCNSL, 12 mo (1-34) for SCNSL pts. One patient had been infected with HIV.
Treatment related mortality was 11% (n = 4/35). 1-year overall survival (OS) was 74% in PCNSL and 69% in SCNSL group. 6-months OS of r/r disease was 75% for PCNSL and 33% for SCNSL. Patients received nivo at dose 3 mg/kg (n = 3), 1 mg/kg (n = 6), 100 mg (n = 3) и 200 mg (n = 1). Median follow-up in pts receiving nivo was 7 mo (0-31). Objective response rate was 58% (n = 7). Complete response was seen in 6 pts (3 PCNSL, 3 SCNSL), partial response – in 1 PCNSL patient, 4 pts had stable disease (2 PCNSL, 2 SCNSL), disease progression was the case in 1 patient with PCNSL. Adverse events (AE) were grade 2 immune arthritis and maculopapular rash. The was no grade 3-4 AE. Eight patients who received nivo are alive at the moment of analysis. Tumor resection was performed in 8 (23%) pts (6 with PCNSL and 2 SCNSL). Consolidation took place in 11 (31%) pts (4 PCNSL, 7 SCNSL). Radiotherapy was performed in 11 pts (31%): 5 PCNSL, 4 SCNSL. Autologous hematopoietic stem cell transplant was performed in 1 patient with PCNSL and 5 pts with SCNSL.
Nivo is a safe and efficient option in some pts with CNS lymphoma. Appropriateness, timing and optimal regimen of nivo therapy should be determined in prospective trials.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immune checkpoint inhibitors (ICIs) are a new option for salvage therapy in relapsed/refractory (r/r) Hodgkin lymphoma (HL) and non-Hodgkin lymphoma. Patients with HIV-related lymphoma may benefit not only from the anticancer activity of ICIs, but also from its potential anti-HIV effect. The publications on ICIs in HIV-related lymphomas is limited by a few case reports.
Nine patients with r/r HIV-related lymphoma were treated with nivolumab (nivo) between 2017-2019. Median follow-up time was 397 days [45-889]. The end points were response to therapy, immune-related adverse effects (IRAE) and overall survival (OS) at 12 months. LYRIC criteria for assessing FDG-PET/CT were applied.
The main characteristics of the study population and outcomes are presented in the table. Median number of prior lines of therapy was 3 (range, 2-4). Four patients received low dose of nivo as monotherapy [NCT03343665] with median of 12 courses 12 (7-12), 5 patients in combination with bendamustine and gemcitabine [NCT03259529] with median of 4 courses 4 (3-11). The median of CD4+ was 382 c/mcl (range, 45-560). The only one patient who did not receive cART due to acute renal failure died early from undetermined cause. Overall response rate (ORR) was 89% with the median time 104 days (73-517); complete remission (CR) was 67% with the median time 107 days (75-265). IRAE were not registered. OS at 12 months was 88.9%. Table: 61P Pts – patients, Ds – diagnose, HL – Hodgkin lymphoma, DLBCL – diffuse large B-cell lymphoma, BeGeR – bendamustine, gemcitabine, rituximab, Nivo/N – nivolumab, CR – complete remission, PR – partial remission, PD – progression disease, auto-HSCT – hematopoietic stem cell transplantationPts. Ds Age HIV load CD4+ cells/mcl cART Nivo N of nivo Response Followed therapy Outcome Follow up 1 HL 33 <40 140 + mono 40 [1] BeGeN 5 CR Auto-HSCT Remission; 882 days 2 HL 41 <40 45 + BeGeN 12 PR Continued [GeN] Relapse; 485 days 889 days 3 HL 36 <40 362 + mono N 40 [1] 10 CR Auto-HSCT Remission; 222 days 4 HL 40 <40 490 + BeGeN 7 CR Auto-HSCT Remission; 427 days 5 HL 37 <40 568 + mono N 40 [1] 6 PR Continued Partial remission; 161 days 6 HL 34 <40 482 + mono N 40 [1] 14 PR Continued Remission; 591 days 7 DLBCL 33 3381 410 + BeGeRN [2] 2 PD - Progression; Died; 45 days 8 DLBCL 38 <40 473 + BeGeRN [2] 7 CR Auto-HSCT Relapse; 266 days 397 days 9 Plasmoblastic Ly 38 <40 174 + mono N 40 [1] 12 CR Continued Remission; 186 days
Overall response rate to nivo in patients with HIV-related lymphomas was 89%, one-year OS – 88.9%. Immune-related adverse effects were not registered. Preliminary data suggest that nivo seems to be an effective and safety treatment option for r/r HIV-related lymphoma.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The programmed-death 1 (PD-1) blockade with nivolumab has demonstrated high efficiency in patients with relapsed and refractory Hodgkin lymphoma (rrHL) with an acceptable toxicity profile. However, most patients treated with immune checkpoint inhibitors (CPIs) will eventually progress on these therapies. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with rrHL. There are concerns that CPIs before allo- HSCT may increase the incidence of graft-versus-host disease, immune-related adverse events, and nonrelapse mortality (NRM). At present, there is no consensus regarding the optimal transplant strategy for patients previously treated with immune checkpoint blockade. The aim of this study was to evaluate outcomes in patients with rrHL who received CPIs as a bridge to allo-HSCT.
We evaluated the results of allo-HSCT in 20 patients who had been transplanted after prior PD-1 blockade between 2017 and 2019 . All patients received reduced-intensity conditioning regimen and post-transplant cyclophosphamide (PTCy)-based GvHD prophylaxis. The best response to PD-1 therapy was a complete response in 9 patients, partial response in 4; 5 patients received transplant during the disease progression and 2 patients were transplanted in indetermined response.
At the time of analysis, median follow-up was 14 months (range, 1-26 months). The 1-year OS and EFS were 95% and 85% respectively, whereas the 1-year cumulative incidences of relapse and NRM were 10% and 5% respectively. Two patients with relapse after allo-HSCT were treated with donor lymphocyte infusion (DLI) in combination with chemotherapy. At the median follow up of 30 days all patients remain alive. 4/20 patients developed severe grade 3-4 GvHD and only 1 patient responded to steroids. The cumulative incidence of chronic GVHD (cGVHD) was 35%.
Our study demonstrates that HSCT after PD-1 blockade is feasible and not associated with higher mortality. The rate of severe acute and chronic GvHD was relatively higher than previously reported for PTCy-based prophylaxis, but was manageable in the majority of cases.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The clinical development of checkpoint inhibitor-based immunotherapy has ushered in an exciting era of anticancer therapy. Despite many reports on anti PD-1 antibody therapy for the treatment of Hodgkin’s lymphoma (HL), the risk of infection among patients receiving nivolumab (nivo) is still unknown.
Between 2016 and 2018, 112 patients with r/r HL were observed and treated with nivo (3 mg/kg) in CIC 725. The median number of nivo courses received was 20 (range, 1-30). 18 patients underwent allo-HSCT after therapy with nivo. The median follow-up period was 1.4 years (1 month-2.6 year). All patients had a standard anti-infective prophylaxis and treatment according to the international guidelines.
During salvage treatment with nivo of r/r HL 11 (10%) patients had documented infection episodes (n = 16): bacterial infections – 37.5% (n = 6), invasive fungal diseases (IFD) – 25% (n = 4) and viral infections – 37.5% (n = 6). The median time to infection episodes was 98 days (12-365) after first nivo administration. Incidence of bacterial infections in study cohort was 5.3% (n = 6). Two patients developed pneumonia, others with one: sinusitis, meningitis cause by
Incidence of infectious complications in r/r HL treated with nivo was 10%. Etiology of infectious complications presented by bacterial infections –37.5%, invasive fungal diseases – 25% and viral infections – 37.5%. Primary chemoresistance was a risk factor for infection complications. Wherewith infections could be managed successfully and carry favorable prognosis.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Tyrosine kinase inhibitors (TKI) are the first-line systemic treatment for patients with advanced hepatocellular carcinoma (HCC), while immune checkpoint inhibitors (ICI) were approved for use in the second-line setting in 2018. Results of phase III studies evaluating the role of first-line ICI use are pending. It is unknown if the sequencing of therapy of TKI and ICI makes a difference in response rate, nor if TKIs can be safely used in the third-line setting after ICI.
Of 114 patients with advanced HCC treated with an ICI at our institution between 30 Dec 2013 and 13 Jun 2018, 59 who also received a TKI were retrospectively identified. Patients were classified into three categories: Group 1, those who had received TKI before an ICI (TKI1-ICI), Group 2 included those who received an ICI followed by an TKI (ICI-TKI2), and Group 3 included those who received a TKI both before and after ICI (TKI1-ICI-TKI2). Response evaluation was done based on RECIST v1.1.
28 patients received TKI1-ICI, 24 received ICI-TKI2, and 7 received TKI1-ICI-TKI2. Median OS was 12.1, 13.9, 31.2m in groups 1, 2 and 3 respectively (p = 0.20), while PFS was 3.1, 2.1 and 3.7 m. (p = 0.40) Response rate to TKI was 3.6%, 12.5% and 28.6% respectively for Group 1, 2 and 3 (p = 0.10), and disease control rate was 21.4%, 25.0% and 71.4% respectively (p = 0.04). 65.7% of the patients who received TKI before ICI experienced adverse events of any grade, similar to 61.3% of patients who received TKI after ICI. The rate of grade 3 or higher adverse events were also similar at 5.8% and 9.7%. There were no grade 5 adverse events.
DCR with TKI was higher when sequenced after ICI and even higher when sequenced after both prior TKI and ICI, suggesting that there may be a role for defining the sequence or combination of TKI and ICI in patients with HCC. No new safety signals were seen with use of TKI following ICI.
Sing Health CIRB.
Bayer.
J. Lee: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Ipsen. D. Tai: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Sirtex; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai. S.P. Choo: Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (self): Sirtex; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene. All other authors have declared no conflicts of interest.
Type 1 diabetes mellitus (T1D) as an immune-mediated effect of immunotherapy-based oncology treatments is observed in 0.5-5% of the patients. Prevention of these symptoms is based on the determination of the basal sugar levels on an empty stomach after the administration of each dose of the drug. The objective of this clinical review is assessing the incorporation of anti-pancreatic islet cell antibodies in the prevention of these events.
A clinical review was carried out with the published cases of T1D secondary to immunotherapy between the years 2012 and 2019 in the current medical literature. We analyzed the determination of anti-pancreatic islet cell antibodies in patients who presented diabetes as an immune-mediated effect, as well as their phenotypic characteristics, the analysis levels and the drugs that had been used.
Between 2012 and 2019 a total of 81 cases have been reported. The two most commonly described molecules were Nivolumab and Pembrolizumab (72/81, 90%), with an average age of 67 years and a predominance of men. Anti-b cell antibodies were observed in 36/81 patients (44%), with a similar frequency between the monotherapy group (31/70, 44%) and the group with combined therapy of anti-CTLA4 and anti-PD1 or PDL1 (5/11, 45%). The most commonly found antibody related to these events was antiglutamic acid decarboxylase (GAD) (34/81, 42%). No antibodies were found prior to the administration of the drug. Table: 65PDiabetes-related autoantibodies • Anti-GAD 34/81 (42%) • Anti-islet cell antibody (ICA) 1/81 (1.2%) • Anti-insulin antibody (IAA) 2/81 (2.5%) • Anti-islet antigen 2 antibody (IA2A) 4/81 (5%) • Anti-zinc transporter 8 antibody (ZnT8A) 1/81 (1.2%)
Determining the level of antibodies related to diabetes prior to the treatment with immunotherapy and during the treatment may prevent immunemediated diabetes. An assessment of the positivity of antibodies at the beginning of the treatment or of seroconversion during administration (as described in the literature) may have an influence on the detection of the development of T1D.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Nintedanib (Vargatef®) is an oral triple angiokinase inhibitor blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity. It is approved in the EU and other countries in combination with docetaxel for treatment of locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after 1st line chemotherapy. Data are still limited regarding efficacy and safety of nintedanib in adenocarcinoma pts who had been pre-treated with ICIs.
This interim analysis included 40 pts with locally advanced, metastatic or locally recurrent lung adenocarcinoma who received nintedanib and docetaxel following pre-treatment with chemotherapy and ICIs within the ongoing NIS VARGADO (cohort B); it updates and extends data previously presented at ESMO 2019.
Median age was 61 years (range: 45 – 80), 23/40 pts (57.5%) were men, and 26/40 pts (65.0%) were ECOG PS0/1. 10/40 pts (25.0%) had brain metastases, and 30/40 pts (75.0%) were current or former smokers. 1st line chemotherapy treatments included pemetrexed (29/40 pts, 72.5%), cisplatin (22/40 pts, 55.0%), carboplatin (21/40 pts, 52.5%), bevacizumab (11/40 pts, 27.5%), vinorelbine (6/40 pts, 15.0%), paclitaxel (3/40 pts, 7.5%), and docetaxel (1/40 pts, 2.5%). 2nd line treatments included nivolumab (25/40 pts, 62.5%), pembrolizumab (9/40 pts, 22.5%), and atezolizumab (5/40 pts, 12.5%). Under nintedanib and docetaxel, 13/29 pts (44.8%) developed a partial response and 12/29 pts (41.4%) showed stable disease; DCR was 86.2% (25/29 pts). Median PFS was 7.2 months (95%CI 2.9 – 8.7). Treatment emergent adverse events (TEAEs) grade ≥3, serious TEAEs, and TEAEs leading to discontinuation were observed in 17/40 pts (42.5%), 19/40 pts (47.5%), and 12/40 pts (30.0%), respectively.
This updated analysis continues to show the clinical benefit and manageable safety profile of nintedanib plus docetaxel in pts with advanced adenocarcinoma NSCLC following treatment with chemotherapy and ICIs.
NCT02392455.
Boehringer Ingelheim Pharma GmbH & Co. KG.
Boehringer Ingelheim Pharma GmbH & Co. KG.
C. Grohe: Advisory / Consultancy: Boehringer Ingelheim. H. Mueller-Huesmann: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): AstraZeneca. J. Atz: Full / Part-time employment: Boehringer Ingelheim. R. Kaiser: Full / Part-time employment: Boehringer Ingelheim.
Checkmate 141, a phase III trial evaluating nivolumab versus standard of care in R/M SCCHN patients after platinum therapy showed a significant improvement in overall survival for nivolumab. This study presents real-world survival data of patients in the United States using nivolumab for head and neck cancer treatment.
A retrospective data analysis was performed using the Flatiron Health’s oncology electronic medical record (EMR) dataset. Data were used from April 2016 to July 2019 with an index date of nivolumab therapy start. Patients were eligible for the study if they were 18 years of age or older, received nivolumab after initial platinum-based therapy, and had at least one month of data after index date.
368 patients met inclusion criteria for this study. Median age was 63.5 years with 79% males and 21% females. The majority of patients (81%) had a history of smoking and an ECOG status of 0 or 1 when reported (75%). The largest proportion of patients (47%) had a primary site of oropharynx, and 47% of patients who had an HPV test were positive. Median and mean follow up from nivolumab therapy start was 6.0 and 8.1 months, respectively. Median duration of treatment for patients receiving nivolumab was 2.3 months (IQR 1.2-5.6) with a median number of 6 doses (IQR 3-12). Most patients received nivolumab as either first-line (29%) or second-line (60%) treatment. The probability of survival at year 1 was 40% (SE 3%), with a median overall survival of 8.1 months (95% CI, 7.0 to 9.8). For the patients who received nivolumab as first-line treatment, 1-year survival probability was 56% (SE 5%) and median OS was 15.2 months (95% CI, 9.0 to 22.1).
This real-world study of nivolumab in R/M SCCHN patients in the United States shows that the improved survival demonstrated by nivolumab in CheckMate 141 translates into similar real-world outcomes for patients, with an even greater benefit in first-line patients. These results are consistent with other observational analyses in Europe and reinforce the survival benefit of nivolumab in R/M SCCHN patients as early as first line.
Bristol-Myers Squibb.
Bristol-Myers Squibb.
P. Singh: Full / Part-time employment: Bristol-Myers Squibb. M. You: Full / Part-time employment: Bristol-Myers Squibb. S. Lubinga: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. Y. Zhang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb.
Real-world data of nivolumab (nivo) in squamous cell cancer of the head and neck (SCCHN) are still very limited. In addition, predictive tools to identify patients (pts) that will benefit from PD-1 inhibitors are lacking.
Retrospective study of pts with SCCHN treated with nivo from 4 third-level hospitals in Spain. Demographics, objective response rate (ORR), duration of response (DOR), time to progression (PD) in responders (TPR), PD-free survival (PFS), overall survival (OS), safety, and predictive value of baseline NLR (NLRBL), NLR at progression (NLRPD), NRL at 12 weeks (NLR12WK) and change in NLR between baseline and 12 weeks after starting IO (NLRBL-12WK), were evaluated. Results expressed as medians (min-max or 95%CI).
Between January 2017 and March 2019, 34 pts (male: n = 26). Age 63 y (51-92). Primary subsite: Larynx (n = 6), oropharynx (n = 12; HPV+: 2), oral cavity (n = 12; HPV+: 4), hypopharynx (n = 6), nasopharynx (n = 1), parotid gland (n = 1). Lines for LA/R-M diseases pre-nivo: 2 (0-4). Strict platinum-refractory pre-nivo: n = 15 (44%). Eight pts (23.5%) received nivo as first-line. Five pts (15%) continued nivo beyond PD. Eight pts (24%) ³1 line post-nivo. No. of nivo cycles: 10 (2-46). ORR: 41% (2 CR, 12 PR, 11 SD, 9 PD). DOR: 16 weeks (2-57). TPR: 29 weeks (12-68). After follow-up (F-U) of 5 m (1-14), estimated PFS: 6 m (95%CI: 3,4-8,6). After F-U of 6,5 m (1-26), estimated OS: 19 m (95%CI 14,6-23,4). Median NLRBL: 3.43 (1.63-7.56). Longer OS with NLRBL < 3.43 vs > 3.43: 22.5 vs 14.5 m (P = 0.072). Among 22 pts with evaluable NLR12WK, median NLR12WK: 3.92 (1.33-22). Longer PFS with NLR12WK < 3.92 vs > 3.92: 9 vs 4 m (P = 0.046). Median NLRBL-12WK: 1.58 (0.12-14.86). No difference in OS or PFS between NLRBL-12WK < 1.58 vs > 1.58 (P = 0.59; P = 0.84). Toxicity G1-2: 73%; G3: 2% (diarrhea).
Baseline and 12-wk NLR may allow to distinguish between long and short-term survivors. Improved response rates and survival in our series may be explained by the lower rate of platinum-refractory disease and the use of nivolumab in the first-line setting as well as beyond progression in a substantial proportion of patients. Treatment was well tolerated. These results merit confirmation in a larger sample.
The authors.
Has not received any funding.
S. Cabezas-Camarero: Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Baseline derived neutrophil–lymphocyte ratio (dNLR) and LDH are prognostic biomarkers for IT in lung cancer. Immune-related adverse events (irAEs) have also been associated with improved outcomes. We investigated whether these factors and additional clinical and laboratory variables predict outcomes of R/M HNSCC pt treated with IT.
Retrospective review of R/M HNSCC pt treated with IT at VHIO from 2015 - 2019 was conducted. dNLR, LDH and variables related to host nutritional status (NS) body mass index (BMI ≥25) and albumin levels (Alb ≥4), were collected at baseline. IrAEs ≥G2 were assessed with CTCAE v.4.0. A cutoff value of dNLR ≥3 and LDH ≥1.5xULN was set by the maximization of the log-rank test. We calculated overall survival (OS) and progression free survival (PFS) with Kaplan-Meier method and constructed univariate Cox models.
Overall, 64 pt were identified, median age was 61y, all ECOG ≤1, 23 treated with single agent IT (36%) or IT combinations 41 (64%). According to the location: 15 pt (23%) had oral cavity carcinoma, 21 (33%) oropharynx, 9 (14%) hypopharynx, 16 (25%) larynx and 3 (5%) unknown primary origin. P16 IHQ was present in 13 pt (21%). Median prior lines were 2 (1 - 6) and median follow-up was 23 months (m) (CI95% 18 - NA). Incidence of IrAEs ≥G2 was 19%. Median PFS was 4.4 m (CI95% 3 – 8.5) and median OS was 10.9 m (CI95% 7.2 – 15.8). Longer PFS and OS were observed in pt achieving tumor response vs stable/progressive disease (HR: 0.07; 15.9 – NA; p < 0.001 and HR: 0.13; 0.05 – 0.32; p < 0.001 respectively). Alb ≥4 was a significant predictor of improved PFS and OS (HR: 0.5; 4.3 – 16.5; p = 0.001 and HR: 0.36; 0.2 – 0.64; p < 0.001 respectively). BMI ≥25 also resulted in better PFS and OS (HR: 0,32; 0,17 - 0,6; p < 0.001 and HR: 0,35; 0.19 - 0.68; p < 0.001 respectively). However, we did not find significant association between dNLR, LDH or irAEs and survival outcomes (PFS or OS).
In our cohort, Alb levels and BMI were strong factors predicting outcomes of IT-treated R/M HNSCC pt. These results suggest that NS should be considered when stratifying pt in ongoing trials. In addition, the lack of prognostic value of dNLR and LDH levels deserves further investigation.
Vall d\'Hebron Institute of Oncology.
Has not received any funding.
All authors have declared no conflicts of interest.
Hyperprogressive disease (HPD) is a new pattern of progressión during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study possible prognostic factors related to HPD.
We collected data of 66 patients diagnosed with advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and May 2019. Several variables as clinical, tumour-related and therapeutical were included and univariate and multivariate Cox regression analysis were performed. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported.
Cohort of 50 men and 16 women, median age of 67 years and 80% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 66% were active or ex-smokers and 34% had never smoked. 62% of patients had adenocarcinoma histology, 32% scamous and 3% had not otherwise specified (NOS) carcinoma histology. 30 of the 66 patients (45%) had 2 or more metastatic sites. 53% of patients had unknown PDL1 status; 9% had no PDL1 expression, 9% low expression and 27% high expression. 82% of patients had progressed to prior line of treatment, while 18% were treatment-naive. Seven of 66 patients (10.6%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 7 patients, and was associated with worse overall survival in the multivariate regression Cox analysis (43.6 vs 11.3 months; HR 4.35, p = 0.0037). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 6.74, p = 0.009).
The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immunotherapy of cancer has changed the paradigm of treatment of many tumours, especially non-small cell lung cancer (NSCLC). The use of immune-checkpoint inhibitors (ICI) is associated in some patients with the development of new immune-related adverse effects (ir-AEs). Our aim was to study if there is any correlation between the appearence of ir-AEs and the efficacy of ICI.
We collected data of 66 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and May 2019. Several variables as clinical, tumour-related and therapeutical were included and univariate and multivariate Cox regression analysis were performed.
Cohort of 50 men and 16 women, median age of 67 years and 80% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 66% were active or ex-smokers and 34% had never smoked. 62% of patients had adenocarcinoma histology, 32% scamous and 3% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 36% M1a, 35% M1b and 24% M1c. 2 patients had driver mutations in EGFR gene. 53% of patients had unknown PDL1 status; 9% had no PDL1 expression, 9% low expression and 27% high expression. 82% of patients had progressed to prior line of treatment, while 18% were treatment-naive. irAEs occured in 55% of patients; 11% developed grade 3 to 4 toxicities. More frequent irAEs were fatigue (61%) and rash (32%). Significant statistical variables in univariate analysis were included in multivariate analysis by Cox regression. The appearence of any grade of toxicity was associated with improved progression-free survival (PFS) (median 5.2 months vs 2.7 months; HR 3.53; p = 0.018; 95% CI [1.24-10.07] ). The use of corticosteroids during treatment with ICI was not related to PFS.
Appearance of immune-related adverse effects during treatment with ICI was associated with better outcomes in our population. The use of corticosteroids during immunotherapy didńt have any deleterious effect on the efficacy of treatment.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immune checkpoint inhibitors anti-PD-1 (Nivolumab and Pembrolizumab) represent a remarkable advance in non-small-cell lung cancer (NSCLC) treatment with impressive clinical activity and durable responses in some patients. However, immunotherapies generate new toxicity profiles called immune-related adverse events (irAEs) that require specific management. Gastrointestinal (GI) irAEs (diarrhea and colitis) are among the most common and if they are left unrecognised or untreated, they can become life threatening. Therefore, the identification of the risk factors for the development of diarrhea could be helpful for the prevention and management of GI irAEs. Among these, the presence of diverticulosis could affect the onset of diarrhea.
This retrospective analysis was conducted in 94 patients with metastatic NSCLC who received Nivolumab at the Papa Giovanni XXIII Hospital in Bergamo between 2015 and 2017. We evaluated the presence of diverticulosis before the start of immunotherapy, the degree and management of diarrhea during therapy and the correlation between the presence of diverticulosis and GI irAEs.
All patients had previously been treated with chemotherapy. 90 patients received Nivolumab at a dose of 3mg/kg while 4 patients received Nivolumab flat dose of 240mg. The RR was 14% and the DCR was 45%. The median PFS has not yet been reached. 19 of 94 patients had a radiological diagnosis of diverticulosis before the start of treatment and 11 of 94 patients developed diarrhea during the therapy. While of the 75 patients without diverticulosis only 7% developed diarrhea, 32% of patients with diverticulosis developed diarrhea. The chi-square test was used for statistical analysis. GI irAEs were in most cases of grade 2 and were treated with steroid therapy without having to resort to other types of immunosuppressive therapy. No patient discontinued treatment due to adverse event.
In our population, the presence of diverticulosis increases the risk of gastrointestinal irAEs. However, these patients can be treated with immunotherapy but they represent a risk class for the onset of diarrhea. Further studies are needed to confirm our findings.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
There is limited information about the response to steroids in treatment of immune-mediated hepatitis (IMH) in patients treated with immune checkpoint inhibitors (ICI). We investigated the incidents of IMH in 307 Danish lung cancer patients with advanced non-small cell lung cancer (NSCLC) and reviewed the efficacy of the IMH treatment.
Data from NSCLC patients medical records were retrospectively registered when treated with ICI between July 2016 and December 2018 at University Hospital Herlev and Rigshospitalet, Copenhagen, Denmark.
In all 307 patients were treated with ICI – 85 patients received nivolumab and 222 pembrolizumab. Age ranged from 21 to 87 years, median 69. IMH was more common with pembrolizumab than with nivolumab (13% vs. 5%). There were 32 patients with grade 1-4 immune-related adverse events (irAEs) IMH (10 %), here off grade 1, 18 (56 %), grade 2, 6 (19 %), grade 3, 7 (22 %) and grade 4, 1 patient (3 %). Onset of raised transaminases ranged from 1-54 weeks, median 8. Time to normalization ranged from 2-464 days, median 24. In 24 patients with grade 1-2 the range was 2-256 days, median 24, until normalization; for grade 3-4 the range was 10-464, median 24. Half of the patients with grade 2 irAEs initiated treatment with steroids and 7 of 8 patients with grade 3-4 irAEs received immediately treatment with steroids. Steroid dose was on average 32 mg/day over a period of 1 year (range 1-32 months). The single patient with grade 4 irAEs also received treatment with mycophenolate mofetil however the transaminases never normalized. One patient with grad 3 irAEs received treatment with ursodeoxycholic acid and tacrolimus due to lack of improvement with steroids. Over a year passed before the transaminases normalized. This patient exclusively underwent liver biopsy which was diagnosed as autoimmune hepatitis. All patients with grade 3-4 had PD-L1 expression above 50% and all permanently discontinued ICI treatment.
Liver toxicity frequency correlates to findings in clinical trials (KEYNOTE-024 and KEYNOTE-042) and are mainly of grade 1. There was no correlation, in this dataset, between dose of steroids and time to normalizing of transaminases in patients treated with immunosuppressants.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Randomized clinical trials in aNSCLC demonstrated that 2L IO prolonged overall survival and lowered AE rates compared with 2L CHEMO. However, real-world (RW) evidence from clinical practice is limited, and the potential cost benefits of lower AE rates have not been examined. Here, we report average costs per patient (pt) associated with grade 3-4 AEs during 2L treatment with IO and CHEMO in aNSCLC from a US payer perspective.
AEs in pts treated with 2L IO or CHEMO for aNSCLC (Mar 2015-Dec 2017) were abstracted from US electronic health records in COTA’s database. Hospitalization costs for each ICD-10 code associated with the management of a grade 3-4 AE during treatment were estimated using the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample 2017 dataset.
Of 596 pts in the analysis, 276 received IO (199 nivolumab) and 320 received CHEMO. The proportion of IO- vs CHEMO-treated pts was higher for pts aged <75 years (79% vs 71%), men (54% vs 47%), and current/former smokers (92% vs 83%); proportions in the IO and CHEMO groups were similar for non-squamous histology (84% vs 83%) and history of brain metastases (37% vs 37%). Overall, 40 (14.5%) IO-treated pts and 68 (21.3%) CHEMO-treated pts had grade 3-4 AEs, resulting in average costs per pt of $9,421 and $15,677, respectively. The main cost and event drivers in both treatment groups were alanine aminotransferase elevation (IO: 36% of total costs [32% of grade 3-4 AEs], CHEMO: 25% [21%]) and leukocytosis, indicative of infection (IO: 22% [28%], CHEMO: 33% [41%]). Table shows average cost per pt in selected subgroups. Table: 74P Average cost of grade 3-4 AEs per patient (Pt)IO (n = 276) CHEMO (n = 320) n Average Cost per Pt n Average Cost per Pt <65 y 107 $6,877 114 $17,203 ≥65 y 169 $11,033 206 $14,832 Male 150 $4,417 150 $10,460 Female 126 $15,379 170 $20,279 White 176 $9,265 233 $17,547 Former/current smoker 255 $7,973 265 $17,292 History of brain metastasis 101 $9,760 117 $20,219 No history of brain metastasis 175 $9,226 203 $13,059 Squamous 43 $3,096 53 $18,749 Nonsquamous 233 $10,634 267 $15,181
In this RW analysis in pts with aNSCLC, 2L IO was associated with lower costs for the management of grade 3-4 AEs than 2L CHEMO.
Writing assistance was provided by Roland Tacke, PhD, of Evidence Scientific Solutions Inc, funded by Bristol-Myers Squibb.
Bristol-Myers Squibb.
Bristol-Myers Squibb.
C.K. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. K. Gupte-Singh: Full / Part-time employment: Bristol-Myers Squibb. A.J. Belli: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. D.C. Lane: Shareholder / Stockholder / Stock options, Was an employee at Bristol-Myers Squibb while this work was done and recently joined COTA: Bristol-Myers Squibb. A. Lakshmanan: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. A.D. Norden: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA.
Immune checkpoint inhibitors (ICIs) are key in the treatment of advanced non-small cell lung cancer (NSCLC). However, there is a paucity of large real-world case series on timing and severity of immune-related adverse events (irAEs) that could inform treatment service provision.
A retrospective study of patients with advanced NSCLC treated with ICIs at The Clatterbridge Cancer Centre between 2016 and 2018 was conducted to review irAEs in the context of therapeutic efficacy. Kaplan Meier analysis, Mann-Whitney and chi-squared tests were used.
303 patients were identified. Median age was 68 years; 83 patients (27%) had a performance status (PS) of 0; 85 (28%) had an ACE-27 comorbidity score ≥2. 277 (91%) had pembrolizumab (107 (35%) first line), 21 (7%) nivolumab and 5 (2%) atezolizumab. Median number of cycles was 6 (range 1-29). Median progression-free and overall survival (PFS/OS) were 5.0 and 10.0 months. IrAEs were reported in 40% of patients and 13% experienced multiple irAEs; 11% were ≥G3. The most common irAEs were dermatitis (12%), dysthyroidism (9%), colitis (6%), hepatitis (5%), arthralgia (5%), pneumonitis (5%); the most common ≥G3 irAEs were pneumonitis (3%), hepatitis (2%) and colitis (2%). Treatment was discontinued due to irAEs in 12% of patients. Median time to irAEs onset by system involved varied between 46 days (hyperthyroidism) and 122 days (arthralgia). There was no association between irAEs and age (p = 0.16), PS (p = 0.46), or ACE-27 score (p = 0.68). 83% of irAEs occurred within 6 months of initiating ICIs; no clear correlation between irAEs incidence and time on treatment was found. Patients with irAEs within 6 months of treatment had longer PFS (7.1 vs. 3.9 months, HR 0.70, p = 0.014) and OS (15.6 vs. 7.7 months, HR 0.48, p < 0.001) than those without irAEs. Notably, patients experiencing irAEs ≥G2 within the first 21 days of treatment had poorer clinical outcomes than those with later irAEs (median PFS 2.9 vs 10.3 months, p < 0.001; median OS 5.9 vs. 20.3 months, p = 0.001).
In our large real-world retrospective cohort study the incidence of irAEs reflected that seen in clinical trials. There appears to be a toxicity-efficacy relationship with irAEs; however, larger studies are required to validate this.
The Clatterbridge Cancer Centre NHS Foundation Trust.
Has not received any funding.
A.C. Olsson-Brown: Honoraria (self): MSD; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): Eli Lily; Research grant / Funding (self): Novartis. C. Escriu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Boeringher Ingelheim; Speaker Bureau / Expert testimony: Pfizer. All other authors have declared no conflicts of interest.
Clinical trials show favorable OS for patients (pts) with incident aNSCLC and programmed death ligand 1 (PD-L1) expression treated with PD-L1 immune checkpoint inhibitor (ICI) pembrolizumab (PEM) or PEM-chemotherapy compared to no ICI. We use real world data to examine OS in pts with PEM-based regimens vs NoICI as initial aNSCLC treatment by PD-L1 expression.
This retrospective study used de-identified administrative claims, including month of death (MoD) from regular operations, spanning 1/2017-12/2018 from a large, national US insurer. Claims were linked with biomarker test data from a CLIA-certified cancer diagnostics lab. During 2018, Medicare Advantage pts having ≥1 claim with diagnosis (dx) of lung cancer (ICD-10 C34), advanced disease (C77-C79), a PD-L1 test (CPT 88360) and test result, Tumor Proportion Score (TPS), were included. Pts were newly diagnosed (no C34 in 2017) and continuously enrolled in 2017 & 2018 or until death in 2018. Cohorts were based on initial therapy as PEM-based or NoICI and TPS result. Pts were followed from dx to MoD or 12/2018. OS was MoD, minus month of dx; otherwise censored at 12/2018. Multivariable Cox proportional hazard regressions compared OS across cohorts.
457 pts met study criteria: 126 PEM-based and 331 NoICI. Median age was 76 years in both cohorts. PEM-based had more males (63% vs 51%; p = 0.02) Median months followed was 6 (PEM-based) and 4 (NoICI). For PEM-based , 23 (18%) had TPS 0, 36 (29%) had TPS 1- 49 and 67 (53%) had TPS 50+. For NoICI, 118 (36%) had TPS 0, 120 (36%) had TPS 1- 49, and 93 (28%) had TPS 50+. 20% (n = 25) of PEM-based and 31% (n = 104) of NoICI died during the study period. Mortality hazard ratios for PEM-based vs NoICI by TPS score were: TPS 0, 0.46 (CI 95% 0.16 – 1.30); TPS 1 to 49, 0.73 (CI 95% 0.35 – 1.52); and TPS 50+,0.35 (CI 95% 0.18 – 0.68). OS was more favorable for the PEM-based cohort for all TPS groups, though only TPS 50+ was significant.
This study used administrative claims and lab test data allowing examination of effectiveness of PEM-based vs. NoICI therapy for aNSCLC. As in clinical trials, this analysis suggests OS benefit for PEM-based vs NoICI. Further analysis with longer follow-up will better assess OS benefit by TPS score.
UnitedHealth Group.
Has not received any funding.
J. Staib: Shareholder / Stockholder / Stock options, Full / Part-time employment: UnitedHealth Group; Shareholder / Stockholder / Stock options: Bristol Myers Squibb; Shareholder / Stockholder / Stock options: Merck; Shareholder / Stockholder / Stock options: Natera; Shareholder / Stockholder / Stock options: NeoGenomics. S. Sudarsanam: Shareholder / Stockholder / Stock options, Full / Part-time employment: NeoGenomics Laboratories. S. Dacosta Byfield: Shareholder / Stockholder / Stock options, Full / Part-time employment: UnitedHealth Group. C. Kennedy: Shareholder / Stockholder / Stock options, Full / Part-time employment: UnitedHealth Group. L. Weiss: Shareholder / Stockholder / Stock options, Full / Part-time employment: NeoGenomics Laboratories.
We often experience long-lasting response of PD-1 inhibitor in advanced NSCLC patients. However, the characteristics associated with long-lasting response to PD-1 inhibitor is still unknown. In this study, we investigated the characteristics of patients who showed long-lasting (≥2 years) response to anti-PD-1 antibodies.
We reviewed consecutive advanced NSCLC patients who received a PD-1 inhibitor monotherapy (nivolumab, or pembrolizumab) between December 22, 2015 and May 31, 2017 at National Cancer Center Hospital in Japan. The cut-off date was June 1, 2019. We defined patients who obtained clinical benefit for more than 6 months as “Responders”. Among them, those who had a durable response for more than 2 years were defined as “Long-term responders” (LTR), and those who responded or shorter than 2 years as “Non-LTR”. We investigated the patient baseline characteristics and clinical outcomes of anti-PD-1 monotherapy including objective response rate (ORR) and maximal tumor shrinkage. Tumor response was assessed by RECIST version 1.1. The PD-L1 expression on tumor cells was assessed by using 22C3 antibody.
A total of 232 patients were included in this analysis. Responders accounted for 37.9 % (88 out of 232). Of these patients, 31 (35.2%) were LTR group and 57 (64.8 %) were non-LTR group. At the time of data cut off, 22 (71.0%) of 31 patients in LTR group showed lasting response of PD-1 inhibitor. There were no significant differences in the baseline characteristics such as age, sex, performance status, driver mutation, clinical stage, and smoking status. Regarding histological distribution, non-squamous cell histology was more common in the LTR group (68% vs. 90%, P = 0.021). The ORR in the LTR group was significantly higher than non-LTR group (80.6% vs. 32.0%, P <0.0001). The median tumor shrinkage (range) in the LTR group was also significantly higher than that in the non-LTR group [72.8 (range: 6.8-100)% vs 48.7(range: 3.9-100)% (P=0.0002)]. In contrast, no difference was found in the PD-L1 expression between two groups (P = 0.213).
Long-lasting response of PD-1 inhibitor was particularly characterized by high tumor shrinkage in patients who had response to PD-1 inhibitors.
The authors.
Has not received any funding.
Y. Okuma: Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Chugai. Y. Goto: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Shionogi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Glaxo Smith Kline; Advisory / Consultancy: Guardant Hearlth; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Dai-ichi Sankyo; Research grant / Funding (institution): Kyorin. H. Horinouchi: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZaneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol Myers Squibb; Speaker Bureau / Expert testimony: Kyowa-kirin; Research grant / Funding (institution): Abbvie; Speaker Bureau / Expert testimony: Dai-ichi Sankyo; Research grant / Funding (institution): Kyorin; Research grant / Funding (institution): Genomic Health. N. Yamamoto: Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy: Cimic; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Kyowa-Hakko Kirin; Research grant / Funding (institution): JansenPharma; Research grant / Funding (institution): MSD. Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): ONO; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristrol-Myers Squibb; Honoraria (self): Boehringer lngelheim; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): MSD; Honoraria (self), Research grant / Funding (institution): Taiho; Advisory / Consultancy, Research grant / Funding (institution): Kyorin; Advisory / Consultancy: Celltrion; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Daiichi-Sankyo. All other authors have declared no conflicts of interest.
aMM still represents a hard-to treat disease, due to its rarity and to the modest activity of standard chemotherapy. Recently, ICIs directed against PD-1/PD-L1 have been tested in clinical trials in chemotherapy pre-treated aMM patients, but their efficacy is still debatable.
We searched PubMed and proceedings of major meetings, to perform a systematic review and meta-analysis (updated at September 30th 2019) of clinical trials testing ICIs in this setting, describing activity in terms of Objective Response Rate (ORR) and Disease Control Rate (DCR). To explore the potential predictive role of PD-L1 expression, we also collected the ORR in subgroups of patients selected for PD-L1 expression (based on the highest cut-off used in each study).
8 studies were selected (1 phase III, 4 phase II, 2 phase IB, 1 real-world EAP data study), including 405 patients, most with pleural MM; 1 registry study was excluded due to inclusion of treatment-naive patients, 1 due to unclear inclusion criteria. 352 patients (87%) were treated with anti-PD-1 (nivolumab [N] or pembrolizumab [P]), 53 (13%) with anti-PD-L1 (avelumab [A]). Overall, ORR was 19.6% (95% CI, 16.0-23.8%) with no significant difference among drugs (N 20.0%, P 22.6%, A 9.4%; p = 0.11); DCR was 56.5% (95% CI, 51.6-61.3%) with no significant difference among drugs (N 54.0%, P 58.7%, A 58.5%; p = 0.66). When restricting the analysis to patients selected for PD-L1 expression (n evaluable=91, based on cut-offs ranging from 1% to 50% in different trials), ORR was 34.1% (95% CI, 25.2-44.3%), ranging from 18.8% to 71.4% in different trials. In unselected patients, median progression-free survival ranged from 2.5 to 6.1 months, and median overall survival ranged from 6.36 to 17.3 months.
To our knowledge, this is the first meta-analysis synthesizing the evidences of activity of PD-1/PD-L1 ICIs in pre-treated aMM. ORR and DCR in unselected patients are encouraging compared to historical results with second-line chemotherapy. Selection based on PD-L1 expression could increase the activity of immunotherapy, but trials were heterogeneous for test and cut-off.
The authors.
Has not received any funding.
M. Tagliamento: Travel / Accommodation / Expenses: Takeda, Bristol-Myers Squibb, Roche. P. Bironzo: Honoraria (self): Bristol-Myers Squibb, BI, AstraZeneca. E. Capelletto: Advisory / Consultancy: BI, AstraZeneca. S. Novello: Speaker Bureau / Expert testimony: AstraZeneca, Abbvie, Celgene, BI, Bristol-Myers Squibb, MSD, Eli Lilly, Pfizer, Roche. M. Di Maio: Honoraria (self): Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Janssen, Takeda, Pfizer; Honoraria (institution): Tesaro. All other authors have declared no conflicts of interest.
Nivolumab is one of immune checkpoint inhibitors, which is reported to have efficacy in previously treated patients with advanced non-small cell lung cancer (NSCLC) in checkmate 017 / 057 / 078. It is suggested nivolumab treatment beyond progression disease (PD) may be associated with improved survival in patients with melanoma and renal cell carcinoma. However, the efficacy of beyond PD in patients with NSCLC is still unclear.
To evaluate the efficacy of beyond PD about nivolumab, we retrospectively reviewed the continuous patients with advanced NSCLC, who received nivolumab as 2nd line treatment in our institution between February 2016 and February 2019. The patients were eligible if they had been diagnosed PD using RECIST v1.1 by 28 February 2019. Baseline characteristics, overall response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), the period between RECIST v1.1 PD and clinical PD, post-PD OS, and safety were evaluated on 26 July 2019.
Of the 144 advancer NSCLC patients treated with 2nd line nivolumab, 95 patients were eligible. Post-PD OS was 12.2 months (95% confidence interval [CI]: 5.8–26.6) in 28 patients continuing nivolumab beyond PD, 9.3 months (95% CI: 6.4–13.8) in 46 patients switching to other anti-cancer therapy, and 0.7 months (95% CI: 0.4–1.7) in 21 patients receiving no further therapy. The median period between RECIST v1.1 PD and clinical PD was 3.8 months (95% CI: 2.8–6.6) in 28 patients continuing nivolumab beyond PD. During nivolumab beyond PD, one patient died due to acute liver involvement and interstitial lung disease, one patient stopped to receive nivolumab due to grade 3 diarrhea, and one patient stopped to receive nivolumab due to grade 2 interstitial lung disease.
Post-PD OS trended to be longer in patients continuing nivolumab beyond PD than in patients switching to other anti-cancer therapy. Within the limitations of this retrospective analysis, this study suggests nivolumab treatment beyond PD may have efficacy and safety in patients with advanced NSCLC.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
N is an oral triple angiokinase inhibitor approved in 61 countries for use with D to treat locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC after first-line chemotherapy (CT). Several immunotherapies are also now approved in various indications in advanced NSCLC, but limited data are available regarding outcomes with N + D after immunotherapy treatment.
LUME-BioNIS is a European, prospective, multicentre, non-interventional study of patients (pts) with advanced adenocarcinoma NSCLC who initiated N + D after first-line CT in routine practice according to the approved N EU label. Information on dates of progression (based on clinical assessment or Response Evaluation Criteria in Solid Tumors) and death and adverse events (AEs) was collected via an electronic case report form. The primary endpoint was overall survival (OS). A subgroup analysis was conducted to evaluate outcomes in pts with prior immunotherapy.
In the 67 pts with prior immunotherapy, median age was 63 years and 27 pts (40.3%) were female. Prior immunotherapy was given in first line in 20 pts (29.9%) and in later lines in 47 pts (70.1%). The most common immunotherapies were nivolumab (39 pts; 58.2%), atezolizumab (13 pts; 19.4%) and pembrolizumab (11 pts; 16.4%). N + D was given in second line in 10 pts (14.9%) and in later lines in 57 pts (85.1%). Median progression-free survival (PFS) was 4.6 months (95% confidence interval [CI]: 3.5–5.7) and median OS was 8.8 months (95% CI: 7.0–11.5). In 65 pts evaluable for safety, the most common on-treatment AEs were malignant neoplasm progression (18 pts; 27.7%), diarrhoea (21 pts; 32.3%), nausea (10 pts; 15.4%) and vomiting (7 pts; 10.8%).
Used according to the approved N label in routine practice, N + D showed clinically relevant effectiveness, with no unexpected safety findings, in pts with prior immunotherapy and CT. The observed median PFS and OS of 4.6 and 8.8 months, respectively, are encouraging, given the use of N + D in third or later lines in 85.1% of pts. These data add to the real-world evidence that can inform clinical decision-making in the changing therapeutic landscape.
NCT02671422.
Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Mark Dyson, DPhil (Berlin, Germany) on behalf of Syneos Health (London, UK).
Boehringer Ingelheim Pharma GmbH & Co. KG.
Boehringer Ingelheim Pharma GmbH & Co. KG.
M. Reck: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: F. Hoffmann-La Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene. K. Syrigos: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: MSD. S. Zöchbauer-Müller: Advisory / Consultancy, fees for participation in the LUME-BioNIS study: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, fees for advisory boards and lectures: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, fees for advisory boards and lectures: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, fees for advisory boards and lectures: Bristol-Myers Squibb; Advisory / Consultancy, fees for advisory boards: Roche; Advisory / Consultancy, fees for advisory boards: AstraZeneca; Advisory / Consultancy, fees for advisory boards: Takeda; Speaker Bureau / Expert testimony, fees for lectures: Pfizer. H. Buchner: Research grant / Funding (self), former employee; received financial support for performing analyses during the conduct of the study: Boehringer Ingelheim Pharma GmbH & Co. KG. T. Kitzing: Full / Part-time employment, current employee of Boehringer Ingelheim Pharma GmbH & Co. KG: Boehringer Ingelheim Pharma GmbH & Co. KG. K.M. Kerr: Advisory / Consultancy, personal fees from Boehringer Ingelheim during the conduct of the LUME-BioNIS study: Boehringer Ingelheim. All other authors have declared no conflicts of interest.
ULTIMATE, a phase III trial, showed a significant superiority regarding progression free survival (PFS) of the combination paclitaxel-bevacizumab versus docetaxel as second or third line treatment for advanced non-small cell lung cancer (NSCLC). With the increase use of immunotherapy in first-line setting, second line strategies must be redefined. Paclitaxel-bevacizumab combination could be an option.
The main objectives were to describe safety and efficacy of this combination in metastatic non-squamous NSCLC as second-line therapy or beyond with a special attention paid to the sub-group treated just after immune checkpoint inhibitors. It was a multicentric retrospective study.
This analysis included from 1st September 2010 to 1st april 2018, 76 patients: 42 (55%) male, 18 (24%) and 36 (47%) treated in second and third line respectively, and 22 (29%) in fourth line or more. Overall response rate (ORR) was 37% (28/76) and disease control rate 74 % (56/76). Median PFS and OS were 5,7 [95%CI: 4,1-6,9] months and 11,2 [95%CI: 8-not reached] months respectively. In second and third line, ORR was respectively 39% and 42%, PFS 4 months [95%CI: 2,5-7,7] and 6 months [95%CI: 4-7], OS 9,4 months [95%CI: 2,7-not reached] and was not reached in third line at 12 months. Grade 3–4 adverse events included asthenia 5% (4/76), neurotoxicity 3% (2/76), bleeding events 4% (3/76), and hematological toxicity 1% (1/76). In the subset of patients treated in third-line or beyond, immediately after immunotherapy (33/76), we note with interest that ORR was 42% (14/33), median PFS was 6,2 [95% CI: 4,6-7,7] months, and median overall survival was not reached at 12 months.
This study shows an acceptable toxicity profile associated with encouraging efficacy of the combination paclitaxel-bevacizumab as second-line treatment or beyond for non –squamous NSCLC patients. Moreover, these results seems to be very promising preliminary findings for patients treated just after immunotherapy. AVATAX is ongoing and should collect data from about 200 patients.
Chantal Decroisette.
Has not received any funding.
C. Chouaid: Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AZ; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: BI; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer and Amgen; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi Aventis; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: GSK. G. Rousseau-Bussac: Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): roche; Travel / Accommodation / Expenses: Bristol-Myers-Squibb, Travel / Accommodation / Expenses: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Mundipharma; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Janssen-Cilag; Travel / Accommodation / Expenses: Boehringer Ingelheim. J. Pinsolle: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pierre Fabre. R. Descourt: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda. M. Geier: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb. C. Decroisette: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Real-world (RW) data are complementary to clinical trial data in bridging information gaps and facilitating decision making. This study compared overall survival (OS) of 1L chemotherapy (chemo) for aNSCLC in RW with pooled OS estimated from a meta-analysis of chemo arms from randomized clinical trials (RCT).
In the meta-analysis, identified phase 3 RCTs reported OS for 1L carbo/cisplatin-chemo regimens in aNSCLC (2006 to 2019, most enrolled pts after 2010). In the RW analysis, treatment-naïve pts with aNSCLC receiving 1L chemo were identified from the Flatiron Health database (Jan 2011 to Mar 2019) to ensure adequate follow up. Four cohorts were selected based on histology and PD-L1 tumor proportion score (TPS, table). Other eligibility criteria (age, ECOG performance status, biomarker status) were applied to approximate the common inclusion/exclusion criteria used in the RCTs. OS was defined as time from 1L chemo initiation until death of any cause.
The non-squamous and squamous RW cohorts regardless of PD-L1 level had median OS (95% CI) 12.9 (11.5 - 14.2) months and 12.4 (11.6 - 13.3) months, respectively; comparable to the meta-analysis (table 82P Median OS in 4 aNSCLC RW cohorts and in RCT meta-analyses CheckMate 026, Keynote 189, IMpower 132, IMpower 130, JMDB, ERACLE, LETS, TRAIL, ECOG 4599, CA031, JML, BEYOND, PRONOUNCE, Gronberg 2009, Rodrigues 2011. CheckMate 026, Keynote 407, JMDB, CA031, IMpower 131, SQUIRE, LETS. CheckMate 026, Keynote 042, MYSTIC. CheckMate 026, Keynote 042, Keynote 024, MYSTICCohorts RW cohorts n RW cohorts Median OS (95% CI), month Meta-analyses Median OS (95% CI), month Non-squamous 1,343 12.9 (11.5 - 14.2) 13.1 (11.8 – 14.4) Squamous 2,019 12.4 (11.6 - 13.3) 10.9 (9.8 – 11.9) PD-L1 TPS ≥ 1% 504 18.1 (14.1 - 20.7) 12.3 (11.4, 13.1) PD-L1 TPS ≥ 50% 227 20.3 (14.6 - 29.5) 12.8 (11.5 – 14.1)
RW OS in broad histology-based populations of 1L chemo pts was similar to meta-analysis estimates from corresponding trial populations. However, RW OS in TPS-based populations, where biomarker information is more commonly available in recent cohorts, was numerically longer than in the corresponding meta-analysis trial populations. Additional analyses are planned to assess IO-chemo in RW and to determine the influence of post-progression immunotherapy and imbalances in prognostic factors on chemo treatment group outcomes.
Bristol-Myers Squibb.
Bristol-Myers Squibb.
D. Waterhouse: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Speaker Bureau / Expert testimony: Genentech/Roche; Honoraria (self), Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy: Abbvie; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Jannsen; Advisory / Consultancy: Amgen; Advisory / Consultancy: McGivveny Global. K.A. Betts: Research grant / Funding (institution), Keith Betts is an employee of Analysis Group, which received funding from Bristol-Myers Squibb for the conduct of the study: Bristol-Myers Squibb. J. Zhao: Research grant / Funding (institution), Employee of Analysis Group, Inc., which received payment for contracted research from Bristol-Myers Squibb: Bristol-Myers Squibb. S. Rao: Full / Part-time employment: Bristol-Myers Squibb. K. Gupte-Singh: Full / Part-time employment: Bristol-Myers Squibb. M. Rutstein: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. M.K. Higashi: Full / Part-time employment: Bristol-Myers Squibb. L. Schwartzberg: Advisory / Consultancy: Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Helsinn; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bristol-Myers Squibb.
Immune checkpoint inhibitors (ICI) have been established as a novel strategy for non-small cell lung cancer (NSCLC). However, definitive biomarkers that can predict response to ICI therapy remains established. Some prostate factors are suggested, Neutrophile-lymphocyte ratio (NLR), advanced lung cancer inflammation index (ALI), Lung Immune Prognostic Index (LIPI), then we investigate their efficiency.
The medical records of consecutive 296 patients with NSCLC who were treated with nivolumab at Kinki-chuo Chest Medical Center between December 17, 2015 and December 31, 2018 were collected. Nivolumab was the only ICI validated for advanced NSCLC in a second-line treatment setting. We investigated the relationship between median progression free survival (PFS) and already known prognostic factors (NLR, ALI, LIPI and so on).
The median age was 70 (range, 40-90) years. 206 patients were male, and 224 patients were good PS group (PS 0-1). The median PFS was 3.0 months in all patients. The median PFS was 4.7 (NLR<4) versus 2.9months (NLR ≦4) [hazard ratio (HR) =0.43; 95% confidence interval (CI) =0.26-0.93], 4.0 (ALI≧18) versus 1.4 months (ALI <18) [HR = 0.56; 95%CI =0.44-0.73], 3.2 (LIPI 0-1) versus 1.3 months [HR = 0.66; 95%CI =0.48-0.89].
NLR, ALI and LIPI score have the potential to be predictive factors of ICI response in NSCLC patients.
The authors.
Has not received any funding.
A. Tamiya: Research grant / Funding (self): Taiho; Research grant / Funding (self): pfizer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Ono pharmaceutical; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Chugai pharmaceutical; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): MSD; Research grant / Funding (self): Kissei. S. Atagi: Research grant / Funding (self): Ono pharamaceutical; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Taiho; Research grant / Funding (self): Chugai pharmaceutical; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Yakult pharmaceutical; Research grant / Funding (self): MSD. All other authors have declared no conflicts of interest.
SCLC represents the subtype with worst survival among lung cancer patients. Despite initial good response to platinum based chemotherapy in extensive disease, these patients relapse fast with an unfortunate prognosis. The majority of overall survival (OS) data reported show a median between 8-10 months (mo) based on randomized clinical trials and meta-analysis.
The aim of this study is to analyze survival outcomes in IV-SCLC patients in real clinical practice based on SEER database and identify which patients have worse outcomes. We selected all patients with SCLC from SEER database diagnosed between 2010-2015. Bivariate analysis was used by chi-square determination for the association of binary qualitative variables and the ANOVA test to compare 2 or more variables. A multivariate analysis using Cox regression was performed, measuring the effect by Hazard Ratios (HR) and their 95% confidence intervals to determine the impact of these prognostic factors on OS. AJCC 7 was used for TNM staging.
We included 26,221 patients with SCLC. Men: 50.7%. 55.7% patients were ≥ 65 years old. Median age: 67 years old. 82% were caucasian. 70.84% were stage IV. These patients showed a median OS (mOS) of 6mo (5.83-6.17). 45.37% of them had liver metastasis (mets), bone: 33.41%, brain: 23.86%, lung: 19.47% and other mets sites: 16.88%. Median OS in patients with liver mets, bone, brain and lung were 4 (3.79-4.21), 6 (5.74-6.26), 6 (5.71-6.29) and 5 mo (4.63-5.37) respectively. Patients involving both lung and liver mets with 3 or more mets sites showed the worst survival with 3 (1.99-4.00) and 4 (3.11-4.89) mo of mOS respectively. The percentage of patients alive at 6, 12, 24 y 60 mo were 47.70%, 21.64%, 5.91% and 1.61% respectively.
This real world data analysis reflects that the chance of having long term survivors in SCLC is very low and that mOS has not been improved over the last years. The introduction of new therapies such as immune checkpoints opens a new opportunity for long term survival and better outcomes in this aggressive disease.
Roche Farma S.A.
Roche Farma S.A.
J. de Castro Carpeño: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZ; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: Tesaro. M. Cobo Dols: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZ; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Boehringer. M. Domine Gomez: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZ; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Abbvie; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer. P. Ruiz Gracia: Full / Part-time employment: Roche. L. Crama: Full / Part-time employment: Roche. M.R. Garcia Campelo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZ; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: PharmaMar; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Abbvie; Advisory / Consultancy, Speaker Bureau / Expert testimony: GSK; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer.
Pts with cancer have disease- and treatment-related symptoms. DPM can facilitate outpatient symptom detection and improve clinical practice, pt quality of life and health benefits. We assessed pt/healthcare professional (HCP) adoption and clinical impact of a DPM tool in CIT-treated pts with a/mNSCLC.
Literature research and pt/HCP advisory boards identified factors influencing DPM use and CIT-related symptoms. These were used to develop a drug-/indication-specific CIT pt module for the Kaiku Health DPM platform, encompassing a symptom questionnaire (per National Cancer Institute Common Terminology Criteria for Adverse Events), HCP symptom overview/alerts, direct pt–HCP communication and pt education for mild/moderate symptoms. The DPM tool was tested over 3 months in Switzerland, Finland and Germany (10 clinics; 45 pts; 2L+ CIT monotherapy). User experience, overall satisfaction and clinical practice impact data from an online survey/HCP interviews were analysed quantitatively/qualitatively.
Of the 21 pt/27 HCP online survey respondents, 73% rated themselves as competent/proficient/expert and 85% used the tool at least weekly; 60% for ≤ 10 min per week (pts)/day (HCPs). Most agreed that the tool facilitated more focused and efficient communication. Preferred functions by pts and HCPs were drug-specific information and symptom alerts, respectively. The table shows time needed for pt tool introduction and HCP time saved per pt visit. Telephone consultation need decreased for 33% of pts. Continuous monitoring led to earlier CIT symptom management in several pts. Tool expectations were met/exceeded for 89% of HCPs. Table: 85PHCPs, n (%) n = 27 Time for pt tool introduction 0 min (none done) 7 (26) < 30 min 18 (67) 30–60 min 2 (7) > 60 min 0 HCP time saved per pt visit ≤ 5 min 6 (22) 6–10 min 5 (19) 11–15 min 1 (4) No time saved 7 (26) More time spent 1 (4) Unsure 7 (26)
The DPM tool educated and empowered pts and saved time on symptom reporting. It also improved care quality, efficiency and pt–HCP communication and enabled earlier symptom management, highlighting the contributions of DPM to clinical care.
Support for third-party writing assistance for this abstract, furnished by Katie Wilson, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
O.O. Schmalz: Advisory / Consultancy, Payment planned: F. Hoffmann-La Roche Ltd; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. C. Jacob: Advisory / Consultancy, External consultant to lead the study design, data analysis, and reporting: F. Hoffmann-La Roche Ltd; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. J. Ammann: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche Ltd; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. B. Liss: Advisory / Consultancy, Payment planned: F. Hoffmann-La Roche Ltd; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. S. Iivanainen: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Lecture: Boehringer Ingelheim; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Kaiku Health; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. M. Kammermann: Full / Part-time employment, Part-time contractor: F. Hoffmann-La Roche Ltd; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. J. Koivunen: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy, Travel / Accommodation / Expenses: Faron; Advisory / Consultancy, Travel / Accommodation / Expenses: Kaiku Health; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. M. Giger: Honoraria (self): F. Hoffmann-La Roche Ltd; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd. A. Klein: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche Ltd; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche. R.A. Popescu: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Vifor Pharma; Advisory / Consultancy: Nutricia; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AbbVie; Non-remunerated activity/ies, Third-party medical writing assistance, furnished by Katie Wilson, PhD, of Health Interactions: F. Hoffmann-La Roche Ltd.
Immune checkpoint inhibitors (ICIs) in patients with pretreated advanced NSCLC (aNSCLC) showed an overall survival (OS) benefit over standard chemotherapy in phase III randomized clinical trials (RCTs). Nevertheless, a significant portion of patients do not benefit from ICIs. The identification of biomarkers to select patients most likely to respond to ICIs is greatly needed in clinical practice. The role of baseline clinical and blood biomarkers as prognostic of response to ICIs was investigated in patients with aNSCLC and a prognostic ImmunoScore is defined.
We retrospectively reviewed clinical data of aNSCLC patients consecutively treated with single agents anti PD-1 or anti PD-L1 as 2nd (81.8%) or ≥ 3rd (18.2%) line at University Hospitals of Valencia and Naples. ECOG PS, sites of metastases, neutrophil to lymphocyte ratio (NLR), LDH and albumin levels were recorded at baseline. The impact of these variables on PFS and OS was assessed through survival analyses (Kaplan Meier method), univariate (log rank test) and multivariate analyses (Cox proportional hazard model).
The analysis included 132 pts. Median PFS and OS were 3 (95% CI 2.74-3.26) and 9 (95% CI 5.90-12.02) months respectively. The univariate analysis for PFS showed that baseline NLR>4 (p = 0.001), albumin <3.5 mg/dl (p = 0.005), PS > 1 (HR 2.96, p < 0.001) and liver metastases (HR 1.72, p = 0.002) were associated with worse outcome. A trend for significance was observed for LDH >400 U/l (p = 0.089). The multivariate analysis for PFS confirmed as statistically significant independent negative prognostic factors PS > 1 (p = 0.001) and liver metastases (p = 0.011). Finally, according to PS, liver metastases, NLR and albumin three different prognostic groups at high (3-4 RF), intermediate (1-2 RF) and low (0 RF) risk for OS were defined. Median OS was respectively 5 (95% CI 3.45-6.55), 7 (95% CI 4.98-9.02) and 23 (95% CI 16.53-29.47) months (p < 0.001).
Baseline evaluation of clinical and blood biochemical parameters can be a tool to predict outcome in patients treated with ICIs for aNSCLC. Moreover, combining them in ImmunoScore may help to identify pts candidates to second or subsequent Iines of therapy who most likely will benefit from ICIs.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immune checkpoint combination therapy with nivolumab and Ipilimumab for untreated metastatic melanoma has shown higher rates of response rates, progression free survival and overall survival compared to monotherapy (Long et al. ESMO 2019), including patients with brain metàstasis, at a cost of higher toxicity. Several clinical factors had been identified as prognostic of response to immunotherapy, such as LDH, dLNR and toxicity.
We analysed all patients with melanoma treated with ipilimumab and nivolumab between March 2017 and September 2019 institution. Statistical analysis was preformed with IBM SPSS Statistics 24.0.
42 patients (p) treated with ipilimumab and nivolumab were included. 22 (52.4%) men, 38 (90%) ECOG 0-1 (%). Stages at treatment: IVA (n = 4), IVB (n = 11), IVC (n = 17), IVD (n = 9). 20p (48%) presented a positive BRAF mutation. 10p (24%) had a previous adjuvant treatment. LDH: N (n = 25, 60%), <1.2xULN (n = 7, 16%), >1.2xULN (n = 10, 24%). Cycles completed: 1 (n = 4), 2 (n = 16), 3 (n = 7), 4 (n = 12). Best Overall Response (BOR): Progressive disease (n = 22, 52%), stable disease (n = 4, 10%), partial response (n = 10, 24%), complete response (n = 6, 14%). Immunorelated adverse events (irAEs): Yes (n = 27, 64,3%), no (n = 15, 35,7%). Hepatitis 15, colitis 5, hypophysitis 5, thyroiditis 1, Nephritis 1. Grades: 1 (n = 2), 2 (n = 14), 3 (n = 8), 4 (n = 3), Number of CNS lesions: 1 (n = 0), 2 (n = 2), 3 (n = 0) and >3 (n = 8). 9 patients presented CNS disease, 4 of them had symptoms requiring steroid treatment. OS from the whole population was 34.7 months (m) (22.6-46.8, IC 95%). Independent predictors of OS where ECOG (p = 0.1, IC 95%), no previous treatment (p = 0.07, IC 95%), LDH (p = 0.02, IC 95%), irAES (p = 0.05), No 25.6m (8,9-42,4), Yes 39.1m (26.1-52.2), IC 95%). BRAF status, cycles, number of extracranial lesions, number of intracranial lesions and dNLR were not found to be predictors of OS. A significant association was found between BOR and irAEs (p = 0.009), LDH (p = 0.018), ECOG (p = 0.027).
In our cohort, LDH, ECOG and irAEs and no previous treatment were found predictors of response and overall survival. Our median OS and ORR were slighly slower than reported in trials.
The authors.
Has not received any funding.
A.M. Arance Fernandez: Honoraria (self): Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Nivolumab and pembrolizumab have been covered in South Korea for mNSCLC as 2nd line or subsequent for PD-L1 expression more than 10% and 50% respectively. The lack of robust evidence makes it challenged for HIRA to identify to which extent benefit standard could be taken as the best to ensure patient access to needed medicines. In that circumstance drug authorizations have been added and HIRA need evidence for expanding reimbursement.
This study is to investigate nivolumab, pembrolizumab efficacy and possible side effects for mNSCLC patients. Efficacy and adverse event data were collected through patient medical chart trying to find factors for patients have better efficacy and survical results.
In total, 1018 out of 1181 patients got response rate and the rest 163 patients couldn't. 1181 patients, No. of treatment was 10.5 and 7.9 for nivolumab and pembrolizumab separately and Duration of treatment (DOT) was 99.9 and 88.9 days. 1018 patients who could get RR, No. of treatment was 9.9 and DOT was 168.7 days. For 163 patients who could not get RR, No. of treatment was 1.4 and DOT was 8.0 days. For 1018 patients, objective RR was 33.6%. Considering 156 of 163 patients died (133 died within 90 days), almost of 163 might be no response. When it comes to considering all patients include 163 patients, RR could be 29%. 163 had differences comparing all patients. They were older (69 vs. 67), had poor performance status (ECOG 2 or more 29% vs. 11%) and liver meta (22.7% vs. 11.8%) and were poor RR of previous therapy. Factors associated with response were Smoking (+), Previous RT (-), irAE(+) and PD-L1 over 50%(+), for OS were PS(+), EGFR(-), Previous RT(-) and irAE(+) and for PFS were stage(-), EGFR(-), Previous RT(-) and irAE(+).
This study's clinical benefit and toxicity for mNSCLC were comparable to those of clinical trials, although population tended to be more heavily treated and have poorer performance status. A favorable outcome could be expected in patients accompanying irAE during immunotherapy and unfavorable in patients who got previous RT. Reimbursement's PD-L1 criteria might be rational according to this study but need further study and analysis.
HIRA.
Has not received any funding.
The author has declared no conflicts of interest.
The enzyme arginase-1 (ARG1) plays a role in immune regulation through the degradation of the amino acid L-arginine. A depletion of L-arginine suppresses T cell function. ARG1-producing cells in the tumor microenvironment thereby inhibit L-arginine-dependent T cell-mediated anti-tumor effects. ARG1-specific anti-regulatory T cells (anti-Tregs) have been identified in cancer patients and healthy donors. We hypothesize that the ARG1 peptide vaccine will activate and stimulate ARG1-specific anti-Tregs to proliferate and infiltrate the otherwise immunosuppressive tumor microenvironment.
The aim of the study is to assess the safety and immunomodulatory characteristics of an ARG1 peptide vaccine in patients with metastatic solid tumors.
In this clinical phase I trial we aim to treat ten patients with metastatic solid tumors following the treatment with standard of care agents. The ARG1 peptide vaccines will be administered subcutaneously every third week for 45 weeks. The primary endpoint is to evaluate safety and toxicity. Immune responses will be assessed using blood- and tumor tissue samples. Clinical responses are evaluated using RECIST 1.1.
Eudra CT no: 2018-000719-26
One third of patients with (R/M SCCHN) are not eligible to receive the standard first-line chemotherapy EXTREME (cisplatin, fluorouracile and cetuximab). In this population, the weekly scheme of carboplatin-paclitaxel demonstrated clinical efficacy an overall survival (OS) of 4.9-12.8 months and a response rate of 20-52%. In a study conducted in our center, patients ineligible to EXTREME due to performance status (PS) 2 or other reasons (excluding PS2) reached a median OS of 3.6 months and 11.5 months, respectively.
A prospective, multicenter, single-arm phase II trial to study the efficacy and safety of durvalumab (anti-PD-L1) combined with carboplatin-paclitaxel in patients with R/M SCCHN ineligible to cisplatin. A first cohort of patients (n = 64) with PS0-1 will be accrued, then a cohort of patients with PS2 (n = 38) if results of the cohort PS0-1 are positive. Patients will receive four 28-day cycles (carboplatin AUC2 and paclitaxel 80mg/m², D1, D8, D15) with 4-weekly infusions of 1500mg durvalumab (pursued for a maximum of 12 months). An initial safety run-in step with predefined stopping rules is being conducted in the first 6 patients of the cohort PS0-1. The primary objective will be to determine the efficacy (12-month OS rate) of the combination. The treatment will be considered for further investigations, if at least 38 successes and 10 successes are observed in cohorts PS0-1 and PS2, respectively. Secondary endpoints will also be investigated: progression-free survival, time-to-treatment failure, OS, response rates, quality of life (QLQ-C30 and QLQ-H&N35) and tolerance profile of the combination. Radiological endpoints will be evaluated using the RECIST version 1.1. Translational objectives will be to study blood and tumor markers (expression of immune checkpoints, immune infiltrate and molecular alterations) as predictive and prognostic factors of efficacy. As of Oct 2nd 2019, a total of 5 patients has been accrued in the safety run-in step.
NCT0372967.
Centre Léon Berard.
AstraZeneca.
J. Fayette: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Innate Pharma; Honoraria (self): Merck; Honoraria (self): Rakuten; Honoraria (self): Biogen.
Anal high-grade intraepithelial lesions (HSIL) precede the development of HPV-associated anal cancer and so present a target for early intervention and cancer prevention. Spontaneous HSIL clearance is associated with systemic CD4 T-cell response to the HPV oncogene E6. Pomalidomide may enhance immune responses to HPV and be therapeutic in HSIL.
This phase II single centre study (NCT3113942) recruited participants with persistent (>12 months) biopsy-proven anal HSIL. Therapy was oral pomalidomide, 2mg for 21 of 28 days for up to 6 months. Primary outcome was response at end therapy (CR defined as histological clearance; PR as ≥ 50% reduction in area); secondary included response after 6 further months observation. Immune activation markers (CD38, HLA DR) were assessed with flow cytometry and antigen-specific CD4+ T-cell responses to HPV E6 and E7 with OX40 immunoassay.
26 participants were enrolled, 24 were evaluable for response. All male; median age 54 (range 41-74). All AIN3 HSIL, median duration HSIL 37 months (15-86), median octants 2 (0.5-5); HPV16 in 55%; multiple high risk HPV types in 50%. Overall response (CR+PR) was 52% (CI: 31-73) at end therapy, increasing to 63% (95% CI 40-81) after 6 further months observation. Adverse events (AEs) were mild and self-limited, including cytopenias, constipation, and rash. Over 137 cycles (c), attributable grade 3/4 events were grade 3 neutropenia (4 c) and grade 3 angina (1 c). Systemic CD4 T-cell responses to HPV E6 but not E7 increased significantly during therapy, peaking day 14 of therapy: baseline 0.06%, (IQR 0.01 – 0.12%), median increase day 14 0.13% (IQR: 0.02 – 0.26%), p = 0.001. Activation of CD4 and CD8 cells increased significantly during therapy. Parameters returned to baseline after therapy.
Low dose oral pomalidomide was well tolerated and induced durable continuing clearance of anal HSIL of multiple genotypes in even in chronic extensive disease. Induction of HPV-specific CD4+ responses and immune activation support an immunological mechanism of action. Immunotherapy with pomalidomide is a promising approach to prevention of anal cancer and potentially other HPV cancers.
NCT3113942.
Kirby Institute, University of New South Wales, Sydney, Australia.
Cancer Institute of New South Wales.
All authors have declared no conflicts of interest.
Cemiplimab demonstrated antitumour activity and an acceptable safety profile in a phase II study of pts with CSCC (NCT02760498). Here, we report efficacy by PST.
The primary objective of the study is to evaluate the objective response rate (ORR) by independent central review (ICR). Pts with metastatic CSCC (mCSCC; Group 1) and locally advanced CSCC (Group 2) received 3 mg/kg Q2W for 96 weeks, and mCSCC received 350 mg Q3W for 54 weeks (Group 3). Data cutoff dates were 20 September 2018 (Groups 1 and 3) and 10 October 2018 (Group 2).
Of the 193 pts enrolled, 128 had cemiplimab as first-line therapy (1LT) and 65 had PST (table). Median follow-up was 9.4 months. The ORR per ICR was 46.9% (95% CI: 38.0–55.9; 17 complete responses [CR] and 43 partial responses [PR]) in pts with cemiplimab as 1LT and 38.5% (95% CI: 26.7–51.4; five CRs and 20 PRs) in pts with PST. The disease control rate per ICR was 75.8% (95% CI: 67.4–82.9) in pts with cemiplimab as 1LT and 64.6% (95% CI: 51.8–76.1) in pts with PST. Estimated 12-month duration of response (DOR) was 88.3% (95% CI: 73.9–95.0) among all 60-responding pts with cemiplimab as 1LT and 90.9% (95% CI: 68.1–97.6) among all 25-responding pts with PST. Estimated Kaplan–Meier 12-month progression-free survival was 56.9% (95% CI: 46.4–66.2) in pts with cemiplimab as 1LT and 46.7% (95% CI: 33.4–58.9) in pts with PST. 12-month overall survival was 90.7% (95% CI: 83.7–94.8) in pts with cemiplimab as 1LT and 76.3% (95% CI: 63.7–85.0) in pts with PST. The most common treatment-related adverse events in all pts were fatigue (n = 37, 19.2%), pruritus (n = 25, 13.0%) and diarrhoea (n = 24, 12.4%) and rash and maculopapular rash (both n = 21, 10.9%).
As demonstrated by the numerically higher ORR, 12-month PFS, and OS, the efficacy of cemiplimab in advanced CSCC may be greater when used as 1LT, supporting its early use for patients with advanced CSCC. Table: 97P Therapeutic setting, number of regimens and type of systemic therapies in pts with PSTPts with PST (N = 65) Therapeutic setting, n (%) Metastatic disease 22 (33.8) Adjuvant 10 (15.4) Neoadjuvant 4 (6.2) Chemotherapy with concurrent radiation 35 (53.8) Other 8 (12.3) Number of regimens at baseline, median (range) 1 (1–4) Type of PST, n (%) Antineoplastic agents 65 (100.0) Platinum compounds 46 (70.8) Monoclonal antibodies 18 (27.7) Pyrimidine analogues 15 (23.1) Taxanes 15 (23.1) Protein kinase inhibitors 4 (6.2) Combinations of antineoplastic agents 3 (4.6) Folic acid analogues 1 (1.5) Other antineoplastic agents 1 (1.5) Corticosteroids for systemic use 1 (1.5) Glucocorticoids 1 (1.5)
NCT02760498.
Medical writing support under the direction of the authors was provided by Kate Carolan, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc. and Sanofi according to Good Publication Practice guidelines.
Regeneron Pharmaceutical, Inc. and Sanofi.
Regeneron Pharmaceutical, Inc. and Sanofi.
D. Rischin: Research grant / Funding (institution), Non-remunerated activity/ies: Regeneron Pharmaceuticals, Inc.; Research grant / Funding (institution): Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme; Research grant / Funding (institution), Non-remunerated activity/ies: Bristol-Myers Squibb; Research grant / Funding (institution), Non-remunerated activity/ies: GSK. N.I. Khushalani: Advisory / Consultancy, Research grant / Funding (self): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): HUYA Bioscience International; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy, Data safety monitoring committee: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: ARRAY Biopharma; Advisory / Consultancy: Immunocore; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Cellgene; Research grant / Funding (self): Amgen; Honoraria (self): Sanofi; Shareholder / Stockholder / Stock options: Bellicum Pharmaceuticals; Shareholder / Stockholder / Stock options: Mazor Robotics; Shareholder / Stockholder / Stock options: Amarin; Shareholder / Stockholder / Stock options: Transenetrix. C.D. Schmults: Advisory / Consultancy, Research grant / Funding (self), Steering committee member: Castle Biosciences; Advisory / Consultancy, Research grant / Funding (self), Steering committee member: Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Sanofi; Research grant / Funding (self): Novartis; Research grant / Funding (self): Genentech; Research grant / Funding (self): Merck; Advisory / Consultancy, Chair for NCCN: NCCN. A. Guminski: Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Sun Pharma; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy: Eisai; Advisory / Consultancy: Pfizer; Non-remunerated activity/ies: Astellas; Research grant / Funding (institution), Clinical trial unit support: PPD Australia. A.L.S. Chang: Advisory / Consultancy, Research grant / Funding (self): Regeneron Pharmaceuticals, Inc.; Research grant / Funding (self): Novartis; Research grant / Funding (self): Galderma; Advisory / Consultancy, Research grant / Funding (self): Merck. K.D. Lewis: Research grant / Funding (self), Grants and personal fees: Regeneron Pharmaceuticals, Inc.. A.M. Lim: Non-remunerated activity/ies: Merck Sharp & Dohme; Travel / Accommodation / Expenses: Bristol-Myers Squibb. L. Hernandez-Aya: Advisory / Consultancy: Massive Bio; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Regeneron Pharmaceuticals, Inc.; Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (self): Immunocore; Research grant / Funding (self): Merck Sharp & Dohme; Research grant / Funding (self): Polynoma; Research grant / Funding (self): Corvus Pharmaceuticals; Research grant / Funding (self): Roche; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Amgen; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Takeda. B.G.M. Hughes: Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Research grant / Funding (institution): Amgen. D. Schadendorf: Research grant / Funding (institution): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Amgen; Advisory / Consultancy: Leo Pharma; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Merck-EMD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Incyte; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution), Patients’ fees: MSD; Advisory / Consultancy, Steering committee honorarium: 4SC; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array; Advisory / Consultancy, Research grant / Funding (institution), Patients’ fees: Philiogen. A. Hauschild: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD/Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Provectus; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Philogen; Advisory / Consultancy, Research grant / Funding (institution): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: OncoSec. E. Stankevich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. J. Booth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. S. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. Z. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. J. Desai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. I. Lowy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. M.G. Fury: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. M.R. Migden: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Regeneron Pharmaceuticals, Inc.; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Travel / Accommodation / Expenses: Sun Pharma.
An ongoing open-label, multiarm, multicenter, phase I study of the anti–CTLA-4 antibody MK-1308 in combination with pembrolizumab in advanced solid tumors (NCT03179436) revealed manageable safety and promising efficacy in patients (pts) with advanced non-small cell lung cancer receiving first-line therapy [Perets et al. J Clin Oncol. 2019;37(suppl):2558]. Here we report data from the small cell lung cancer (SCLC) cohort of this study.
In the dose confirmation phase, pts with advanced SCLC received MK-1308 at 75 mg Q6W + pembrolizumab 200 mg Q3W (up to 35 cycles). The primary end point was safety, and the secondary end point was ORR based on blinded independent central review (BICR) per RECIST v1.1. PFS based on BICR per RECIST v1.1 and OS were exploratory end points. The database cutoff date for this analysis was June 3, 2019.
Forty pts with previously treated advanced SCLC (second-line or beyond) were enrolled and dosed; median duration of follow-up was 11 mo. At data cutoff, 32 pts (80%) discontinued study treatment—23 (58%) due to progressive disease, 4 (10%) due to AE, 2 (5.0%) due to clinical progression—and 3 (7.5%) withdrew consent. Median age was 66 years; 60% of pts were male and 65% had ECOG PS 1 at baseline. Seven pts achieved partial response according to BICR assessment, for an ORR of 18% (95% CI, 7.3-33). Eight pts (20%) had a best overall response of stable disease and 21 (53%) had progressive disease. Response duration ranged from 2.9 to 8.4+ mo. At the time of the data cutoff, 5 of 7 responses (71%) were ongoing. Median time to response was 2.1 mo (range, 1.1-12). Median PFS was 2.0 mo (95% CI, 1.9-3.9), and the 6-mo PFS rate was 26%. Median OS was 11 mo (95% CI, 5.9-not reached), and the 6-mo OS rate was 66%. Treatment-related adverse events (TRAEs) as determined by the investigator occurred in 32 pts (80%). Grade 3 TRAEs were reported in 11 pts (28%); no grade 4-5 events were reported. Three pts (7.5%) discontinued treatment due to TRAEs.
In heavily pretreated pts with SCLC, MK-1308 + pembrolizumab was generally well tolerated with encouraging antitumor activity.
NCT03179436.
Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): MOGAM Institute; Honoraria (self), Research grant / Funding (self): Dong-A ST; Honoraria (self), Research grant / Funding (self), Licensing / Royalties: Champions Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Yuhan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Research grant / Funding (self): Dizal Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics; Shareholder / Stockholder / Stock options: Gencurix Inc. K. Yoh: Research grant / Funding (institution): MSD. J. Bar: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: OncoHost; Advisory / Consultancy: VBL; Research grant / Funding (institution): Pfizer. A. Nagrial: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Incyte. D.R. Spigel: Leadership role: Centennial Medical Center; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Boehringer-Ingelheim; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Genentech; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. M. Gutierrez: Shareholder / Stockholder / Stock options: COTA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Esanex; Advisory / Consultancy: Guardant 360; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Foundation Medicine. D-W. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. D. Rasco: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron. M. Satouchi: Honoraria (self), Research grant / Funding (institution): MSD. M-J. Ahn: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy: Alpha Pharm. D.H. Lee: Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): ChongKunDang; Honoraria (self): CJ Healthcare; Honoraria (self): Eli Lilly; Honoraria (self): Janssen; Honoraria (self): Menarini; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Samyang Biopharm; Honoraria (self), Advisory / Consultancy: ST Cube; Honoraria (self): Takeda. C. Maurice-Dror: Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche. S. Siddiqi: Full / Part-time employment: Merck & Co., Inc.. X. Li: Full / Part-time employment: Merck & Co., Inc.. J. Cyrus: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R.A. Altura: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R. Perets: Advisory / Consultancy: Karyopharm; Advisory / Consultancy: BiolineRx. All other authors have declared no conflicts of interest.
Anti-tumor immunity is critically regulated by immune checkpoints such as TIM-3, PD-1 or TIGIT. Notwithstanding the remarkable success of the antibody-mediated immune checkpoint blockade in the clinics, many key immune receptors remain orphan or poorly characterized, hindering the development of novel therapeutics. This is partially due to technical challenges associated with the study of membrane-expressed proteins and identification of receptor binding partners. Here, we present a new technology for receptor-ligand discovery, which we apply to investigate interactions established by key inhibitory immune receptors.
A new platform was developed for high sensitivity receptor-ligand discovery in high throughput, the Conditioned Media Alpha Screen. Using this method, prominent immune receptors were screened for binding to a library consisting of ≈1,200 single transmembrane proteins in the human genome. The new interactions were confirmed using biophysical and cell-based methods for functional characterization of select receptor-ligand pairs.
Using this technology Interleukin-20 receptor subunit alpha (IL20RA) was identified as the first counter-receptor for B7-H3. Furthermore, the natural killer cell receptor KIR2DL5A is identified as a new binding partner for PVR, an interaction that is fully validated using orthogonal methods and cellular assays. Here we show that KIR2DL5A engagement by PVR expressed on tumor cells results in reduced natural killer cell cytotoxicity. PVR deletion or treatment with an anti-KIR2DL5A antibody restored NK-mediated cytolysis of tumor cells. Additionally, competition assays show that PVR interacts with both TIGIT and KIR2DL5A on the cell surface, suggesting a previously unrecognized mechanism of action.
Here we developed a new platform for elucidation of secreted or membrane protein interactomes. The power of this technology is demonstrated by identification of new interactors for emerging therapeutic targets such as PVR or B7-H3. These results provide insights into immune receptor biology and highlight potential new cellular targets, ultimately serving as a unique tool to inform therapeutic development.
The authors.
Genentech Inc.
All authors have declared no conflicts of interest.
BO-112 is a dsRNA (poly I:C) formulated with polyethylenimine, that upon Intratumoral (IT) injection acts by activating TLR3, RIG-1 and MDA-5. This induces immunogenic cell death and potentiate systemic therapy with checkpoint inhibitors in animal models. In patients (pts), single-agent BO-112 IT increases necrosis, apoptosis and expression of pro-immune genes in solid cancers, with a manageable safety. 1 mg was the dose combined with anti-PD-1 in the current clinical trial (NCT02828098).
BO-112 was combined with anti PD-1 in 28 pts with solid tumors primarily resistant to anti PD-1 (nivolumab or pembrolizumab). A lesion >1 cm amenable to IT injection was required. 28 pts were treated with 1 mg IT BO-112 qw x 2 or 3 doses before continuing the previous anti PD-1 combined with BO-112, until progression, limiting toxicity or up to 1y. Pre & post BO-112 biopsies from injected lesion were analysed. Response was first assessed by RECIST 1.1 at week 8-12.
BO-112 related AEs and biological effects at interim analysis are summarized in the table. The combination was well tolerated. No deaths were associated with BO-112. Of 18 evaluable pts for response, at first assessment: 2 have achieved an objective partial response (PR) (1 melanoma and 1 renal carcinoma), with 1 of them continuing treatment; 11 patients had stable disease (SD); 5 patients progressed (PD). Additionally 6 patients progressed prior to the first evaluation, 3 died before efficacy assessments and 1 received palliative radiotherapy and was considered not evaluable. Table: 100PAll G3-5 TEAEs (%) G3-4 BO-112 related TEAEs (%) Necrosis (D > 5%) (%)* CD8+ T cell infiltrate (D > 5%) (%)* *evaluable All N = 28 18 (64) 1 (4) 10 (50) 7 (35) Melanoma N = 10 7 (70) 0 5 (56) 4 (44) Non-Small lung cancer N = 13 8 (62) 1 (8) 3 (38) 1 (13) Other N = 5 3 (60) 0 2 (67) 2 (67)
BO-112 combined with anti PD-1 shows a manageable safety profile, direct antitumor effects and innate and adaptive immune system activation. Efficacy analyses suggest potential to reverse primary resistance to anti-PD1 treatment. Studies in other indications, including combination with radiotherapy, are planned.
NCT02828098.
none
Bioncotech Therapeutics.
Bioncotech Therapeutics.
I. Marquez-Rodas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bioncotech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Regeneron; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Non-remunerated activity/ies: Biosequence; Research grant / Funding (institution): Idera. P. Lopez-Casas: Full / Part-time employment: Bioncotech. M. Martin: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Tahio; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Daiichi. D. Tersago: Full / Part-time employment: Bioncotech. M. Quintero: Full / Part-time employment, Officer / Board of Directors: Bioncotech. I. Melero: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Alligator; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: Tusk; Advisory / Consultancy: Numab; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: F Star; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.
We conducted a phase Ib dose-confirmation study of indoximod with radiation, followed by indoximod with cyclic temozolomide therapy, to evaluate safety and overall survival (OS) in children with newly diagnosed DIPG (diffuse intrinsic pontine glioma). Indoximod is a small-molecule inhibitor of the IDO pathway that reverses immune suppression imposed by tumor microenvironments. DIPG is a uniformly fatal orphan disease with no curative treatment options.
Children age 3 to 21 years, with newly diagnosed DIPG were eligible for treatment with oral indoximod (38.4 mg/kg/day divided BID, throughout) combined with fractionated conformal radiation therapy (54 Gy in 30 fractions), followed by cyclic oral chemo-immunotherapy using indoximod combined with temozolomide (200 mg/m2/day, days 1-5 of each 28-day cycle). The indoximod dose was the previously determined recommended phase-II dose (RP2D), and the study design called for phase I monitoring to confirm safety of this dose in DIPG patients.
Thirteen children (median age 9 years, range 5 to 20 years) with newly diagnosed DIPG were treated using this indoximod-based radio-chemo-immunotherapy regimen. The 12-month OS was 62% (8/13) and estimated median OS was 14.5 months (follow-up range 4.8 to 22 months) with 4 patients remaining in follow-up. This compares favorably to the expected 12-month OS of approximately 45% and median OS of approximately 10.8 months from published historical controls (Kilburn, et al; 2017). Two patients experienced near-complete responses until showing relapse at 7.6 months and 13.3 months of study therapy. Patients were followed with quantitative volumetric analyses of MRIs and serial measurements of peripheral blood inflammatory monocytes, T cell activation, and pro-inflammatory cytokines. The most common adverse events attributed to indoximod were thrombocytopenia, diarrhea, nausea, vomiting, and fatigue.
Adding indoximod-based immunotherapy to conventional radiation and chemotherapy for up-front therapy of children with DIPG appears to be well tolerated with improved outcomes.
NLG2105, NCT02502708.
NewLink Genetics Corporation.
NewLink Genetics Corporation, Alex\'s Lemonade Stand Foundation, Cannonball Kids cancer Foundation, Beloco Foundation, Eli’s Block Party Foundation, Hyundai Hope on Wheels Foundation, Northern Nevada Children’s Cancer Research Foundation, CAM Fund, Press On Foundation.
T.S. Johnson: Research grant / Funding (institution): NewLink Genetics Corporation. E.P. Kennedy: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. N. Vahanian: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. D.H. Munn: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: NewLink Genetics Corporation. All other authors have declared no conflicts of interest.
This trial is based on a combination strategy with two immunostimulatory agents in the search of synergism that may induce responses with long-term clinical benefit in ABC pts. Safety data from the run-in-phase were published in ESMO IO 2018. Here, we report the results from the phase II part of the study.
HER2-negative ABC pts previously treated with anthracyclines and taxanes (unless contraindicated), ≤ 4 chemotherapy lines and/or ≥ 2 hormone therapy lines, and irrespective of PD-L1 status, were eligible. Study treatment consisted of 21-day cycles (cy) of P 200mg on day 1 and Gem 1250mg/m2 on days 1 and 8 until progressive disease (PD) or unacceptable toxicity, whatever occurred first. Primary objective was Objective Response Rate (ORR).
Thirty-six pts were included in the first stage of a Simon’s design. Recruitment was stopped as only 5 pts presented an objective response (partial) (≥ 7 responses needed to continue recruiting pts). Median age was 52 years (range 31-77), 21 pts had triple negative disease, the majority of pts had an ECOG performance status ≤ 1 (n = 35), visceral involvement (n = 28) and ≥ 2 metastatic locations (n = 27). Median number of prior lines (any therapy) for ABC was 4 (range 0-11). Pts received a median of 4.5 cy of Gem and 4 cy of P (same range for both drugs, 1-24). The median relative dose intensity of P and Gem was 100% and 80%, respectively. Treatment discontinuation due to PD was reported on 29 pts. The ORR was 15.2% (95% confidence interval (CI) 5.1-31.9) and the Clinical Benefit Rate was 17% (95% CI 33.5-69.2); median duration of objective response was 4.3 months (mo) (95% CI 2.3-7.4), median Progression-Free Survival was 3.1 mo (95% CI, 2-4.3), and median Overall Survival was 7.9 mo (95% CI 6.5-10.3). Eight pts were on treatment ≥ 6 mo before PD (2 pts on 11.4 and 16.1 mo). Grade (G) ≥ 3 AEs related to the study treatment were reported on 14 pts (39%), being neutropenia the most common G3 (22.2%) and G4 (5.6%) AE.
P can be safely combined with Gem, the combination did not meet the efficacy objective in terms of ORR but 22.2% pts were on treatment ≥ 6 mo.
NCT03025880.
GEICAM Spanish Breast Cancer Group.
MSD.
J. Cruz: Honoraria (self), Advisory / Consultancy: Glaxo; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. M. Ramos Vazquez: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. J. Cortés: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Celgene; Advisory / Consultancy: Cellestia; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biothera Pharmaceutical; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Advisory / Consultancy: Polyphor; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Advisory / Consultancy: GSK; Honoraria (self): Novartis; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (institution), MedSIR (Stock, patent and intellectual property): Ariad Pharmaceuticals. Baxalta GMBH/Servier Affaires. Bayer Healthcare. Guardanth Health. Piqur Therapeutics. Puma C. Queen Mary University of London. Seagen. All other authors have declared no conflicts of interest.
Combinatorial therapy including the immunotherapy is revolutionizing the effective treatment of cancer. It achieved unprecedented responses in advanced-stage patients, including complete cures and long-term survival. However, immunotherapy also has limitations, such as its relatively low response rates and the development of severe side effects. These drawbacks are gradually being overcome by improving our understanding of the immune system, as well as by establishing combination regimens in which immunotherapy is combined with other treatment modalities.
Herein, we report the method of coassembly of two structurally defined materials, each comprised of photothermal agent and a small molecule immunostimulant molecularly self-assembled. One organic polymer has excellent photothermal properties; the other one has designed for efficient immmune activation, contributing to superior stability during circulation.
The coassembled nanoparticles (NPs) possesses superior photothermal conversion efficiency as well as efficient encapsulation and controlled release of cytotoxic molecules and immunomodulatory agents. NPs loaded with immunostimulant has proven to be a highly efficacious combination photothermal/immunotherapeutic nanoplatform against Triple Negative Bresat Cancer xenograft model. When loaded with imiquimod, a potent small molecule immunostimulant, NPs is found to be highly effective against breast cancer model, particularly when photothermal/immuno-therapy is given. Such dual therapy not only eradicates the light-irradiated primary tumours, but also activates systemic antitumor immunoactivity, causing tumour death at light-unexposed distant tumour sites.
In conclusion, this “photothermal immunotherapy” approach, photothermal ablation of tumour cell death reduces tumour growth and releases tumour antigens into the surrounding milieu, while the immunoadjuvants potentiate host antitumor immunity. Our results indicated that combined photothermal immunotherapy is more effective than either immunotherapy or photothermal therapy alone against primary treated and distant untreated tumours in a mouse breast cancer model.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Triple Negative Breast cancer (TNBC) is a complex challenging disease that is not amenable to conventional treatment. Our research group has recently portrayed hydrogen sulphide (H2S) and its synthesizing enzymes, cystathionine β-synthase (CBS) and cystathionine-γ-lyase (CSE), as potent oncogenic mediators for TNBC progression. Recently, H2S has been casted as a potential modulator of cancer immune surveillance as well. Yet, the impact of H2S on the immunological profile of TNBC cells has never been investigated. Natural Killer (NK) cells are the native sentinels of the immune system that plays an indisputable role in TNBC-immune surveillance. TNBC immune suppressive tumour microenvironment is also rate-limiting step when immunotherapeutic approaches are tackled in case of TNBC patients. Thus the main aim of this study is to identify the role of endogenous H2S on NK cells' activating ligands present on TNBC cells, immune suppressive tumour microenvironment and net effect on NK cells cytotoxicity.
Breast tissues were collected from 80 BC patients. ER, PR, HER-2 and Ki-67 levels were quantified using immunohistochemistry. MDA-MB-231 and MCF7 cells were cultured and transfected with different oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. IFN-γ and TNF-α in cellular supernatant was measured using representative ELISA kits. NK cells were isolated from 30 healthy controls. The cytotoxicity of NK cells was measured using LDH Cytotoxicity Assay.
MICA, MICB and ULBP2 were significantly down-regulated in TNBC tissues and cell lines. Knocking down of CBS and CSE using siRNAs resulted in a marked increase in MICA/B and ULBP2 expression in MDA-MB-231 cells. Nonetheless, knocking down of CBS and CSE resulted in a marked induction in IFN-γ production and attenuation of TNF-α levels. Upon co-culturing with healthy NK cells, Knocking down of endogenous H2S resulted in a marked increase in NK cells cytotoxicity.
This study showed that knocking down of CBS and CSE resulted in a improving NK cells cytotoxicity and alleviating tumor-induced immune suppressive microenvironment in TNBC patients.
German University in Cairo.
Has not received any funding.
All authors have declared no conflicts of interest.
The antibody-based cancer immunotherapies targeting the Programmed cell Death1-Programmed Cell Death Ligand 1 (PD1-PDL1) interaction have shown unprecedented clinical success again several types of cancer. Our present study aims to discover small molecule PD1-PDL1 inhibitors that may offer several advantages as compared to antibodies, such as higher oral bioavailability, lower cost, better tumor infiltration, and relatively shorter half-life that is especially helpful in controlling any potential adverse immune reactions.
We identified several small molecule inhibitors based on the available crystal structures of human PD1-PDL1 complex as well as apo forms of PD1 and PDL1. Specifically, we first carried out long molecular dynamics simulations to identify “druggable” binding pockets on the binding interfaces of PD1 and PDL1 proteins, followed by molecular docking and consensus-scoring of approved and experimental drugs into those pockets. The top virtually selected compounds were then tested in AlphaLISA and ELISA assays measuring inhibition of the PD1-PDL1 interaction, followed by functional cell-based assays.
Through integrated virtual and experimental screening protocols, we have identified several potent PD1-PDL1 inhibitors with remarkable activities in both the cell-free and cell-based assays. Notably, one of our top active molecules showed activity as comparable to that of the anti-PD1 antibody used as the positive control in these studies. This is remarkable considering the newly-discovered molecules have relatively low molecular weight and still are capable of inhibiting PD1-PDL1 protein-protein interaction with large binding interface of ∼1,970 Å2. Our results provide support for future investigation of these molecules in vivo.
In summary, we have been successful in identifying novel, non-peptide small molecule inhibitors of PD1-PDL1 interaction through rational design. Considering their remarkable activity and clinical status, they may present immediate clinical potential against cancers expressing PDL1. They may also prove to be ideal starting points for the design of more potent, selective drug-like inhibitors of PD1-PDL1 interaction.
Widener University, Chester, PA, USA.
W. W. Smith Charitable Trust.
All authors have declared no conflicts of interest.
Glioblastoma multiforme (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Immunotherapy with chimeric antigen receptor (CAR) T cells is gaining attention as a promising strategy to treat this disease. An ideal candidate to target with CAR T cells is the tumor specific variant III of the epidermal growth factor receptor (EGFRvIII), which represents a mutation found in more than 30% of glioblastoma patients. However, anti-EGFRvIII-CAR modified T cell therapy has shown only limited effects in GBM patients, in all likelihood due to the immunosuppressive microenvironment that CAR T cells encounter in the tumor microenvironment (TME) of gliomas. To make gliomas susceptible to CAR T cell therapy, combinatorial approaches to convert the TME are required.
Mice received 5Gy TBI on day 15 post implantation, followed by intra-tumoral injection of IL-12:Fc on day 20 and infusion of EGFRvIII-directed CAR or non-transduced T cells on day 21. To perform functional analysis, we adopted high-parametric flow-cytometric characterization of the TME using 23 independent parameters 8 days after CAR T cells injection. We utilized unsupervised validated clustering approaches (FlowSOM and CellCNN) to discriminate between different cell populations.
Here, we demonstrate that the combination of a single dose of local IL-12 with anti-EGFRvIII-CAR T cells synergizes to increase long-term survival in a syngeneic mouse model of GBM. IL-12 not only boosted the pro-inflammatory and cytotoxic activity of anti-EGFRvIII-CAR T cells, but also induced a complete remodelling of the tumor microenvironment (TME) with strong endogenous anti-tumor immune T cell responses. These findings highlight the capacity of IL-12 to induce an immunologically “cold” tumor such as GMB to acquire responsiveness to CAR T cells therapy.
This study demonstrates the capacity of IL-12 as local “adjuvant” therapy to boost the efficacy of CAR T cells and to awake the endogenous anti-tumor T cell responses.
University of Zurich.
University Research Priority Project and Advanced T-cell Engineered for Cancer Therapy.
M. Pule: Honoraria (self), Honoraria (institution): Autolus LTD. All other authors have declared no conflicts of interest.
During the last decade, a revived enthusiasm about T-cell related therapies emerged after promising clinical outcomes. Nevertheless, many patients (especially with solid tumours) still do not have adequate therapeutic options. The complexity of the tumour microenvironment is a likely factor acting in detriment of many of those therapies by multiple suppressive mechanisms. To tackle a complex mechanism, an oncolytic adenovirus 2 (Ad5/3-E2F-d24-hTNFa-IRES-hIL2, a.k.a. TILT-123) was engineered to enable T-cell therapies in those circumstances.
To study the efficacy of TILT-123 together with different T-cell related therapies (adoptive cell transfer, checkpoint inhibitors and CAR T cell therapy) different models were used including mouse, Syrian Hamster and patient derived in vivo models for different indications were tested.
Antitumor efficacy analyses showed complete responses in all animals receiving a T-cell therapy or checkpoint inihibitor (aPD1 or aPDL-1) and the T-cell enabling virus. Further, other aspects such as safety, influence on different immune populations, abscopal effect, antitumor memory and ability to replace lympho-depleting chemotherapy and postconditioning with high-dose IL-2 treatment were studied.
The use of TILT-123 to enable T-cell therapies (including checkpoint-inhibiting antibodies) delivered encouraging preclinical results pointing to it as a valuable approach to increase the number of patients that benefit from T-cell therapies. Those results include not only cell based therapies but also checkpoint inhibitors, a kind of therapy that is making the difference in the field and becoming first-line treatment for an increasing number of indications. Because of the favourable preclinical studies, the first in human clinical trials with TILT-123 will start in the upcoming months.
The authors.
TILT Biotherapeutics.
V. Cervera-Carrascon: Full / Part-time employment: TILT Biotherapeutics. R. Havunen: Full / Part-time employment: TILT Biotherapeutics. J.M. Santos: Full / Part-time employment: TILT Biotherapeutics. A. Hemminki: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TILT Biotherapeutics. All other authors have declared no conflicts of interest.
Extracellular phosphatidylserine (PS) is a potent modulator of immune responses. In addition to exposure during apoptosis, PS is observed on activated platelets, leukocytes, endothelial cells, tumor cells, and exosomes. While PS exposed during apoptosis is known to suppresses inflammatory responses in phagocytic cells, whether either form of exposed PS acts directly on T lymphocytes has not been extensively studied.
HEK293 cells expressing GPR174 and GloSensor were used to detect GPR174 agonism. Immune cells were stimulated with anti-CD3/CD28 with GPCR inhibitors, NECA, or PS liposomes; and cytokines in media were measured. WT or GPR174-KO mice inoculated with syngeneic tumor cells and treated with anti-GITR (DTA-1) were evaluated for tumor growth.
Here we show that PS suppresses T cells through GPR174, a Gαs-coupled GPCR. PS liposomes were more potent than lyso-PS in stimulating GPR174, and PS exposed on various cell types agonized GPR174. Several GPR174 inhibitors of different chemical classes were identified. PS liposomes attenuated Th1 cytokine production from human T cells and WT but not GPR174-KO mouse T cells, and GPR174 inhibitors reversed this suppression. Th1 cytokines were increased by GPR174 inhibition in the presence of tumor exosomes. GPR174 inhibition or genetic deletion also reduced CTLA-4 expression, an immune checkpoint known to be induced by cAMP. Compared to WT mice, GPR174-KO mice significantly controlled tumor growth when Treg were transiently depleted with anti-GITR. GPR174 is similar to A2A/B adenosine receptors in that both suppress Th1 immunity through cAMP in response to products of cell stress and death abundant in the tumor microenvironment. Inhibition of GPR174 and A2A/B synergistically increased cytokine production, GPR174 and A2A/B agonists suppressed T cells to the same extent as both combined, and A2A/B inhibition was more effective on GPR174-KO T cells vs. WT T cells.
Our findings suggest that for T cells to effectively overcome cAMP-mediated immunosuppression in the tumor microenvironment, both GPR174 and the adenosine pathway must be inhibited.
Omeros Corporation.
Omeros Corporation.
M.A. Gavin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. A. Gragerov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. E. Espling: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. A. Rohde: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. T. Sexton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. C. Doulami: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation. G. Gaitanaris: Shareholder / Stockholder / Stock options, Full / Part-time employment: Omeros Corporation.
FimaVacc is a vaccine formulated by the photosensitising compound fimaporfin and a toll-like receptor (TLR) agonist, and is administered intradermally followed by illumination of the vaccination site. In preclinical studies, fimaVacc has been shown to improve MHC class I antigen presentation, resulting in strongly enhanced cytotoxic and helper T-cell responses to various types of peptide and protein vaccines.
A phase I clinical study with fimaVacc has been performed in healthy volunteers to study the safety and immunogenicity of this novel vaccine. The subjects were vaccinated with HPV16 E7 peptides and Keyhole Limpet Hemocyanin (KLH) protein, serving as model antigens for peptide- and protein-based vaccines. Both antigens were formulated with fimaporfin and the TLR3 agonist poly-ICLC (Hiltonol) and administered in up to three vaccinations. Local and systemic adverse effects were assessed for safety, and cellular and humoral immune responses were analysed by ELISPOT, flow cytometry and ELISA assays to determine the immunogenicity of fimaVacc.
The principle of the fimaVacc technology will be presented, together with preclinical results showing that fimaVacc strongly enhances both cellular and humoral immune responses and improves anti-tumour effects in mouse models. The clinical study showed that intradermal vaccination with fimaVacc was well tolerated, with no systemic side effects and generally only mild local reactions. Elispot analysis showed that fimaVacc can significantly increase the number of healthy donors displaying a T-cell response to HPV peptide vaccination. Furthermore, Elispot and flow cytometry analyses demonstrated an enhancement of both HPV-specific CD4+ and CD8+ T cells upon fimaVacc treatment.
The photochemically based fimaVacc vaccination technology can be applied safely in humans, and enhances T-cell responses to an HPV peptide vaccine over what is achieved in a control group which received antigen + adjuvant without fimaVacc.
NCT02947854.
PCI Biotech AS.
PCI Biotech AS.
S. Janetzki: Advisory / Consultancy: PCI Biotech AS. V.T. Edwards: Full / Part-time employment: PCI Biotech AS. H. Olivecrona: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: PCI Biotech AS. S.H. van der Burg: Advisory / Consultancy: PCI Biotech AS. T. Otterhaug: Shareholder / Stockholder / Stock options, Full / Part-time employment: PCI Biotech AS. A. Hogset: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: PCI Biotech AS. All other authors have declared no conflicts of interest.
The majority of neoantigens arise from unique mutations which are not shared between individual patients. Thus, neoantigen-directed immunotherapy is a fully personalized treatment. Novel technical advances in next-generation sequencing and artificial intelligence (AI) allow fast and systematic prediction of cancer neoantigens for each individual patient. In this study, the proprietary AI platform PIONEERTM is used for fast and accurate identification of tumor-derived neoantigens to be included in an immunotherapy (NeoPepVac), tailored to each individual patient. NeoPepVac immunotherapy, consisting of 5-15 predicted neoantigens as synthetic peptides, is formulated with a novel cationic liposomal adjuvant (CAF09b) to strengthen CD8+ T-cell immunity towards cancer. Immune checkpoint inhibitors, targeting PD-1 or PD-L1, are administered before, during and after neoantigen-targeted immunotherapy to augment the activity of induced immune responses.
The study is designed as an open phase I/IIa trial. Patients with either unresectable or metastatic melanoma, non-small cell lung cancer (NSCLC) or bladder (urothelial) cancer who meet the criteria for treatment with anti-PD-1 or anti-PD-L1 are included. The NeoPepVac immunotherapy is given every second week, for a total of 6 immunizations. Blood samples are collected before, during and after NeoPepVac treatment to monitor the induction of a neoantigen-specific immune response and immune-related changes.
Four patients have been included and treated with personalized NeoPepVac immunotherapy. So far, only CTCAE Grade 1 mild flu-like symptoms have been observed as NeoPepVac-related AEs at the first dose level (500 mg total peptide). At least 50% of the neoantigens are generating a specific T-cell response as determined by IFN-γ ELISPOT analyses of patient PBMCs.
So far the vaccine is well tolerated and safe. Neoantigen prediction and immunotherapy manufacturing is feasible within 6 weeks of patient enrolment using the PIONEERTM platform. Preliminary analyses indicate induction of NeoPepVac-specific immune responses.
EudraCT: 2018-002892-16.
Inge Marie Svane.
Innovations fonden.
J.V. Kringelum: Full / Part-time employment, PhD, Director, Genomic Immuno-Oncology: Evaxion. T. Bogenrieder: Full / Part-time employment, CMO at Evaxion: Evaxion. B. Rønø: Full / Part-time employment, PhD, Director, Cancer Vaccines: Evaxion. A.B. Sorensen: Full / Part-time employment, Project Manager, Personalized Immuno-oncology: Evaxion. N.V. Petersen: Full / Part-time employment: Evaxion. L.V. Andreasen: Leadership role: SSI. D. Christensen: Leadership role, Full / Part-time employment: SSI. P.L. Andersen: Leadership role, Full / Part-time employment: SSI. All other authors have declared no conflicts of interest.
Immune checkpoint inhibitors offer the prospect of long term disease control in solid tumor types. NY-ESO-1 is a cancer-testis antigen expressed by 20% of advanced gastric cancers, known to induce humoral and cellular immune responses. Combination of anti-PD-1 with radiotherapy is currently investigated. Radiotherapy has the ability to promote immunogenic cell death leading to the release of tumor antigens, increasing infiltration and activation of T cells. In this study, we investigated the immune response to the NY-ESO-1 antigen in metastatic gastric cancer treated with anti-PD-1 (pembrolizumab).
T cells response to the NY-ESO-1 antigen was investigated by ELISPOT against NY-ESO-1 PepMix, against the 43 single peptides overlapping the NY-ESO-1 whole protein and the NY-ESO-1 HLA-A2 restricted peptide. The IEDB1 prediction database was used to predict the patient’s HLA DR, DQ and DP binding to NY-ESO-1. We subsequently characterized the phenotypic and functional activity of the patient T cells using flow cytometry analysis.
We have identified a novel promiscuous immunogenic NY-ESO-1 peptide restricted to the 4 HLA-DQ and HLA-DP alleles and containing the known NY-ESO-1 HLA-A2-02:01 (P157-165) immunogenic epitope. CD8+ T cells were increased during combined therapy and at disease resolution in which its PD-1+CD8+ subset was increased during combined therapy and resolution then decreased at disease progression. The CD107+ cytotoxic subset of the CD8+/HLA-A2-NY-ESO-1-dextramer+ T cells was markedly increased during combined therapy and at resolution then dramatically decreased at re-progression.
We have identified a novel promiscuous anti-NY-ESO-1 immunogenic CD4+ peptide containing the P157-165 HLA-A*02:01/CD8+ epitope that was highly presented at disease resolution and decreased at progression after combined radiotherapy/anti-PD-1 immunotherapy. Our study showed that radiation therapy combined with immune checkpoint blockade would enhance the immune response that correlates with the patient clinical outcome.
Hamad Medical Corporation.
Hamad Medical Corporation.
All authors have declared no conflicts of interest.
JZCA is a phase Ia/Ib study with the primary objective to assess the safety and tolerability of LY3381916 as monotherapy (Part A) and in combination with LY3300054, an anti-PD-L1 antibody (Part B). In the doseescalation part, safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of LY3381916 monotherapy (Part A) and in combination with LY3300054 (Part B) were investigated in patients (pts) with advanced solid tumors to determine the recommended phase II dose (RP2D).
Pts with advanced/metastatic solid tumors received LY3381916 orally from 60mg-600mg once daily (QD), 240mg twice daily (BID) (Part A), or LY3381916 60mg-240mg QD in combination with LY3300054 700mg intravenously every 2 weeks (Part B).
LY3381916 was administered to 42 pts at the cut-off date of July 12, 2019. The most common treatmentrelated adverse events (AEs) were nausea and fatigue. Dose-limiting toxicities were observed in 3 pts (1 pt, Part A 240mg BID with Grade 3 [Gr] ALT/AST increase and systemic inflammatory response syndrome; 2 pts, Part B 240mg QD with Gr 3 fatigue and Gr 3 immunerelated hepatitis). The best objective response was SD, with 7 pts in monotherapy and 5 pts in combination dose escalation. LY3381916 clearance was 12 L/h; mean terminal half-life was ∼6h. Increases in drug exposure were proportional to dose with no apparent differences in PK between monotherapy and combination therapy. In monotherapy pts, PD data showed >90% IDO1 inhibition in ex-vivo whole blood and sustained reduction of plasma kynurenine (Kyn) at steady state for all doses. Sustained plasma Kyn reduction was observed in 76% of combination pts. Tumor tissue Kyn levels were decreased in > 60% of pts with treatment (67% mono; 64% combo). An increase in tumor CD8+ T cells (IHC and RNA-seq) was predominantly observed at the 240mg QD dose with LY3300054. RNA-seq expression was consistent with a dose-dependent increase in activated CD8 effector T cells (i.e., granzyme B, perforin) in the combination treatment.
LY3381916 is safely administered as monotherapy and in combination with LY3300054. The 240mg dose QD is the RP2D for combination with PD-L1 in expansion cohorts.
NCT03343613.
Editorial assistance was provided by Gina Moore, Syneos Health.
Eli Lilly and Company.
Eli Lilly and Company.
B. O\'Neil: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. S. Jalal: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Astex. C. Massard: Honoraria (institution): Eli Lilly and Company. J. Wallin: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. A. Szpurka: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company; Spouse / Financial dependant: Eli Lilly and Company. D. Wang: Full / Part-time employment: Eli Lilly and Company. V. Regnier Galvao: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. M.S. Xia: Full / Part-time employment: Eli Lilly and Company. K. Crowe: Full / Part-time employment: Eli Lilly and Company. S. Geeganage: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. T. Doman: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company; Spouse / Financial dependant: DWA Health Care Communications Group. L. Gandhi: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. X. Xu: Shareholder / Stockholder / Stock options: Eli Lilly and Company; Full / Part-time employment: Eli Lilly and Company. J. Bendell: Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Five Prime; Research grant / Funding (institution): Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Medimmune; Advisory / Consultancy: Celgene; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Talhho; Advisory / Consultancy: Marcogenics; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): LEAP therapeutics; Research grant / Funding (institution): TG therapeutics; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: BI; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.
Although monoclonal antibodies binding the EGF-receptor (cetuximab, panitumumab) or CD38 (daratumumab) show therapeutic efficacy, many cancer patients still develop resistance. Therefore, new therapies are necessary. Nanobodies are highly soluble immunoglobulin domains derived from heavy chain antibodies (hcAbs) that naturally occur in camelids. Replication defective AAV (adeno associated virus) vectors, when equipped with a tumor targeting ligand, can be used for the delivery of (suicide) genes to tumor cells.
We generated recombinant chimeric nanobody-based human IgG1 hcAbs, by fusing EGFR- or CD38-specific nanobodies derived from immunized llamas to the hinge, CH2 and CH3 domains of human IgG1 (1, 2). To promote cytotoxic effector functions we introduced CDC (complement dependent cytotoxicity)-enhancing and ADCC (antibody-dependent cell-mediated cytotoxicity)-enhancing mutations into the CH2 and CH3 domains of human IgG1. As a second strategy to target CD38-overexpressing cells, we inserted CD38-specific nanobodies into the VP1 capsid protein of AAV2 (3). We analyzed the capacity of these constructs to target EGFR and CD38 in tumor cell lines and multiple myeloma (MM) patient bone marrow samples using proliferation, CDC, ADCC and AAV-transduction assays.
EGFR-specific hcAbs effectively blocked the proliferation of tumor cell lines (HNSCC, head and neck squamous cell carcinoma and mCRC, metastatic colorectal cancer) expressing WT EGFR and cetuximab/panitumumab-escape variants of EGFR. EGFR- and CD38-specific hcAbs mediated effective ADCC towards tumor cell lines (HNSCC, mCRC and MM respectively). HcAbs carrying the hexabody mutation were more potent at inducing CDC than parental hcAbs. Display of CD38-specific nanobodies on the AAV capsid resulted in a 20- to 100-fold enhanced transduction of myeloma cells in patient bone marrow samples. Some of these results have recently been published (1, 2) or accepted for publication (3). We will present updated data on tumor cell lines and patient samples.
Nanobody-based hcAbs and nanobody-displaying AAV hold promise as novel tools to target solid and hematological tumors.
Friedrich Koch-Nolte.
DFG (German Research Foundation) and SFB (Collaborative Research Centres).
The author has declared no conflicts of interest.
Glioblastoma (GBM) is a highly malignant brain tumour with no curative treatments. Immunotherapies, including immune checkpoint inhibitors (ICI) are under clinical evaluation, but have not yet been proven to have major impact. The low immune infiltration and modest mutational load of most GBM suggest that combination therapies will be required to improve sensitivity to immunotherapies.
Two mouse GBM models were used, the immunogenic GL261 and the stringent, less mutated SB28. A novel, brain-penetrant, microtubule-targeting agent, BAL101553 (BAL) which induces tumour cell death through activation of the spindle assembly checkpoint, and an agonistic anti-CD40 antibody were combined with ICI (antibodies targeting PD-1 and CTLA-4) to evaluate potential therapeutic synergy. Tumours were analyzed molecularly (mutations, transcriptional profiling) and immunologically (immune infiltration, therapy response in T/B-cell deficient mice).
Well-tolerated combination therapies that significantly enhanced survival were identified in both SB28 and GL261 GBM models. The aggressive SB28, most representative of untreated human GBM, was most responsive to BAL combined with anti-CD40 (median survival in days: vehicle=27, anti-CD40=29, BAL=42, BAL/CD40=49); this effect was found to be T-cell independent as a similar result was observed in SB28 glioma-bearing immunodeficient (RAG1 KO) mice. The immunogenic GL261 model was, as predicted, responsive to ICI; it was relatively insensitive to BAL and anti-CD40 monotherapies but responsive to a combination of these two treatments (median survival in days: vehicle=28, anti-CD40=30, BAL=33, BAL/CD40=40).
Combination GBM therapies that include immunomodulation will likely require selection of patients according to immunological characteristics. Most clinical exploration of immunomodulators focusses on enhancing T-cell mediated anti-tumour immunity but our data suggest that synergistic combination of a tumour checkpoint controller and immunostimulation can be appropriate for poorly immunogenic GBM that is refractory to T-cell control.
The authors.
Basilea Pharmaceutica Ltd.
P. McSheehy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. F. Bachmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. H. Lane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. P.R. Walker: Advisory / Consultancy, Research grant / Funding (self): Basilea Pharmaceutica Int. Ltdtd. All other authors have declared no conflicts of interest.
The reconstitution of a fully functional human immune system in the NCG mouse (hu-NCG) provides a unique opportunity to assess the efficacy of new drug candidates acting on human immune cells such as T cells, myeloid cells and NK cells. Enhanced NCG mice have been further developed to boost the differentiation of myeloid and NK cells, allowing scientists to efficiently test new antibodies or small molecules targeting these immune cell populations.
A fully functional human immune system has been reconstituted in NCG mice after the transplantation of CD34+ human stem cells (hu-NCG model). Then, cell-line derived xenografts (CDX) and patient derived xenografts (PDX) have been engrafted in the hu-NCG model. The tumor growth has been monitored and the immune response assessed by flow cytometry.
We observed infiltration of human immune cells in the tumors. Furthermore, checkpoint inhibitors such as anti-PD1 strongly reduced tumor growth in hu-NCG demonstrating the potency of this model in onco-immunology. Alternatively, we demonstrated that hu-NCG, immunized against cancer antigens elicits strong T cell response as well as IgG production.
Collectively, the huNCG mouse model demonstrats its relevance for the preclinical testing (Mono and Combo therapies) of drugs in immuno-oncology.
The authors.
Transcure Bioservices.
All authors have declared no conflicts of interest.
ICI has revolutionized the treatment of lung cancer, with new approaches in 1L NSCLC. The aim of this study is to compare the efficacy of treatments that combine chemotherapy (CH) plus a PD1/L1 inhibitor in clinical trials (CT) and the benefits in the different subgroups of patients.
We performed a searching in Pubmed to identify CT. Key words were: NSCLC, PD1/L1 and CH. All phase III trials that combined CH with an antiPD1/L1 were selected. The results were combined in MA with the corresponding forest plots and presented as Hazard Ratios (HR) and Odds Ratio (OR), with 95% CI. DerSimonian-Laird random effects models for main and subgroup analyses has been implemented.
A total of 86 publications were reviewed, 6 of them met the inclusion criteria with 3,807 patients. 6 pair wise MA was performed. Control arm in all studies was platinum doublet CH. Bevacizumab was added in 1 trial in the control and experimental arm. 4 studies tested an antiPD-1, and 2 antiPD-L1. 2 studies included EGFR/ALK mutated patients (EGFR/ALK+). PFS final data was reported in all the studies and overall survival (OS) in 4. The addition of PD-1/L1 inhibitors was associated with significantly prolonged progression-free survival (PFS) (HR: 0.59, 95% CI: 0.55-0.64, p < 0.001) and OS (HR: 0.75, 95CI: 0.64-0.87; p < 0.001). Women, ≤65 years old, PS 0, never smokers, liver metastasis (mx) and PD-L1 ≥50% were the subgroups with better benefit (table). Just one trial showed PFS and OS improvement in EGFR/ALK+. Numerically better ORR was obtained in the IMpower150 (56.4%) trial for non-squamous (sq) NSCLC and KEYNOTE407 for sq NSCLC (57.9%).
The association of immunotherapy plus CH is a better treatment option for all patients in 1L NSCLC. Standard subgroups are the most benefited, except liver mx patients and EGFR/ALK+ especially benefited for the combination of an antiPD-L1 and an antiVEGF. 117P OS by subgroupsHR (CI 95%) Women 0.51 [0.32-0.84] Men 0.75 [0.64-0.87] <65 0.62 [0.46-0.84] ≥65 0.74 [0.63-0.87] PS 0 0.65 [0.49-0.88] PS 1 0.72 [0.60-0.87] Never smoker 0.47 [0.26-0.85] Smoker 0.71 [0.56-0.91] No liver mx 0.61 [0.55-0.67] Liver mx 0.69 [0.46-1.0] PD-L1 H 0.66 [0.52-0.82]
The authors.
Roche Farma S.A.
F.J. Afonso-Afonso: Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: IPSEN; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sanofi. M. Amenedo Gancedo: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: PharmaMar; Speaker Bureau / Expert testimony: Roche. M.C. Areses Manrique: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Boehringer. B. Campos Balea: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer. N. Fernández-Núñez: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehinrger; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi. J.L. Firvida Perez: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. J. García González: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer. M. Lázaro Quintela: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: GSK; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Tesaro. L. León-Mateos: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer. J. Ruíz-Bañobre: Advisory / Consultancy: Boehringer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: IPSEN; Travel / Accommodation / Expenses: PharmaMar; Speaker Bureau / Expert testimony: Roche. D. Pérez Parente: Full / Part-time employment: Roche. L. Crama: Full / Part-time employment: Roche. P. Ruiz Gracia: Full / Part-time employment: Roche. L. Santomé Couto: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Boehringer. All other authors have declared no conflicts of interest.
CD95/CD95L signalling plays an important role in cancer cells resistant to CD95-mediated apoptosis and CD95L inhibition can overcome this mechanism. Several mechanisms related to apoptosis induction or dysfunction of effector T-cells via CD95L in the tumour microenvironment (TME) have also been investigated, with supporting evidence from preclinical melanoma models.
An autochthonous mouse model of melanoma (TiRP), genetically engineered to express P1A (defined MAGE-type antigen) mimics the T-cell suppressive effects of the TME through CD95L, which normal transplantation models cannot replicate. An advanced version of this murine melanoma TiRP model has been recently developed. This model can generate synchronized tumours in multiple mice in which treatments can be compared simultaneously while maintaining the advantages of the previous model regarding the role of CD95L in the TME interaction. This enhanced TiRP model was used to verify the effect of CD95L inhibition on apoptosis of tumour specific TILs using asunercept.
In this novel synchronized in vivo melanoma model, asunercept decreased intra-tumour apoptosis among tumour-specific T cells by 67% vs controls (9% vs 28%, p = 0.04). This validates the immune-suppressive interaction between the TME and infiltrating tumour-specific T cells in this model. Furthermore, cross-species specific asunercept prevents T cell apoptosis triggered by the tumour microenvironment, highlighting a rationale for potential application of CD95L inhibition in immuno-oncology for other solid tumours.
Selective CD95L inhibition by asunercept might have potential clinical implications in different tumours beyond recurrent glioblastoma, including cutaneous melanoma. To date, asunercept has demonstrated clinical efficacy and safety in patients with recurrent glioblastoma and myelodysplastic syndromesand may warrant further investigation in clinical trials.
The authors.
Apogenix AG.
A. Krendyukov: Full / Part-time employment: Apogenix AG. N. Kneisel: Full / Part-time employment: Apogenix AG. J. Zhu: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research. C. Merz: Full / Part-time employment: Apogenix AG. D. Richards: Full / Part-time employment: Apogenix AG. C. Gieffers: Full / Part-time employment: Apogenix AG. B. van den Eynde: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: iTeos Therapeutics.
MIRACULUM (NCT03269565) is a multicenter open-label parallel-arm phase II study investigating the antitumor activity of prolgolimab, an IgG1 anti-PD-1 monoclonal antibody with Fc silencing “LALA” mutation, in patients with advanced melanoma. Final analysis after ≥12 months of follow-up is presented.
Patients (pts) with unresectable or metastatic melanoma, without autoimmune disease, no prior BRAF/MEK inhibitors, and anti-PD-1 or anti-CTLA-4 therapy were eligible. Pts received prolgolimab 1 mg/kg Q2W (arm 1) or 3 mg/kg Q3W (arm 2) until disease progression or intolerable toxicity. A statistical hypothesis that prolgolimab has significant anti-tumor effect (ORR more than 28%) was tested for each study arm.
126 pts (63 in each arm) received at least one dose of prolgolimab (mITT population). Baseline pt characteristics were generally balanced between the arms. Prior systemic therapy was administered in 17 (27%) and 16 (25%) pts in arm 1 and 2, respectively. Stage II-III unresectable disease was observed in 4 (6.4%) pts in arm 1 and in 2 (3.2%) pts in arm 2. As of Feb 22, 2019, median follow-up was 13.8 mo (95%CI, 13.2-14.7) in arm 1 and 14.5 mo (95%CI, 13.9-15.2) in arm 2. The study met its primary endpoint in both study arms. In arm 1, 38% ORR was achieved, including 5 CR and 19 PR, and the disease control rate (DCR) was 64%. In arm 2, 29% ORR was achieved, including 2 CR and 16 PR, and the DCR was 46%. 12-mo OS rates were 74.6% for 1 mg/kg Q2W and 54.0% for 3 mg/kg Q3W. 12-mo PFS rates were 41.3% for 1 mg/kg Q2W and 34.9 for 3 mg/kg Q3W. Median response duration was not reached; 83% of all responses were ongoing at data cutoff. Treatment-related AEs (TRAEs) occurred in 55.6% and 54.0% of pts, including 12.7% and 3.2% with grade 3-4 TRAEs in arm 1 and 2, respectively. Immune-related AEs (irAEs) occurred in 36.5% of pts in arm 1 and 34.9% of pts in arm 2, including 7.4% and 1.6% of pts with grade 3/4 irAEs in each arm.
Both dosing regimens of prolgolimab (1 mg/kg Q2W and 3 mg/kg Q3W) have durable antitumor activity and a manageable safety profile in patients with advanced melanoma.
NCT03269565.
BIOCAD.
BIOCAD.
S. Tjulandin: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. M. Fedyanin: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. L. Demidov: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. V. Moiseyenko: Research grant / Funding (institution): BIOCAD. S. Protsenko: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. S. Odintsova: Speaker Bureau / Expert testimony: BIOCAD. T.Y. Semiglazova: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. M. Nechaeva: Speaker Bureau / Expert testimony: BIOCAD. O. Kozlova: Full / Part-time employment: BIOCAD. M. Shustova: Full / Part-time employment: BIOCAD. A. Garipov: Full / Part-time employment: BIOCAD. R. Ivanov: Full / Part-time employment: BIOCAD. All other authors have declared no conflicts of interest.
It has been shown that androgens are immunosuppressive. Androgen deprivation with GnRH agonists regenerates the thymus and its functions in adults, leading to increase in blood and lymphoid organ lymphocytes, in naive lymphocytes with expansion of TCR Vbeta repertoire, and in Tumour Infiltrating Lymphocytes (TILs) in prostate tumours. This phase I study evaluated the safety of triptorelin in combination with nivolumab, as well as its potential to reverse resistance to PD-1 inhibitors in male melanoma patients.
Treatment consisted of triptorelin 3.75 mg i.m. every 4 weeks and nivolumab 3 mg/kg i.v. every 2 weeks. Bicalutamide 50 mg p.o. QD was added for the first 28 days. Evaluation of response was performed after 3 months. Triptorelin PK was assessed and various PDy markers were measured in blood and tumour samples. Planned treatment duration was 48 weeks.
Fourteen male patients were included, of whom 11 were white and 3 were black, with mean age 65 years (range 45-82). At screening 4 were locally advanced while 10 had distant metastases (2 with M1a, 1 with M1b, 6 with M1c and 1 with M1d). Ten patients had cutaneous melanoma, 2 patients had mucosal melanoma, and 2 had an unknown primary. Safety: No grade 4 AEs were reported. Five grade 3 AEs were reported in 4 patients, of which one (abdominal pain) was attributed to triptorelin and resolved after 39 days (causing no treatment interruption as it started on the day treatment was discontinued due to progression), and one (neutropenia) was considered related to nivolumab and resolved following treatment interruption for 14 days. Efficacy: BOR (RECIST 1.1) was assessed as 2 PR, 5 SD, and 7 PD. The two patients with PR showed reductions from baseline in Target Lesions of 76% (one pancreas metastasis) and32% (two inguinal lymph nodes), following an initial pseudoprogression.
The association of triptorelin to nivolumab was well tolerated and yielded partial response in two patients.
Debiopharm International S.A.
Debiopharm International S.A.
C. Robert: Advisory / Consultancy: Novartis, Bristol-Myers Squibb, MSD, Roche, Sanofi, Amgen, Pierre Fabre. F.J. Lejeune: Honoraria (self): Debiopharm International SA. C. Lebbé: Honoraria (self): Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen, Pierre Fabre, Pfizer, Incyte; Advisory / Consultancy: Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen; Travel / Accommodation / Expenses: Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Roche, Bristol-Myers Squibb, Novartis ,Amgen; Advisory / Consultancy: Aventis. T. Lesimple: Research grant / Funding (self): Roche; Advisory / Consultancy: MSD, Novartis, Pierre Fabre. E. Lundström: Full / Part-time employment: Debiopharm International SA. V. Nicolas: Full / Part-time employment: Debiopharm International SA. B. Gavillet: Full / Part-time employment: Debiopharm International SA. V. Grégoire: Full / Part-time employment: Debiopharm International SA. P. Crompton: Full / Part-time employment: Debiopharm International SA.
High-dose interleukin-2 (HDIL-2) represents a curative treatment option in metastatic melanoma (MM) and renal cell carcinoma (RCC) patients, although still in need of improving its therapeutic efficacy. Radiotherapy (XRT) strongly synergizes with immunotherapy and may boost the effects of HDIL-2 allowing for less toxic schedules.
In this proof-of-principle phase II study, biological markers of immunological response were considered as primary endpoints in previously treated MM and RCC patients. The treatment consisted of 3 daily doses of XRT (6-12 Gy) delivered to one lesion before the first and third IL-2 infusion (18 MIU/m2/day by IV infusion for 72 h), repeated every 3 weeks for a maximum of 6 cycles. In a first stage, 4 out of 7 enrolled patients showed an immunological response allowing the recruitment of a further 12 patients according to the minimax two-stage Simon design. The immunological efficacy of the combined XRT/HDIL-2 treatment was assessed measuring the proportion of circulating immune effectors specific for tumor antigens known to be expressed in MM and in RCC (i.e. Tyrosinase, gp100, Mart-1, 5T4, CAIX/G250, EGFR, survivin, MAGEA3 and NYESO1) by means of INF-γ Elispot assay. Moreover, the predictive value of pre-treatment serum biomarkers was also assessed.
Since September 2012 a total of 19 patients have been enrolled (9 RCC and 10 MM patients of which 6 uveal, 2 mucosal and 2 cutaneous) with a median age of 55 years. Assessed clinical responses were 4 PR (3 RCC and 1 MM), 6 SD (2 RCC and 4 MM) and 9 PD. Median PFS was 3.2 and 2.9 months and median OS was 8.7 and 6.7 months, for RCC and MM respectively. According to CTCAE 4.0, the majority of toxicities was grade 1-2. IL-2 dose was never reduced, nor was the infusion interrupted. Interestingly, we found an enhancement greater than 10% of antigen-specific spot-forming cells (SFCs) for at least one tumor antigen after treatment in 16 out of 19 patients. Moreover, we detected much lower serum basal levels of IL-8 and IL-1b in responders (CR/PR/SD=10) compared to non responders (PD = 9).
HDIL2/XRT combined treatment is well tolerated and fairly active in the MM and RCC settings.
EudraCT: 2012-001786-32.
The authors.
Italian Ministry of Health as part of the “Ricerca Finalizzata 2009 - Direzione Generale della Ricerca Scientifica e Tecnologica” Call for Project Proposals.
All authors have declared no conflicts of interest.
The anti-programmed cell death protein-1 (PD-1) inhibitor is the recommended second-line therapy for advanced hepatocellular carcinoma (HCC) after sorafenib failure. However, only a small subset of patients benefited from anti-PD-1 therapy due to a limited response rate. The goal of this study is to evaluate the impact of ablation on the tumor in patients with advanced HCC who had stable disease or atypical response during single anti-PD-1 therapy after sorafenib failure.
This prospective study enrolled 50 patients treated with an anti-PD-1 inhibitor of nivolumab or pembrolizumab monotherapy between July 2015 and Nov 2017. Thirty-three cases with stable disease or atypical response to anti-PD-1 inhibitor received subtotal thermal ablation. The safety and the response of ablation during anti-PD-1 therapy were evaluated. The survival was estimated by the Kaplan-Meier curve.
Of all 50 patients treated with anti-PD-1 therapy, the rate of response, stable disease, atypical and typical progression were 10% (n = 5), 42% (n = 21) 32% (n = 16) and 12% (n = 6), respectively. Additional ablation improved efficacy with tolerable toxicity, and the response rate was increased from 10% to 24% (12/50). The median time to progression, progression-free survival, and overall survival were 6.1 months (95% confidence interval [CI], 2.6-11.2), 5 months (95%CI, 2.9-7.1) and 16.9 months (95%CI, 7.7-26.1), respectively.
Additional ablation could increase the objective response rate with tolerated toxicity and achieved a relatively better median survival, in advanced HCC patients who had stable or atypical progressive diseases during anti-PD-1 therapy, which may provide a potentially promising strategy to treat advanced HCC.
NCT03939975.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
To address current need for preclinical human-based immuno-oncology models, we have established a method to grow 3D cultures of intact fragments of patient-derived breast cancer tissue; Patient-Derived Explant Cultures (PDECs). PDECs offer many advantages over other cancer model systems. For example, PDECs preserve the human tumor microenvironment, reflect inter- and intra-patient tumor heterogeneity and results are obtained within one week. Up to 16 samples can be obtained from one clinical sample, allowing the same ‘patient’ to be experimentally treated with different drug regimens and/or measurement of more than one endpoint. Recently we have used PDECs to assess the efficacy of novel synthetic lethal treatment regimens (Haikala et al., Nature Comm. 2019; Tervonen et al., Oncogene 2016).
To assess whether PDECs are also a suitable model for IO studies we performed immunoprofiling experiments with FACS, RT-PCR and immunofluorescence of PDECs and the primary tumor they were derived from.
These experiments showed that the immune-contexture, i.e. the number and activation status of different immune cell types, is similar in PDECs than in the primary tumor. In addition, using serial cell imaging we found that activation of resident immune cells in PDECs using anti-PD-1 (an immune checkpoint inhibitor) or Immunocult (T Cell Activator) resulted in shrinkage of some PDECs, while others were unaffected. In addition, the presence of increased levels of cancer cell death in PDECs treated with anti-PD-1 and Immunocult suggests that the resident immune cells in PDECs can mediate cancer cell killing.
Our data support our hypothesis that PDECs retain a similar immunocontexture as the original tumors, and can be interrogated with immunomodulatory compounds relevant to current immunotherapies.
The authors.
Academy of Finland, Juselius Foundation, Cancer Organisations.
All authors have declared no conflicts of interest.
Rose bengal disodium (PV-10) is a small molecule oncolytic immunotherapy in clinical development for treatment of solid tumors. When administered by intralesional injection, PV-10 can produce an immunogenic cell death that may induce a T-cell mediated immune response against treatment-refractory and immunologically-cold tumors. Given this mechanism of action, we investigated treatment of metastatic uveal melanoma with percutaneous hepatic PV-10.
PV-10-LC-01 (NCT00986661) is an open-label phase I basket study evaluating the safety, tolerability, and preliminary efficacy of intralesional PV-10 in patients with solid tumors metastatic to the liver. Percutaneous injections of PV-10 are administered to one or more designated hepatic tumor(s) with a maximum sum of diameters £4.9 cm. Response assessments using 2D EASL criteria are performed at Day 28, then every 3 months. Patients with additional injectable tumors may receive further PV-10 after Day 28. Eligible patients may receive standard of care checkpoint blockade immunotherapy during treatment with PV-10.
In a single-center cohort of uveal melanoma patients with hepatic metastases, to date, the study has screened 15 patients with metastatic uveal melanoma; eleven patients have been consented, enrolled, and received at least one PV-10 treatment cycle; five have received a second treatment with intralesional PV-10 for a total of 18 injected hepatic tumors. Three patients have received PV-10 with initiation of standard of care checkpoint blockade. One patient was on immunotherapy prior to PV-10 treatment. In 11 injected tumors with response assessment, the objective response rate has been 36%. Toxicities have been self-limiting and consistent with established patterns, including photosensitivity, pink urine, and transaminitis that resolved in < 7 days.
Percutaneous PV-10 exhibited acceptable safety and tolerability with encouraging evidence of activity in injected lesions. Updated enrollment as well as safety and efficacy data of the uveal melanoma cohort will be presented at the meeting.
NCT00986661.
Provectus.
Provectus.
S. Patel: Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Cardinal Health; Advisory / Consultancy: Castle Biosciences; Leadership role, Data Safety Monitoring Board Chair: Immunocore; Advisory / Consultancy: Incyte; Honoraria (self): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Provectus; Leadership role, Research grant / Funding (institution), Data Safety Monitoring Board chair: Reata. E.A. Wachter: Shareholder / Stockholder / Stock options, Full / Part-time employment: Provectus. All other authors have declared no conflicts of interest.
Rose bengal disodium (PV-10) is a small molecule oncolytic immunotherapy in clinical development for treatment of solid tumors. Upon intralesional injection, it can produce immunogenic cell death and a T-cell mediated immune response against treatment-refractory and immunologically-cold tumors.
PV-10-LC-01 (NCT00986661) is an open-label phase I basket study evaluating safety, tolerability and preliminary efficacy of PV-10 in patients (pts) with solid tumors metastatic to liver. PV-10 is administered percutaneously to 1 or more hepatic tumors 1.0-4.9 cm in diameter with response assessment via contrast-enhanced CT, MRI and/or FDG PET at Day 28 then q12w. Pts with multiple injectable tumors may receive further PV-10 after Day 28. Eligible pts can receive concomitant standard care checkpoint blockade immunotherapy. In a single-center cohort of uveal melanoma pts we compared overall response and progression-free survival (PFS) using 2-dimensional European Association for the Study of Liver (2D-EASL) criteria and criteria that consider lesions outside of the liver (RECIST 1.1, irRC, irRECIST and iRECIST).
Eight pts who received at least 1 injection of PV-10 and had baseline and follow-up imaging were assessed: 5 received 2 doses and 3 received 1 dose. There was a difference in overall response by RECIST vs. the other criteria in 4 pts: these pts developed progression on RECIST but remained stable by 2D-EASL, irRC, irRECIST and iRECIST with disparate PFS of 91 days (RECIST) vs. 145 days. Progression by RECIST was based on appearance of new lesions for 3 pts and increase in target lesion size in 1 pt; in 1 pt the injected lesion demonstrated complete response based on 2D-EASL obtained after progression as determined by RECIST. For the remaining pts, overall response of stable disease was concordant between all response criteria; 2D-EASL demonstrated sustained partial response in injected lesions in 2 of these pts.
Imaging response assessment of pts treated with PV-10 using RECIST may lead to premature and inaccurate determination of progression. 2D-EASL provides information specific to the behavior of injected lesions. Immunotherapy-centric criteria (irRC, irRECIST and iRECIST) could be a useful alternative to 2D-EASL.
NCT00986661.
Provectus Biopharmaceuticals.
Provectus Biopharmaceuticals.
E.A. Wachter: Full / Part-time employment: Provectus Biopharmaceuticals. All other authors have declared no conflicts of interest.
The majority of cancer patients are resistant to immune therapy; only around 15% respond to immune checkpoint inhibitors (ICI). Thus, strategies able to increase ICI response are of great interest. Recent work suggests radiotherapy (RT) can act as an immunomodulator to increase the proportion of ICI responders and improve clinical outcomes. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by intratumoral injection, designed at the nanoscale to increase RT energy dose deposition within the tumor. The result is increased radiation-dependent tumor cell killing, without increasing radiation exposure of healthy tissues. Preclinical and early clinical data suggest NBTXR3 activated by RT can increase the anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect while also producing a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders.
The NANORAY-1100 study is a multicenter, open-label, phase I study that aims to evaluate the safety and tolerability of R3/RT/PD-1 in three cohorts of participants with either: (1) Locoregional recurrent (LRR) or recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the head and neck (HN) field, (2) Lung metastases originating from any primary cancer eligible for anti-PD-1 therapy, or (3) Liver metastases originating from any primary cancer eligible for anti-PD-1 therapy. Participants will be enrolled such that approximately two-thirds of each cohort will be anti-PD-1 non-responders. NBTXR3 injection volume is based on percentage of gross tumor volume (GTV), as determined per central review. The primary objective is to determine the RP2D of R3/RT/PD-1. The secondary objectives are to evaluate the anti-tumor response (objective response rate; ORR) of R3/RT/PD-1, the safety and feasibility of NBTXR3 injection, and the body kinetic profile of NBTXR3. Exploratory objectives will assess biomarkers of response to R3/RT/PD-1, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling.
NCT03589339.
Nanobiotix, SA.
Nanobiotix, SA.
C. Shen: Honoraria (self): Nanobiotix. K. Jameson: Full / Part-time employment: Nanobiotix. J. Weiss: Honoraria (self): Nanobiotix. T. Hackman: Honoraria (self): Nanobiotix. D. Corum: Full / Part-time employment: Nanobiotix. J.A. Akulian: Honoraria (self): Nanobiotix. R. Dixon: Honoraria (self): Nanobiotix. A. Pearson: Honoraria (self): Nanobiotix. J. Frakes: Honoraria (self): Nanobiotix. P. Said: Full / Part-time employment: Nanobiotix. H. Miraoui: Full / Part-time employment: Nanobiotix. E. Baskin-Bey: Full / Part-time employment: Nanobiotix. T. Seiwert: Honoraria (self): Nanobiotix.
Checkpoint Inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (mNSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for pts with poor prognostic features or negative predictive clinical factors for CPI benefit, including PD-L1 negative (-) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor. BEMPEG + CPI has demonstrated promising efficacy and can convert PD-L1(-) tumors to PD-L1(+) in pts with multiple solid tumors (Diab A, ASCO 2018; Siefker-Radtke A, ASCO-GU 2019). Given the early efficacy data and favorable safety profile of BEMPEG + nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO).
This phase I/II multinational trial evaluates BEMPEG + PEMBRO in pts with locally advanced or metastatic solid tumors. There are two key components to the study: 1) Dose optimization: which includes 3 + 3 and step-up dosing (U.S. enrollment only) and will include ∼40 pts with first- and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma, regardless of PD-L1 status; 2) Dose expansion: which includes ∼58 first-line mNSCLC pts (enrolling globally). The expansion cohort will evaluate the preliminary anti-tumor activity of BEMPEG, in combination with PEMBRO, in first-line mNSCLC, regardless of PD-L1 status (<1%, 1-49%, and >50%). The primary objectives in the dose optimization cohorts are safety and tolerability of the combination and to determine the maximum tolerated dose, recommended phase II dose and optimal dosing schedule of BEMPEG in combination with PEMBRO in locally advanced or metastatic solid tumors. The primary objective in the dose expansion cohort is objective response rate by RECIST 1.1. Enrollment is ongoing.
NCT03138889.
Nektar Therapeutics.
Nektar Therapeutics.
M. Reck: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene. F. Cappuzzo: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Lilly. D. Rodriguez-Abreu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Hoffmann-La Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer-Ingelheim. D.C. Cho: Advisory / Consultancy: Puretech; Advisory / Consultancy: Nektar Therapeutics; Advisory / Consultancy: HUYA; Advisory / Consultancy: Prometheus; Advisory / Consultancy: Genentech; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Exelixis. M.J. Riese: Advisory / Consultancy: Abbvie; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (self): Incyte. A. Gupta: Leadership role, Employed by Nektar: Nektar Therapeutics. T. Chan: Leadership role, Employed by Nektar: Nektar Therapeutics. R. Saab: Leadership role, Employed by Nektar: Nektar Therapeutics. S. Singel: Leadership role, Employed by Nektar: Nektar Therapeutics. W. Lin: Leadership role, Employed by Nektar: Nektar Therapeutics. M. Tagliaferri: Advisory / Consultancy, Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Employed by Nektar: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Bluebird Bio. D.R. Spigel: Honoraria (institution), Research grant / Funding (institution): Abbvie; Honoraria (institution), Research grant / Funding (institution): Aeglea; Honoraria (institution), Research grant / Funding (institution): Amgen; Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Research grant / Funding (institution): Celgene; Honoraria (institution): Evelo; Honoraria (institution), Research grant / Funding (institution): Foundation Medicine; Honoraria (institution), Research grant / Funding (institution): Genentech/Roche; Honoraria (self), Research grant / Funding (institution): GlaxoSmithKline; Honoraria (institution): Illumina; Honoraria (institution), Research grant / Funding (institution): Ipsen; Honoraria (institution), Research grant / Funding (institution): Lilly; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution): Moderna Therapeutics; Honoraria (institution), Research grant / Funding (institution): Nektar; Honoraria (institution), Research grant / Funding (institution): Novartis; Honoraria (institution): PharmaMar; Honoraria (institution), Research grant / Funding (institution): Pfizer; Honoraria (institution), Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Transgene; Honoraria (institution): Armo; Honoraria (institution): Precision Oncology; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): CellDex; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Grail; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): OncoGenex. All other authors have declared no conflicts of interest.
VCN-01 is an oncolytic adenovirus with replication restricted to cells with a nonfunctional retinoblastoma pathway. Upon selective replication VCN-01 expresses the matrix remodeling-enzyme hyaluronidase to enhance virus spreading and tumor uptake of different therapeutics, including immune check-point inhibitors. In a phase I performed in pancreatic carcinoma VCN-01 reached tumors after systemic administration and induced CD8-infiltration, tumor inflammation and PD-1/PD-L1 up-regulation. We hypothesize these intratumor effects may help to overcome the observed resistance to Durvalumab and other PD-(L)-1 checkpoint inhibitors
NCT03799744 is a multi-center, open-label dose-escalation phase I study evaluating the safety, tolerability and efficacy of the combination of VCN-01 plus durvalumab in R/M HNSCC patients who have progressed on prior PD-(L)-1 checkpoint inhibitors. Patients need to have neutralizing antibodies levels against adenovirus ≤1/350 dilution to be included. The study follows a 3 + 3 design with two dose levels for VCN-01 (3,3.1012 & 1.1013 vp) combined with Durvalumab at a fixed dose of 1500mg intravenous (i.v.). Two treatment arms are explored: I) Concomitant single i.v. dose of VCN-01 with durvalumab on cycle 1 day 1 followed by durvalumab Q4W; II) Sequential single i.v. VCN-01 on cycle 1 day -14 plus durvalumab on cycle 1 day 1 followed by durvalumab Q4W. Patients continue durvalumab Q4W until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to evaluate the safety and tolerability of VCN-01 with durvalumab in the two regimens of administration and to establish the recommended phase II dose. Secondary objectives are progression free survival, overall response rate by irRECIST /RECIST, VCN-01 pharmacokinetics and shedding in blood. Other exploratory biomarkers will be analyzed in tumor biopsies (immune markers), serum (hyaluronidase levels), stool (microbiome) and imaging (dynamic contrast-enhanced MRI, diffusion weighted imaging and T2 mapping). The study opened recruitment in April 2019 with 7 out of 18 planned patients enrolled at time of submission.
NCT03799744.
Catalan Institute of Oncology (ICO).
VCN Biosciences, AstraZeneca.
M. Jove: Advisory / Consultancy: Boehringer Ingelheim. I. Braña: Advisory / Consultancy, Research grant / Funding (self): Orion Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Gliknik; Research grant / Funding (self): GSK; Research grant / Funding (self): Janssen; Research grant / Funding (self): KURA; Research grant / Funding (self): MSD; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Shattuck; Research grant / Funding (self): Northern Biologics; Research grant / Funding (self): Rakutan Aspirian; Research grant / Funding (self): Naobiotics. M. Taberna: Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Merck; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Nanobiotics. E. Garralda: Leadership role, Research grant / Funding (institution): Novartis; Leadership role: Principia Biopharma Inc; Leadership role: Lilly, S.A; Advisory / Consultancy, Leadership role: Roche / Genentech Inc; Leadership role: Loxo Oncology Inc; Advisory / Consultancy, Leadership role: F.Hoffmann La Roche Ltd; Leadership role: Symphogen A/S; Speaker Bureau / Expert testimony, Leadership role, Travel / Accommodation / Expenses: MSD; Leadership role: Incyte; Leadership role: Pharma Mar; Leadership role: Kura Oncology; Leadership role: Macrogenics; Leadership role, Travel / Accommodation / Expenses: Glycotope; Leadership role: Pierre Fabre; Leadership role: Cellestia Biotech; Leadership role, Travel / Accommodation / Expenses: Menarini Ricerche; Leadership role: Blueprint Medicines; Leadership role: Beigene; Leadership role: Sierra Oncology; Leadership role: Genmab; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services ; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: NeoMed Therapeutics; Advisory / Consultancy: SeaGen; Speaker Bureau / Expert testimony: ThermoFisher. G. Capella: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo Piqueras: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. All other authors have declared no conflicts of interest.
Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases, and is characterized by a poor response to chemotherapy and a low survival rate. Treatment targeting the immune checkpoint inhibitor pathway PD-1/PD-L1 has been found to be effective against NSCLC with manageable side effects, but with only 20-25% of patients showing a positive response there is an urgent need for additional immunotherapy options for this group of patients. LAG-3 and PD-1 are often co-expressed and upregulated on T cells leading to immune exhaustion and tumor growth, and co-blockade of the LAG-3 and PD-1 pathways has been shown to synergize to improve T cytotoxic cell responses.
In order to perform a comprehensive immunoprofiling of NSCLC tumors we used MultiOmyx™, an immunofluorescence (IF) multiplexing assay that utilize a pair of directly conjugated Cyanine dye-labeled (Cy3, Cy5) antibodies per round of staining. Using a 16-marker panel we have analyzed the proportion of B cells, T cell subtypes, M1/M2-type tumor-associated macrophages, as well as the expression of PD-1, PD-L1, LAG-3, and TIM-3 in 20 samples from patients with NSCLC.
LAG-3 was found to be expressed mainly on T cytotoxic cells in both subtypes, but the overall density of LAG-3 was 59% higher in squamous cell carcinoma (SCC) tumors compared to adenocarcinoma tumors. In both SCC and adenocarcinoma subtypes TIM-3 was found primarily on tumor-associated macrophages (TAMs), followed by an equal distribution on helper and cytotoxic T cells. When analyzing the proportion of T cytotoxic cells infiltrating into the tumor area, we observed an apparent synergy between LAG-3 and PD-1, suggesting a therapeutic benefit of dual checkpoint blockade of LAG-3 and PD-1 in NSCLC.
It is our hope that these data will help provide new insights into the biology of NSCLC that can ultimately be used to explore novel immunotherapeutic interventions for lung cancer treatment.
NeoGenomics.
NeoGenomics.
A. Juncker-Jensen: Full / Part-time employment: NeoGenomics. M. Nagy: Full / Part-time employment: NeoGenomics. J. Kuo: Full / Part-time employment: NeoGenomics. E. Leones: Full / Part-time employment: NeoGenomics. F. Sahafi: Full / Part-time employment: NeoGenomics. K. Pham: Full / Part-time employment: NeoGenomics. E. Parnell: Full / Part-time employment: NeoGenomics.
Immune system plays an important role in cancer evolution. However, cancer cells affect the immune system and use it for its growth and survival. Tumour infiltration lymphocytes and PDL-1 expression proved to play an important prognostic role in different malignancies. We aimed at evaluating this role in laryngeal cancer.
We prospectively analyzed the pre-treatment paraffin blocks for laryngeal cancer patients, whether on the laryngoscopy or operative specimens, to identify the CD8-positive cells in the tumour epithelium or stroma and the PDL-1 expression on the tumour cells. Appropriate tissue was used as positive control; placenta for PDL-1 and tonsil for CD8. A total score formed of the sum of percentage and intensity of PDL-1. A final comprehensive rate was considered as low expression when combined percentage and intensity score from 0 to 4, and high expression when score from 5-7. According to the distribution, the CD8+T cell invasion was divided into strong infiltration (> 10/100 of epithelial cells; >20/100 stromal cell infiltration) and weak infiltration (< 10/100 epithelial cells; < 20/100 stromal cell infiltration).
40 patients were included in our study; 12 patients had early stage disease (I or II) and 28 with advanced stage (III or IV). PDL-1 expression was positive in 92.5%. Neither the PDL-1 nor CD-8 were found significantly correlated to OS in the whole population, however patients with advanced stage, median OS was significantly low for negative or low compared to high PDL-1 expression (11.7 vs 25.2 months (p = 0.036)), a trend of better OS in high CD8 Epithelial expression (25.1 versus 15.9, P = 0.514) and again trend of higher OS in high CD8 Stromal expression (25.3 versus 15.6 months, p = 0.375). Also there were significant correlation between the CD8 expression in the tumour epithelium and stroma with the PDL-1 expression with p-value of 0.001 and < 0.0001 respectively.
There is a positive correlation between tumour infiltration lymphocytes and PDL-1 expression in laryngeal squamous carcinoma and the higher PDL-1 expression in advanced stage laryngeal cancer is associated with better OS.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immunosenescence, the age-related decrease in immune competence, is characterized by decreased adaptive immunity and increased low-grade inflammation. This may lead to altered anti-tumor immune responses and thus affect tumor immune infiltrate in older patients with cancer. However, detailed tumor infiltrate characterization in breast cancer (BC) has not yet been performed in the context of aging.
This exploratory study investigated age-related changes in the tumor microenvironment of patients with early BC (grade I-III, ER+, HER2-). Patients were subdivided into three age categories: 35-45 years (y) (N = 15), 55-65y (N = 19), ≥70y (N = 31). Stromal tumor infiltrating lymphocytes (sTILs) percentage was assessed following published guidelines. Immune infiltrate characterization was established by determining CD68 grade and scoring additional immune markers (CD3, CD4, CD5, CD8, CD20 and FOXP3) with a newly developed analysis pipeline using the QuPath software. In the oldest group, the geriatric 8 (G8) score was obtained as a correlate for clinical frailty level.
With increasing age, sTILs percentage significantly decreased, concomitant with significantly lower Tcells (CD3+ and CD5+), cytotoxic Tcells (CD8+) and Bcells (CD20+) densities in the whole tumor area. When assessing tumor regions separately, significant age-related decreases in immune cell density in invasive front (CD3+, CD5+, CD8+, CD20+ cells) and tumor center (CD3+, CD5+, CD8+ cells) were observed. No age-related changes were seen for CD4+ and FOXP3+ cell infiltration nor for CD68 grade in the tumor. G8 score showed a significant inverse correlation with regulatory Tcells (FOXP3+) density in tumor center. However, spatial distribution of the immune cell populations did not depend on age nor frailty level.
In conclusion, sTILs percentage and density of several immune markers in the tumor significantly differed between young and older patients with BC. Moreover, density of regulatory T-cells was higher in frailer patients (lower G8 score). This may indicate that tumor immune responses in these patients may be less effective, and approaches for immunotherapy may vary depending on patients’ age/frailty level.
Hans Wildiers.
FWO.
All authors have declared no conflicts of interest.
Development of novel immunotherapeutics in oncology is of crucial interest and their good testing at preclinical stage relies on i) the features of the animal model used and ii) the application of an appropriate comprehensive strategy for the deep delineation of mechanisms underlying resistance/sensitivity to a drug.
Using a syngeneic sarcoma mouse model, treated with anti-PDL1, we investigated by intratumoral microdialysis and flow cytometry the immunometabolic profile and immune landscape of the tumour, respectively. The anti-tumor effect of PDL1 blockade was assessed through tumour growth monitoring and tumoral biopsies were also collected for gene expression analysis. Finally, involvement of CD8 T cells in the anti-tumour PDL1 blockade-mediated activity was addressed using a specific depleting antibody -based strategy.
When compared to a non-tumour area, data obtained from tumour microdialysates highlighted i) a slight Kynurenine pathway activation, ii) a strong Arginase activity, and iii) a high Adenosine production. Interestingly, anti-PDL1 effect was associated with a decrease of the tumoral Adenosine level thus arguing for an important role of the Adenosine axis in the control of the anti-tumour immune response. In addition, PDL1 blockade led to an intratumoral CD45+ leukocytes enrichment, with a higher abundance of lymphocytes also displaying increased level of IFNgamma. In contrast, macrophages – CD11b+/F4:80+ - were limited upon treatment, especially the immunosuppressive CD11b/Gr1Low/Int cellsubsets, in favor of an increase of the M1/M2 macrophages ratio. Interestingly, CD8 depletion fully abrogated anti-PDL1 anti-tumour effect thus showing the unequivocal role of this population. Finally, gene expression analysis revealed, in addition to an interferon signature, changes in genes from the myeloid / neutrophil subsets including Arg1 and key chemokines.
Altogether, this multiparametric dataset gives i) a better understanding of intrinsic features of the preclinical model and deeper insights into the mechanism of action of an effective drug, and ii) might serve as a platform combination-based strategy for comprehensive explorations of novel candidates.
Alban Bessede.
Explicyte Immuno-Oncology.
A. Bessede: Shareholder / Stockholder / Stock options, Full / Part-time employment: Explicyte. All other authors have declared no conflicts of interest.
Patients selected based on PD-L1 expression for second-line immune checkpoint inhibitor (ICI) treatment are often identified using archival specimens collected months or years prior to starting immunotherapy. Such patients may have received and failed multiple lines of standard of care (SOC) treatments with subsequent potential impact on PD-L1 expression and immune microenvironment.
We have analysed formalin fixed paraffin embedded (FFPE) tissues in a cohort of NSCLC patients (n = 16) taken during resection performed as first-line surgical treatment for which radiotherapy, SOC chemotherapy, and second-line immunotherapy clinical follow-up data are available. The immune microenvironment was evaluated by immunohistochemistry (IHC) plus digital image analysis for CD3, CD8, PD-L1, CD68 and CD163, and by Nanostring using the IO360TM gene expression panel, with the aim of exploring whether immune signatures predictive of response to ICI therapy may be identified in such samples.
Clinical follow-up data indicated objective response to ICI therapy for 4/16 patients (n = 2 Nivolumab, n = 1 Pembrolizumab, n = 1 Durvalumab) with time from first diagnosis to receiving second-line ICI treatment ranging from 5 to 102 (mean 33.6) months. During this time these patients received various lines of radiotherapy and SOC chemotherapy prior to receiving immunotherapy. While the Tumor Inflammation Signature was not predictive of response, gene expression analysis did identify several signatures associated significantly with response, including increased abundance of CD8 T cells, cytotoxic cells, cytotoxicity, MHC class II antigen presentation and Melanoma-Associated Antigens (MAGE). These data were supported by a significant elevation of CD8 T cells by IHC in the responder versus non-responder populations, from a mean of 329 to 961 CD8+ T cells/mm2.
Taken together these data demonstrate that despite various lines of previous radiotherapy and chemotherapy spanning several years, immune profiles associated with response to second-line immunotherapy can be detected in surgical first-line resection samples.
The authors.
Has not received any funding.
M. Bhagat: Shareholder / Stockholder / Stock options, Officer / Board of Directors: TriStar Technolgoy Group. All other authors have declared no conflicts of interest.
Immune-checkpoint inhibitors have shown high objective response rates and long-lasting clinical benefits in several studies, thus revolutionized cancer treatment. Pleomorphic dermal sarcoma (PDS) is a rare cutaneous tumour with local recurrences and distant metastases occurring up to 20% of the cases. With only limited treatment options in advanced stages, there is a strong rationale to explore novel treatments in PDS. In order to achieve this, the profiling of the immune environment in PDS needs to be first explored.
We collected 14 PDS cases that underwent primary surgical resection at University Hospital Cologne. With formalin-fixed paraffin-embedded (FFPE) materials, we performed a comprehensive immune-phenotype analysis using immunohistochemistry and multiplex gene expression analysis, as well as quantitative assessment of immune cells through quantitative image-analysis. Based on these findings and our preliminary studies, two patients with advanced PDS were enrolled in programmed cell death protein 1 (PD-1) inhibitor therapy.
Eight out of fourteen PDS cases (57%) showed abundance of CD8-positive T-lymphocyte infiltration. Three cases that had above median level of infiltration (hereinafter referred to as CD8-high) displayed high expression levels of immune-related cytokines, immunotherapy response markers, MHC-I expression, and infiltration by PD-L1-, PD-1- and LAG-3-expressing immune cells. The multivariate analysis revealed that CD8-high group highly expressed CD74, LYZ and HLA-B while the CD8-low cases overexpressed CXCL14. In addition, M2 tumor-associated macrophages (TAMs) were localized at the tumor invasion front. Likewise, both patients showed good response to anti-PD-1 therapy in combination with or without radiotherapy and remain in complete remission until now.
We provide the initial comprehensive immune-phenotype profiling of PDS and two representative cases that were successfully treated with immune-checkpoint inhibitor for the first time. These results will aid in further assessment of PDS cases and formulate the qualification criteria for immunotherapy in individuals presenting this rare skin malignancy.
University Hospital Cologne.
EFRE 2018 (ImmunePredict).
All authors have declared no conflicts of interest.
Immunotherapy is proving successful in several tumour settings, although many cancer types remain less responsive. Pre-existing tumour infiltrating lymphocytes and PD-L1 expression associate with response to immunotherapy and cancers have been classified into response subtypes according to these biomarkers. To enable a simultaneous comparative assessment of the immune microenvironment in multiple tumour indications, we have constructed a multi-tumour TMA comprising matched cores for each donor from IM and TC.
In this study, we employed a TMA comprising cores taken from formalin fixed paraffin embedded (FFPE) non-treated surgical resections for donors diagnosed with squamous NSCLC (SCC; n = 13), adeno NSCLC (ADC; n = 12), small cell lung cancer (SCLC; n = 9), oestrogen receptor positive breast cancer (ER+BC; n = 12), Herceptin positive BC (Her2+BC; n = 12) and triple negative BC (TNBC; n = 12). Serial sections were stained by immunohistochemistry for several immune biomarkers (CD163, CD68, PD-L1, CD8, CD3, PD-1, Foxp3, CD4, CD20). Immune infiltrates were analysed by digital image analysis and PD-L1 was scored by a pathologist to deliver both the tumour proportion score (TPS) and the combined positivity score (CPS).
By taking an average of all cores (IM and TC) for each disease indication, we demonstrate that SCC, ADC and TNBC are more highly infiltrated, and that while tumour PD-L1 (TPS) was absent in ER+BC and Her2+BC, the contribution from infiltrating immune cells (CPS) was greatest in SCC and TNBC. Interestingly, a reciprocal profile for CD163:CD68 was observed for LC versus BC, with the M2-like CD163+ macrophage/monocytic population exceeding the CD68+ macrophage population in BC, whereas the converse was observed for LC. Immune infiltrates were reduced in TC compared with IM, and distinct case-by-case immune microenvironments were revealed within each disease indication.
Using an immuno-oncology focussed TMA we have revealed distinct immune profiles in multiple tumour subtypes simultaneously, providing a valuable basis against which to profile novel immune targets.
The authors.
Has not received any funding.
M. Bhagat: Shareholder / Stockholder / Stock options, Officer / Board of Directors: TriStar Technolgoy Group. All other authors have declared no conflicts of interest.
We have reported higher density of tumour-infiltrating lymphocytes (TILs) and PDL1 expression correlated with better outcome in treatment naive gastric cancer patients. Here the prognostic value of residual disease (RD) TILs and PDL1 expression is further evaluated.
Immunohistochemistry was performed on a tissue microarray including 310 neoadjuvant chemotherapy GC specimens using PD1, PDL1 and PDL2 antibodies. T cell markers CD3 and CD8 were also stained and quantified by automated image analysis.
The median age was 58.5 years (range: 22--89 years). There was a positive correlation between TIL level and PDL1 expression. 37.8% of the cases showed membranous PD-L1 expression in tumor cells and 74.9% in infiltrating immune cells. PDL1 expression rate was rather higher in poorly differentiated samples and in patients without metastasis. CD8+ and CD3+ T cell densities were significantly lower with increasing post-NAC tumor size. CD8+ T dell density was also negatively correlated with tumor invasion level and lymph node metastasis. CD3+ and CD8+ T cell densities were significantly associated with improved OS, although only CD8+ T cell density remained a significant predictor in multivariate analysis [HR:0.974(95%CI:0.954-0.994), P = 0.013].
High CD8+ T cell density is closely related with late tumor stage, and significantly predicts improved overall survival in gastric cancer patients after neoadjuvant chemotherapy.
Jiafu Ji.
Has not received any funding.
All authors have declared no conflicts of interest.
Extracellular adenosine (Ado) is an immunosuppressive metabolite generated by the sequential activities of CD39 and CD73. High Ado, predominantly signaling through the A2AR, dampens immune responses and suppresses antitumor immunity. iTeos Therapeutics developed an A2AR antagonist, EOS100850, specifically designed to be a potent, highly selective and non-brain penetrant agent for treating a wide range of cancers.
The development of mIHC is a high-powered practical approach for phenotyping and correlating cellular interactions in the tumor microenvironment, which can also be used to monitor the response to treatment. We have optimized a 6-color mIHC panel for A2AR, CD39, CD73, TNAP, Cytokeratin and DAPI using tonsillar and breast cancer (BC) specimens using detection reagents. We also used an immune mIHC panel (CD4, CD8, CD20, CD68, FoxP3, Cytokeratin). Serial sections of tonsillar and BC tissues were stained and imaged at 20X on the Vectra Polaris (Akoya) platform and analyzed with InForm.
Optimal dilutions for each antibody were first determined. A2AR staining was detected on immune cell subpopulations. CD39, CD73 and TNAP were expressed on immune cells and endothelial cells (EC). CD73 expression was elevated in Tertiary Lymphoid Structures. Then the order and pairing with an optimal fluorophore was examined. The relative positivity for the Ado pathway markers was accomplished first by full mIHC staining on tonsil tissues and subsequent validation on BC specimens. In BC tissues, A2AR, CD39 and TNAP expression was detected on various immune cell populations and EC. CD73 was additionally expressed by tumor cells. We also detected immune cells on BC tissue sections to characterize the cellular expression of Ado pathway markers, and to allow making correlations between expression of the Ado pathway markers and TIL infiltrate.
We have established a specific mIHC protocol to identify the Ado pathway in cancer specimens. Characterization of Ado pathway markers in conjunction with infiltrating immune subpopulations in matched pre- and post-therapy patient specimens will now be investigated to identify specific tumors and treatments that will most likely benefit from combination therapy with EOS100850.
iTeos Therapeutics.
iTeos Therapeutics.
A. Pabois: Full / Part-time employment: iTeos Therapeutics. V. Bodo: Shareholder / Stockholder / Stock options, Full / Part-time employment: iTeos Therapeutics. A. Boisson: Advisory / Consultancy: iTeos Therapeutics. S. Crosignani: Shareholder / Stockholder / Stock options, Full / Part-time employment: iTeos Therapeutics. O. De Henau: Full / Part-time employment: iTeos Therapeutics. M. Detheux: Shareholder / Stockholder / Stock options, Full / Part-time employment: iTeos Therapeutics. S. Garaud: Advisory / Consultancy: iTeos Therapeutics. J. Lager: Full / Part-time employment: iTeos Therapeutics. C. Martinoli: Full / Part-time employment: iTeos Therapeutics. M. Mercier: Full / Part-time employment: iTeos Therapeutics. C. Naveaux: Advisory / Consultancy: iTeos Therapeutics. N. Thomas: Advisory / Consultancy: iTeos Therapeutics. N. Wald: Full / Part-time employment: iTeos Therapeutics. A. Vezzu: Full / Part-time employment: iTeos Therapeutics. K. Willard-Gallo: Advisory / Consultancy: iTeos Therapeutics. E. Houthuys: Shareholder / Stockholder / Stock options, Full / Part-time employment: iTeos Therapeutics.
In head and neck cancers, the number of intra-tumoral lymphocytes associates with improved survival. The impact of the exact cellular composition and localization of these lymphocytes, however, is less well studied. In the current study, we assessed the prognostic values of density, localization and cellular networks of defined lymphocyte populations in early-stage oral tongue cancer.
Patient with T1-T2, primary oral tongue squamous cell carcinoma and treated with surgical resections and without any peri-operative (chemo) radiotherapy were included in a discovery cohort (n = 47). Multiplexed in-situ immunofluorescent staining was performed using FFPE sections for CD4, CD8, CD20, pan-cytokeratin and cellular nuclei (DAPI); and spatial distributions of 3 lymphocyte populations were assessed in the tumour and stromal compartments, both at the invasive margin (IM) and the center of tumours (CT). Using algorithm-based pathology and nearest neighbor analysis (NNA), we have computed cellular densities and networks for lymphocytes and related these immune parameters to overall survival (OS). Findings were validated using another cohort of patients with identical clinical characteristics (n = 91).
In our discovery cohort, we observed a high stromal density of CD20-positive B cells at IM but not CT, which correlated with OS (p = 0.005, HR 0.225). NNA demonstrated that survival benefit particularly related to the number of CD20 cells in the vicinity of CD4 cells and the frequency of B cells touching each other. The prognostic value of B cell-rich areas was validated in a second cohort, but only for those patients with low stromal densities of CD4 T cells (in accordance to discovery cohort, p = 0.007, HR = 0.275).
Our study highlights the prognosis of B cell-rich areas in early-stage oral-tongue cancer patients, particularly in the context of low intra-tumoral CD4 T cell densities.
The authors.
Erasmus MC, Rotterdam, the Netherlands and HRH Princess Chulabhorn College of Medical Science, Bangkok, Thailand.
All authors have declared no conflicts of interest.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal, incurable disease and desmoplasia is one of its fundamental characteristics. Though a significant body of literature has been published regarding the disease, mechanisms for PDAC progression, invasion and metastasis still remain unclear. Stromal elements have been demonstrated to serve both pro- and anti-tumoural functions. Macrophages, one of the most abundant immune cell populations in the tumour microenvironment (TME), are a major component of the immune infiltrate in PDAC.
Employing a multi-omics approach, PDAC cell lines and primary macrophages were CTAP (cell-type specific labelling using amino acid precursors)-labelled and admixed together for a prolonged period of time. To identify cell-of-origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream Tandem mass tag (TMT)- proteome and secretome analysis.
Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a pro-invasive phenotype to PDAC cells when co-cultured in 3D, regardless of EMT status. Preliminary integration of cell culture transcriptomes with CTAP-TMT proteomes and secretomes implicates several key epithelial- and macrophage-derived signalling molecules as principal instructing signals for mediating the observed pro-invasive phenotype.
Blockade of these signalling molecules or their receptors disrupted the crosstalk between PDAC cells and macrophages within the TME and impaired the ability of macrophages to induce a pro-invasive phenotype to PDAC cells.
The author.
Has not received any funding.
The author has declared no conflicts of interest.
MUC16 mutation has been shown to be associated with survival outcomes in cancers, but the association of MUC16 mutation with clinical outcomes of immunotherapy remains to be explored. Here we performed clinical validation of MUC16 mutation as a predictive biomarker of immune checkpoint inhibitor (ICI) in patients with cancer.
This study analyzed genomic data from the cBioPortal database. Nonsynonymous mutations of MUC16 were considered. Kaplan-Meier survival analysis and logistic regression models were applied. Primary outcomes were overall survival (OS) and progression free survival (PFS).
A total of 2,129 cancer patients treated with ICI were included. The tumor mutation burden of patients with MUC16 mutations was substantially higher than in those without the mutations (Wilcoxon rank sum test, P < 0.0001). Patients with MUC16 mutations were associated with better OS benefits from ICI in non–small cell lung cancer (NSCLC) (hazard ratio [HR] 0.38, 95% CI 0.17 to 0.86) and in pancancer (HR 0.79, 95% CI 0.65 to 0.96) compared with wild-type population. Similar findings were observed in terms of PFS in NSCLC (HR 0.70, 95% CI 0.57 to 0.87) and in pancancer (HR 0.42, 95% CI 0.28 to 0.64).
We demonstrated that MUC16 mutation can predict survival benefit from ICI therapy in cancer, and suggested that MUC16 mutation should be integrated into predictive biomarker panels for ICI therapy and be validated in future prospective clinical trials.
Herui Yao.
Grants from the National Natural Science Foundation of China (81372819, 81572596, U1601223), the Natural Science Foundation of Guangdong Province (2017A030313828), the Guangzhou Science and Technology Program (201704020131), the Sun Yat-Sen University Clinical Research 5010 Program (2018007).
All authors have declared no conflicts of interest.
Mutation in the gene encoding Protein Tyrosine Phosphatase Receptor T (PTPRT) has been shown to influence survival outcomes in cancers. However, the association of PTPRT mutation with clinical outcomes of immune checkpoint inhibitor (ICI) remains unclear. Here we performed comprehensive analysis of PTPRT mutation frequency and clinically validated PTPRT mutation as a predictive biomarker of ICI in patients with cancer.
This study analyzed cancer genomic data from the cBioPortal database. All patients treated with ICI were included. Nonsynonymous mutations of PTPRT were considered. Kaplan-Meier survival analysis and logistic regression models were applied. Primary outcomes were overall survival (OS) and progression-free survival (PFS).
Among 2129 patients with non–small cell lung cancer (NSCLC) (n = 510), melanoma (n = 596), and other tumor types (n = 1,023), the tumor mutation burden of patients with PTPRT mutation was significantly higher than in those without the mutations in NSCLC, melanoma, and pancancer (Wilcoxon rank sum test, all P < 0.0001). Among patients receiving ICI, PTPRT mutation compared with PTPRT wild-type was associated with better OS in melanoma [hazard ratio (HR) 0.66, 95% CI 0.50 to 0.88] and in pancancer (HR 0.63, 95% CI 0.52 to 0.77), and was associated with better PFS in NSCLC (HR 0.55, 95% CI 0.35 to 0.87).
We demonstrated that PTPRT mutation can predict survival benefit from cancer ICI therapy. PTPRT mutation might be an important component of the immunogenetic landscape and should be integrated into predictive biomarker panels for ICI therapy and be validated in future prospective clinical trials.
Herui Yao.
This study was supported by grants from the National Natural Science Foundation of China (81372819, 81572596, U1601223), the Natural Science Foundation of Guangdong Province (2017A030313828), the Guangzhou Science and Technology Program (201704020131), the Sun Yat-Sen University Clinical Research 5010 Program (2018007).
All authors have declared no conflicts of interest.
In recent years, research has focussed on targeted immunotherapeutic therapies in UM are disappointing and questions remain regarding the mechanisms leading to metastases and the tumor’s resistance to treatment. Genetic predictors for metastatic tumor behavior is the loss of BRCA1-associated protein 1 (BAP1) expression. NF-κB is a principal coordinator of innate immunity and inflammation and has emerged as an essential endogenous tumor promoter. We hypothesize that genetic changes not only influence the immunological microenvironment but also drive metastasis in UM and that NC-NFκB proteins (p52 & RelB) are the consequence of a highly-inflammatory profile.
In our study, based on the expression of CD3 (infiltrating lymphocytes) and CD68 (infiltrating macrophages), we divided our study cohort into two categories: UM with inflammation and UM without inflammation. Expression of BAP-1 and NC-NFκB proteins (RelB & p52/NFκB2) was evaluated using immunohistochemistry. Real-time PCR was performed on 60 frozen tumor samples. The presence of p52/RelB heterodimer detected by Co-immunoprecipitation in UM with inflammation.
In the inflammation group, activation of NC-NFκB proteins found in 82% and 64% of cases while the loss of BAP-1 was observed in 82% of cases. Loss of BAP-1 protein along with activation of NC-NFκB proteins was seen in 70% of cases of the inflammation group. Loss of BAP-1 along with activation of C-NFκB proteins was statically significant with inflammatory factors such as CD34 + (p = 0.036), IL-6 (p = 0.012), LBD>15mm (p = 0.031) and epithelioid cell type (p = 0.027). In the inflammation group fold-change value of RelB (5.21) & NFκB2 (4.65) genes was reduced to 2.85 (RelB) & 2.34 (NFκB2) gene in the non-inflammation group. Mutation of BAP-1 was more frequently seen in the inflammation group than the non-inflammation group. Loss of BAP-1, along with the activation of NC-NFκB proteins, was associated with reduced metastasis-free survival and overall survival (p < 0.05).
Our preliminary data reveal that in an inflammation group loss of BAP-1 showed the synergistic role with the activation of NC-NFκB proteins and are the poor prognostic indicators of overall survival.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Immunotherapy has revolutionized cancer treatment, but clinical success is still limited to a subset of patients, underlining the need for novel therapeutic targets. Available ex vivo platforms for drug screening show limitations due to only partial recapitulation of tumor-intrinsic features and of the interactions of tumours with stromal/immune cells. Here, we review our 3D InSightTM tumour models, a complex platform allowing us to study the efficacy of immune-targeting agents on tumour infiltration and killing by peripheral blood mononuclear cells (PBMCs) using clinically relevant models of 3D tumour microtissues from patient-derived xenografts (PDX) with high translational potential.
Lung carcinoma GFP-A549 cells were cultured with dermal fibroblasts and PBMCs in Akura 96/384-well plates. To generate a pro-inflammatory tumour microenvironment, PBMCs were activated with cytokines, anti-CD3/CD28 or their combination. We assessed the effect of PD-1 inhibitors in combination with cytokines for potential synergistic anti-cancer effects. 3D InSight™ tumour Microtissue from Melanoma PDX were labeled with CellTracker to monitor for tumour cell viability once exposed to PBMCs. Killing activity and effector function of T cells were evaluated by measuring tumour microtissue size by automatic stage fluorescence microscopy and measuring release of IL-6, TNF, IFNγ and GM-CSF with a MAGPIXTM Luminex system over time. Immune tumour infiltration was quantified and the impact on survival was assessed histologically.
Combination treatment with cytokines and anti-PD-1 led to higher release of IL-6/TNF/IFNγ/GM-CSF and increased tumour microtissue infiltration by CD8+ T cells, resulting in enhanced tumour killing.
Our 3D InSightTM tumour models can be successfully employed for optimal high throughput screening of biologics to unveil the efficacy and anti-tumour properties of immune-targeting therapeutic agents.
InSphero.
InSphero AG.
All authors have declared no conflicts of interest.
Recent work has shown that immune activity in breast cancer (BC) plays a role in treatment responses and long-term outcomes. TIL scoring is now implemented as a prognostic marker in clinical practice. Studies show that high tumor infiltrating lymphocytes (TIL) are more often detected in triple negative and HER2 positive subtypes. TIL contain a heterogeneous population of immune cells dominated by T cells but also consist of many others. Neoadjuvant therapy (NAT) is increasingly administered in patients with locally advanced BC, allowing a resection of the tumor and to evaluate the in vivo response. While cytotoxic agents such as Anthracyclines elicit immunogenic cell death, the impact of NAT on TIL has only been sporadically studied.
A detailed assessment of the tumor microenvironment (TME) includes evaluation of TIL density, composition and functionally. Following NAT, lymphocyte subpopulations were quantified using flow cytometry(FACS) and these data were compared to untreated BC patients. Tumor tissue supernatants were stored for assessment of immunoglobulins (Ig). The FFPE blocks from matched biopsies and surgical tissues were stained with HE, chromogenic IHC and multiplex IHC. The stromal and intratumoral TIL were scored by two experienced pathologists.
Our preliminary data correlate better responses with highly infiltrated biopsies, consistent with published work. Overall, the trend following NAT is for a decrease in TIL density, but with great inter-patient variation. FACS analysis of immunophenotypes shows a shift from CD4 to CD8 T cells and an increase in memory B cells after NAT. An assay for Ig subtypes detected decreases in IgG1/IgM and increases in IgG2/IgA. Multiplex IHC analysis of the TME in a patient with residual cancer detected active immune responses surrounding the remaining tumor that were characterized by CD8 TIL attached to the malignant cells, suggesting their recognition and killing.
NAT provokes changes in immune activities at the tumor site in early BC, with some of these alterations apparently linked to specific treatments. Our ongoing efforts are designed to provide detailed insight into the alterations associated with different NAT modalities and define prognostic biomarkers.
The authors.
FRNS, Télévie, Les Amis de l\'Institut Bordet, Lambeau Marteau.
A. Pabois: Full / Part-time employment: Iteos therapeutics. All other authors have declared no conflicts of interest.
Patient outcomes with pancreatic ductal adenocarcinoma (PDA) remain dismal, despite the introduction of combination chemotherapies. Response to therapy is hampered by tumour stroma, which is highly heterogeneous but poorly characterised. The clinical success of immunotherapy in certain cancer types justifies investigation in PDA using a personalised approach of selecting pre-clinical models.
Patient PDA samples (n = 70; International Cancer Genome Consortium) were subjected to hierarchical clustering using a gene set representing CD8 and regulatory T cells to identify sub-groups. Syngeneic mouse models recapitulating these sub-groups (cross-species analysis) were developed using cell lines from genetically engineered mouse (GEM) models. Models bearing subcutaneous tumours were treated with anti-GITR agonist (DTA-1; 10mg/kg) or isotype (IgG2b) and tissues were collected for 12-color fluorescence activated cell sorting (FACS), NanoString and immunohistochemistry (IHC).
Using clustering analysis, we identified four distinct patient PDA immune sub-groups with differential expression of T cell genes. These sub-groups showed differential expression of glucocorticoid-induced TNF receptor (GITR) and its associated genes. Hence, we hypothesised that these groups may respond differently to anti-GITR therapy in vivo. As expected, the three syngeneic models showed differential response to anti-GITR treatment. Model with increased GITR expression (>2-fold; NanoString and immunoblot) showed a significant (p = 0.02) survival benefit and a modest decrease in tumour burden upon anti-GITR treatment (n = 10) compared to the isotype control (n = 7) and the other two models. We observed anti-GITR mediated increase in GITR+ CD8+ cells and no change in GITR+ FOXP3+ cells (FACS, NanoString and IHC) along with increased gene expression of Pdcd1, Lag3, Spn and Itk.
Our models recapitulate the immunological gene expression profiles observed in patient PDA samples making them a highly useful resource to study personalized immunotherapies. This integrated study highlights the importance of patient selection to maximize therapy benefit and spare immune related adverse events.
The authors.
Bristol-Myers Squibb.
D. Cunningham: Research grant / Funding (self): Amgen; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Merrimack; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Celgene; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Bayer; Research grant / Funding (self): 4SC; Research grant / Funding (self): Clovis; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Janssen; Research grant / Funding (self): Merck. N. Starling: Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): Eli Lilly; Honoraria (self): Merck Serono; Honoraria (self): MSD Oncology; Honoraria (self): Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. A. Sadanandam: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Merck KGaa; Research grant / Funding (self): Pierre Fabre. All other authors have declared no conflicts of interest.
Endogenous retroelements are a main source of targetable tumor-specific antigens that have the potential to augment host adaptive antitumor responses. KLRC3 gene encodes for the NKG2E and NKG2H isoforms of NKG2 family of transmembrane receptors. Current data support that NKG2E represents the main protein isoform.
Genome, mobilome and molecular evolutionarily analysis were performed through the corresponding tracks of UCSC Genome Browser Database. NKG2E protein expression data were downloaded from the Human Protein Atlas. NetMHCII 2.3 was used to predict MHC class II binding scores.
In normal tissues, NKG2E protein is scarcely expressed in a rare subset of immune cells in the intestinal tract and lymphoid tissue. Vice versa, in tumor tissues NKG2E expression is detected in > 75% of tumor cells in cases of liver, breast and ovarian cancer as well as in 25-75% of tumor cells in cases of thyroid, stomach and prostate cancer. NKG2E protein is encoded by the long isoform of KLRC3 gene. The last exon of this mRNA is derived via an Alu-element exonization, which provides the last 14 aa of the coding region. Previous analysis showed that the 14 aa Alu-peptide is hydrophobic and impels the intracellular retention of NKG2E protein thereby impeding its function as a transmembrane receptor. A previous study revealed the presence of highly-specific IgG autoantibodies against the Alu-peptide in a disease known to stimulate Alu RNAs overexpression, but not in healthy individuals. The latter signifies not only a high immunogenicity but also that the host is mostly immunologically ignorant rather than tolerant of the Alu-peptide. Accordingly NetMHCII analysis identifies the Alu-peptide as a HLA-DRB1_0103 and -DRB1_1101 high binder.
NKG2E protein represents an aberrant molecule that is misexpressed in multiple cancers, including immunologically “cold” tumor types. Characterization of the rare immune cells producing the aberrant NKG2E molecule in normal tissues warrants further research. Subsequent studies could inquire into a TCD4-specific TCR usage that would allow for the inoculation of cancer patients with autologous CD4-T cells reactive against the Alu-peptide.
Spyros I. Papamichos.
Has not received any funding.
The author has declared no conflicts of interest.
The ovarian tumour microenvironment is an abundant source of tumour-infiltrating lymphocytes (TILs) which can be readily harnessed for infusion in the context of adoptive TIL therapy. This strategy has been proven feasible, but it appears clinically ineffective in ovarian cancer patients due to the absence of tumour-reactive TILs and the presence of immunosuppression. Hence, we hypothesized that an oncolytic adenovirus expressing Tumour Necrosis Factor (TNF)-alpha(a) and Interleukin (IL)-2 (Ad5/3-E2F-D24-hIL-2-IRES-TNFa; TILT-123) could overcome this by generating a proinflammatory microenvironment and reinvigorating TIL anti-tumour activity.
Fresh explants from metastatic or primary tumour sites were obtained from stage III-IV ovarian cancer patients and short-term cultures were established in the absence or presence of oncolytic adenovirus. The remainder of the tumour explant was used to generate clinically relevant TILs which were co-cultured with autologous T cell-depleted single cell suspensions pre-treated with or without oncolytic adenoviruses. Cytokine content changes and TIL reactivity was assessed during culture by flow cytometry or interferon (IFN) gamma(g) enzyme-linked immune sorbent assay.
Treatment of short-term cultures with oncolytic adenovirus coding for TNFa and IL-2 introduced profound changes within the microenvironment, which were characterized by an increase in proinflammatory cytokines and decrease in suppressive cytokines. Further benefits were seen in T-cell depleted ovarian cancer single-cell suspensions infected with cytokine-coding oncolytic adenovirus, which enabled significant production of IFNg by autologous TILs. Such levels were not seen in co-cultures where no virus or the backbone oncolytic adenovirus (no cytokine transgenes) was added.
These data illustrate the potential of oncolytic adenovirus coding for TNFa and IL-2 to rewire the ovarian tumour microenvironment for effective TIL anti-tumour reactivity. This approach may improve the efficacy of adoptive TIL therapy in ovarian cancer patients, thus warranting further clinical investigation.
TILT Biotherapeutics Ltd.
TILT Biotherapeutics Ltd.
J.M. Santos: Full / Part-time employment: TILT Biotherapeutics Ltd. V. Cervera-Carrascon: Full / Part-time employment: TILT Biotherapeutics Ltd. M. Siurala: Full / Part-time employment: TILT Biotherapeutics Ltd. T. de Gruijl: Advisory / Consultancy: TILT Biotherapeutics Ltd. A. Hemminki: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.
Current hepatocellular carcinoma (HCC) immunotherapy trials only yield modest outcome, suggesting that possibly strong intrinsic immunosuppressive network needed to be tackled. Conventional chemotherapies are found to exert immunomodulatory effect on the tumor microenvironment (TME). Our study investigated anti-tumor activity of 5-FU in combination with anti-PD-L1, using pre-clinical HCC mouse model, and evaluated the immunomodulation in TME after drug treatments.
For the orthotopic HCC in vivo experiment, 6-8-week-old male C57BL/6 mice were injected intrahepatically with 5x10^5 RIL-175 luc+ cells. In order to assess its immunomodulatory effect on HCC TME rather than on direct tumor-killing effect, 5-FU was administrated (i.p.) 3 times per week at a relative low dose—20mg/kg. Whilst, anti-PD-L1(10mg/kg) was delivered (i.p.) every 5 days. Tumor growth was monitored via in vivo imaging. Tumor, liver, spleen and blood was collected afterwards, followed by immune profiling analysis via flow cytometry.
In terms of in vivo imaging results, mice with single anti-PD-L1 treatment showed significant response in tumor growth amongst other groups. Meanwhile 5-FU monotherapy and combined treatment group showed no difference with vehicle group. We found an increased amounts of T lymphocytes and NK cells in the tumor site after anti-PD-L1 single treatment, suggesting that these immune active cells contributed to the anti-tumor effect. Tumor-infiltrating myeloid cells, particularly P-MDSC, elevated upon 5-FU treatment in both single and combined group, suggesting that they may play a role in mediating immunosuppression.
This study illustrated that anti-PD-L1 monotherapy enriched tumor-infiltrating T lymphocytes and NK cells, possibly accounting for the deferred tumor growth. However, the accumulation of myeloid cells in 5-FU treated mice hinders the anti-tumor activity of anti-PD-L1 from this orthotopic HCC mouse model. Therefore, low dose of 5-FU may initiate immunosuppressive mechanism to alter the effectiveness of anti-PD-L1 in HCC.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Human cancers are heterogenic and thus response to immune checkpoint inhibitors (ICIs) such as anti-PD-1 or anti-PD-L1 antibody treatments can be vastly different, with only ∼20% of treated patients responding and some initial responders developing resistance. However, the mechanism of action (MOA) underlying these differences has yet to be revealed. In this study we treated syngeneic tumor-bearing mice with anti-PD-1 antibody in combination with targeted immune cell depletion in order to understand how different lineages of immune cells impacted anti-PD-1 efficacy.
Selected immune cell subpopulations were depleted in four different subcutaneous murine syngeneic models (MC38, CT26.WT, EMT6 and Hepa 1-6) and anti-PD-1 (10mg/kg) was administered either following the depletion (only for anti-CD25) or concurrently with the depletion antibodies. The effectiveness of each depletion was assessed by flow cytometry analysis of tumor, blood and spleen at the end of each study. Tumor samples from few sub-groups of MC38 and Hepa1-6 models were processed for proteomics analysis (collaboration with Biognosys).
As expected, depletion of CD8+ T cells completely abolished the antitumor effects of anti-PD-1 treatment in MC38, EMT6 and CT26.WT, confirming the crucial roles of CD8+ T cells in tumor killing; Interestingly, anti-PD-1 efficacy in Hepa1-6 was only modestly attenuated by eliminating CD8+ T cells, indicating a vital role of non-CD8+ effector cells in mediating anti-PD-1 efficacy in this particular line. Depletion of NK showed a minor impact on the efficacy of anti-PD-1 treatment, whereas the depletion of macrophages largely promoted the efficacy of anti-PD-1 in MC38 and CT26.WT; however, weakening the effect of anti-PD-1 in the Hepa 1-6 model. Depletion of Treg demonstrated synergistic effects with anti-PD-1 treatment in controlling CT26.WT and EMT6 tumors.
Our studies show an unequivocal role of CD8+ T cells in anti-PD-1 induced tumor growth inhibition. However, other immune cell lineages may act differently upon PD-1 blockade release, presumably depending on specific tumor microenvironment.
The authors.
CrownBio, Biognosys.
All authors have declared no conflicts of interest.
Oncolytic viruses (OV) induce potent antitumor treatment effects not only via direct tumour infection and lysis but also via activation of innate and adaptive immune responses. As such, they show strong synergism in combination with various immunotherapy strategies. Here we address the question to what extend intratumoral viral replication of the vesicular stomatitis virus variant VSV-GP affects the tumour microenvironment of three different syngeneic mouse tumour models B16, TRAMP and LLC.
To model tumours with higher permissivity for OVs we generated interferon receptor deficient cells (TRAMP-IFNAR1-/- and LLC1-IFNAR1-/-). Bio-luminescent imaging was used to assess intratumoral virus propagation. Efficacy of VSV-GP was assessed in vivo in syngeneic C57BL/6 mice. The tumour micro environment was studied using flow cytometry, histology, multiplex cytokine ELISA and NanoString® transcriptome analysis.
Intratumoral viral propagation was enhanced in the IFNAR1-/- tumours compared to B16. In LLC1-IFNAR1-/- tumours, VSV-GP treatment resulted in significant upregulation of over 300 immune-related genes, increase in tumour infiltrating lymphocytes and expression of pro-inflammatory cytokines. In contrast, immune activation markers in virus replication-restricted B16 tumours were only slightly increased. Yet, based on transcriptional analysis, we found a common VSV-GP treatment-associated immune gene signature. Furthermore, we have observed that VSV-GP induces an up-regulation of inflammatory cytokines in all tumour models, such as type-I IFN, IFN-γ and TNF-α, which correlates with an increase of the T-cell infiltration in the tumour. Other cytokines, such as IL-6 or IL-10, were found to be differently regulated depending on the model.
In conclusion, we present a number of immune-activating consequences of virotherapy treatment in syngeneic tumour models with varying degree of virus propagation. Higher virus activity in the tumour qualitatively and quantitatively shapes the tumour microenvironment differently compared to tumours with restricted virus activity.
The authors.
Christian Doppler Research Association.
G. Wollmann: Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim. B. Spiesschaert: Full / Part-time employment: Boehringer Ingelheim. P. Erlmann: Full / Part-time employment: Boehringer Ingelheim. B. Stierstorfer: Full / Part-time employment: Boehringer Ingelheim. D. von Laer: Advisory / Consultancy: Boehringer Ingelheim; Shareholder / Stockholder / Stock options, Licensing / Royalties: ViraTherapeutics. P. Mueller: Full / Part-time employment: Boehringer Ingelheim. All other authors have declared no conflicts of interest.
We reported in recent publication that bacterial lipopolysaccharides (LPS) and mast cells are involved in the pathogenesis of the premalignant lesion, oral lichen planus (OLP). However, the mechanisms beyond such effect remain unknown. We therefore investigated the role of the antimicrobial peptide response, via human β-defensin 2 (hBD-2), in promoting OLP pathology and its potential contribution to oral squamous cell carcinoma (OSCC).
Biopsies from premalignant oral lichen planus (OLP) patients, OTSCC patients and healthy controls were used. Two OTSCC cell-lines and normal human keratinocytes (HOKs) were used for in vitro studies. HBD-2 and other targets were mapped by immunohistochemistry and double-labelling immunofluorescence. Immunoreactivity was analysed by ImageJ2 software. The highly sensitive droplet-digital PCR technology and qRT-PCR were utilized to study the clinical- and in vitro-derived samples, respectively. H4R was challenged with the specific agonist HST-10 and the inverse agonists/antagonists ST-1007.
hBD-2 was highly induced in OLP lesions. The expression was lower in OTSCC tissues while very low levels of hBD-2 mRNA were observed in OTSCC cells. Mast cells were the main non-epithelial producers of hBD-2 in OLP lesions. Histamine synergistically induced TNF-α- and IFN-γ-mediated production of hBD-2 in HOKs. Furthermore, H4R activation inhibited TNF-α-mediated induction of epithelial hBD-2 while ST-1007 reversed such effect.
Dysregulated production of hBD-2 could enhance a proinflammatory vicious circle in OLP, which can further damage healthy neighbouring cells and may over time promote carcinogenesis. Histamine and H4R can modulate hBD-2 response in oral epithelium and may serve as promising targets for therapeutic interventions.
TULES Research Group.
Doctoral Program in Oral Sciences, University of Helsinki.
All authors have declared no conflicts of interest.
Immunosuppressive neutrophils with surface expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) existed at both tumor sites and blood in patients with head and neck squamous cell carcinoma (HNSCC). Their immunosuppressive activities were proved to be induced by endoplasmic reticulum (ER) stress. In addition, ER stress of cancer cells could be “transmissed” to nearby myeloid cells such as dendritic cells and macrophages. Based on these findings, we hypothesized that ER stress of HNSCC could induce LOX-1 expression and immunosuppression of nearby neutrophils.
Conditioned medium (CM) from SCC25 cancer cells with or without treatment of thapsigargin (THG), a common ER stress inducer, was collected. Human neutrophils, isolated from peripheral blood of healthy donors, were then cultured in differently prepared conditioned medium. After 4 hours of culture, LOX-1 expression of neutrophils was evaluated by flow cytometry. In addition, the immunosuppressive effects of these conditioned neutrophils were evaluated by their abilities to inhibit nonspecific T cell proliferation using interleukin-2 (IL-2)/anti-CD3/anti-CD28 system.
Higher percentages of neutrophils expressed LOX-1 after they were cultured in CM from THG-treated SCC 25 cells than in CM from naïve SCC 25 cells. Moreover, conditioned neutrophils by THG-treated SCC 25 cells had more inhibitory effects in T cell proliferation than conditioned neutrophils by naïve SCC25 cells.
ER stress induction of SCC25 could enhance both LOX-1 expression and immunosuppressive activities of neutrophils.
The authors.
Ministry of Science and Technology, Taiwan.
All authors have declared no conflicts of interest.
We recently showed that IL-17F expression correlates with better overall survival in oral tongue cancer (OTSCC) patients. Moreover, IL-17F inhibited OTSCC cell proliferation and migration. However, anti-angiogenic drugs showed limited effects in cancer treatment, where cancer cells use “de novo” vessel-like channels called vasculogenic mimicry (VM) to enhance nutrient supplies. Therefore, we aimed to investigate the vasculogenic mimicry in OTSCC and the potential effect of IL-17F on such phenomenon.
we used qRT-PCR immunostaining, and Western blotting methods to investigate the expression of VM-related markers (such as CD31, CD34 and VEGFA) at both gene and protein level, respectively. The capacity to create tube-like (channel-like) structures in 3D matrices were assessed in two different OTSCC-derived cell lines (the highly-aggressive HSC-3; and the less-invasive SCC-25). Tube-formation assays were used to examine the effects of IL-17F on angiogenesis using cancer cell lines and human umbilical vein endothelial cells (HUVEC), with or without antiangiogenic agents.
OTSCC cell lines showed differential expression of CD31, CD34 and VEGFA genes. The level of such markers was dependent on the 3D matrix (Matrigel). OTSCC cells expressed abundant CD31 and CD34 receptors. In addition, we confirmed the presence of VM in more advanced-stages of OTSCC patients. Importantly, both HSC-3 and SCC-25 created channel-like structures when cultured on Matrigel matrix. Interestingly, IL-17F inhibited the tube-formation in HUVEC cells, and showed promising anti-angiogenic effects in vitro.
Our findings confirm the role of VM in OTSCC carcinogenesis. Here, we suggest that IL-17F counteracts the tumorigenic activity in OTSCC, in part, through the antiangiogenic effect in the tumour microenvironment, and hence further studies are warranted. Harnessing IL-17F in the current management approaches in advanced OTSCC patients may lead to promising immunotherapeutic strategies against OTSCC.
University of Helsinki.
University of Helsinki, Doctoral program in clinical research (KLTO).
The author has declared no conflicts of interest.
Standard treatment of oropharyngeal squamous cell carcinoma (OPSCC) is associated with strong morbidity, whereas immunotherapeutic approaches using PD-1:PD-L1 checkpoint blockade only show moderate response rates in OPSCC patients. Therefore, the development of a complex therapeutic protocol combining checkpoint inhibition with other targets is needed for better responses. The significance of tumor-infiltrating B cells (TIL-Bs) in shaping antitumor immunity remains unclear; therefore, we analyzed frequency, phenotype, prognostic value and possible roles of TIL-Bs in OPSCC.
In this study, we evaluated the density and distribution of TIL-Bs in FFPE samples from 2 cohorts of OPSCC patients. Than we assessed the phenotype of TIL-Bs by means of flow cytometry in fresh tumor samples immediately after radical surgery. The acquired data were corelated with the clinical outcome of the patients.
We observed that CD20+ TIL-Bs and CD8+ T cells formed non-organized clusters with clearly interacting cells and the densities of both intraepithelial CD20+ B cells and B/CD8+ T cell interactions have prognostic significance for the overall survival of OPSCC patients. Furthermore, a high density of TIL-Bs was associated with an activated B cell phenotype and a high density of direct B cell/CD8+ T cell interactions significantly correlated with the abundance of HPV16-specific CD8+ T cells.
Our results indicate that high abundance of TIL-Bs and high density of direct B cell/CD8+ T cell interactions can preselect patients with excellent prognosis who would profit from less invasive treatment. Furthermore, including B cells as an additional target in novel immunotherapeutic protocols may help to establish the desired sustained antitumor T cell responses in OPSCC patients.
Kamila Hladikova.
Sotio a.s.
All authors have declared no conflicts of interest.
Glioblastoma multiforme (GBM) is one of the most malignant primary brain tumor and is known to create an immunosuppressive microenvironment that hampers the efficacy of therapies. We demonstrated that GBM microenvironment is infiltrated with a large proportion of bone marrow-derived macrophages (BMDMs) that possess a strong immune suppressive activity. Following 5-aminolevulinic acid (5-ALA) administration to patients before surgery, BMDMs show the highest protoporphyrin IX (PPIX) fluorescence emission, compared to immune and non-immune cells. Since PPIX is the precursor of heme we wondered if the presence of this metabolite could be the consequence of an altered iron metabolism in BMDMs, and if this pathway could be linked to their immunosuppressive activity.
GBM tissues were dissociated and subjected to immunomagnetic or FACS sorting for the separation of BMDMs. The expression of HMOX1, the gene coding for heme oxygenase-1 (HO-1) which is a central enzyme in the iron pathway, was analyzed by RT-PCR. BMDM immune suppressive activity was evaluated as the ability to suppress the proliferation of T lymphocytes also in the presence of HO-1 inhibitors. In order to optimize the experimental conditions, immunosuppressive macrophages derived from M-CSF treated monocytes from healthy donors were set up. Another in vitro model of immunosuppressive cells, bone marrow derived-myeloid derived suppressor cells (BM-MDSCs), was tested.
HMOX1 expression was found to be upregulated in BMDMs compared to other cells. The treatment of BMDMs with a HO-1 inhibitor was able to restore T cells proliferation in immune suppressive assays. The recovery of immunosuppression following treatment with the inhibitor has also been demonstrated in macrophages and in BM-MDSCs.
Our results show that the connection between iron metabolism and immune response could be exploited from a therapeutic point of view. In particular, HO-1 plays a role in BMDM-induced immunosuppression and could represent a new target to relieve the immunosuppressive microenvironment present in GBM patients.
University of Padua.
AIRC.
All authors have declared no conflicts of interest.
Lung, breast, melanoma, colorectal or renal carcinoma cells frequently metastasize to the central nervous system (CNS) and the frequency of CNS metastases increases with a prolonged survival of cancer patients. New anti-cancer therapies frequently fail to reduce metastatic burden. Tumor-associated macrophages act as pro-tumorigenic cells facilitating tissue remodeling, invasion and metastasis. The CNS is equipped in resident macrophages, including microglia, perivascular, meningeal and choroid plexus macrophages, that may interact with metastatic cancer cells and create a permissive niche in the CNS. The literature review shows accumulation of activated microglia in different cancer metastases.
We evaluated systematically the abundance and morphology of microglia and other macrophages on tissue microarrays and sections from breast cancer metastases using immunohistochemistry. Searching for a potential attractant of microglia, we evaluated the expression of Osteopontin (OPN) on sections from breast cancer metastases and the protein levels in six human breast cancer cell lines. The responses of microglial cultures to breast cancer MDA-MB-231 cells were characterized. Invasion of breast cancer cells in co-cultures with microglial cells was evaluated using a Matrigel assay.
We found activated, amoeboid microglia in tissues surrounding breast cancer CNS metastases. OPN was expressed mainly by metastatic breast cancer cells and its high expression was also noted in CNS metastases from different cancers. Invasiveness of MDA-MB-231 cells co-cultured with murine or human microglial cells was significantly increased. OPN was produced by human breast cancer cells, but not by non-transformed cells. Its expression was blocked by minocycline, a clinically used antibiotic.
Our study shows that metastatic cancer cells may employ microglia to facilitate colonization of brain parenchyma. OPN production is elevated in cultured breast cancer cells and CNS breast cancer metastases. OPN can mediate interactions between microglia and metastatic cancer cells. Minocycline interferes with those interactions and may impair creating a metastatic niche and cancer progression.
Nencki Institute of Experimental Biology.
Foundation for Polish Science Team Tech Core Facility: Development of comprehensive diagnostics and personalized therapy in neuro-oncology.
All authors have declared no conflicts of interest.
Glioblastoma (GBM) is a common and aggressive brain tumour, which is resistant to standard therapies. Clinical and experimental data demonstrated upregulation of Arginase 1 (ARG1) gene and protein in malignant gliomas, particularly in tumour infiltrating microglia and macrophages. Elevated Arginase 1 expression leads to depletion of L-arginine required for T cell and natural killer cell proliferation. A novel, selective small molecule arginase inhibitor - OAT-1746- was developed by OncoArendi Therapeutic SA and we evaluated its antitumour efficacy as a monotherapy and in combination with antibody against PD-1.
Efficacy of the inhibitor in blocking microglia dependent glioma invasion has been determined in Matrigel invasion assays. Its potential cytotoxicity towards microglia and glioma cells in vitro has been evaluated with a MTT metabolism test. Antitumour activity of targeting drugs was assessed in a murine Gl261 glioma model. Tumour volume was measured using an in-vivo imaging system after 21 and 28 days. Immune heterogeneity of glioma microenvironment was analysed by flow cytometry.
The co-culture of microglial cells with glioma cells increased the invasiveness of U87 MG and LN18 glioma cells. This microglia dependent invasion was reduced significantly and in a dose dependent manner in the presence of inhibitor. OAT-1746 orally administrated (twice a day) to animals implanted intracranially with GL-261 glioma cells reduced tumour volumes at day 21st and 28th as determined using an in vivo-imaging X-treme. While tumour growth was reduced with OAT-1746 or anti-PD-1 as monotherapies, the inhibition was higher when combination of OAT-1746 or anti-PD-1 was provided. OAT-1746 effectively crossed the BBB and increased arginine levels in brains of mice bearing gliomas. arginine levels in brains of mice bearing gliomas.
These results demonstrate that arginase is a key mediator of immuno suppression in gliomas, and inhibiting Arg1 shifts the immune response toward a pro-inflammatory environment. Our results suggest that combining OAT-1746 with other immunotherapies may improve responses in glioblastoma.
Molecular Neurobiology, Nencki Institute of Experimental Biology.
Project DIMUNO: “Development of new cancer therapies based on selective antitumour immunomodulators”, co-financed by the National Centre for Research and Development.
All authors have declared no conflicts of interest.
Triple-negative breast cancer (TNBC) patients are the least fortunate in terms of diagnosis, prognosis and treatment compared to other BC subtypes. Chemotherapy remains the standard treatment, with remarkable rate of resistance. Immunotherapy, on the other hand has shown promising approaches for this aggressive BC subtype. A critical determinant of the success of the immunotherapeutic approaches introduced recently in the clinics is the tumour microenvironment (TME). Our research group has recently highlighted the potential role of IL-10 in shaping the TME of TNBC patients. In this study, we focus on the main pro-inflammatory cytokine, tumour necrosis factor-α (TNF-α), in modulating TME in TNBC cells. In a more translational approach, ncRNAs have been casted as vital regulators of the immune system. A new frontier in the ncRNA world is the cross talk between miRNAs and lncRNAs. In this study, we aimed to investigate the role of microRNA-17-5p and its cross-talk with the oncogenic long non-coding RNAs: MALAT1 and H19 in regulating TNF-α in the TME of TNBC.
Forty BC patients were recruited. In-silico analysis was performed. MDA-MB-231 cells were cultured and transfected with miR-17-5p oligonucleotides, MALAT1 and H19 siRNAs. Total RNA was extracted and quantified by qRT-PCR. Cellular viability, Colony forming ability and cellular migration were measured using MTT, colony forming assay and scratch assay respectively.
miR-17-5p was down-regulated while MALAT1, H19 and TNF-α were markedly upregulated in TNBC patients. In-silico analysis showed that miR-17-5p binds to MALAT1, H19 and TNF-α. Ectopic expression of miR-17-5p resulted in a significant reduction in H19, MALAT1 and TNF-α. Reciprocally, knocking down of MALAT1 or H19 resulted in a marked induction in miR-17-5p levels. However, MALAT1 and H19 siRNAs decreased TNF-α levels. Functionally, miR-17-5p resulted in a marked reduction in cellular viability, colony forming ability and cellular migration of TNBC cells.
miR-17-5p/MALAT-1/H19/TNF-α represents an immunomodulatory loop that diverts the host immunity in favour of anti-tumour response.
German University in Cairo.
Has not received any funding.
All authors have declared no conflicts of interest.
Signal Regulatory Protein α [SIRPα] is a polymorphic protein, strongly expressed on myeloid suppressive cells. BI 765063 (OSE172), a humanized IgG4 monoclonal antibody (mAb), is a selective antagonist of SIRPα/CD47 interaction and does not bind to SIRPɣ, known to assist T cell co-stimulation and migration. BI 765063 strongly binds V1 allele, one of the 2 major functional allele of SIRPα expressed in more than 80% of general population and Asian (in 60%). Anti-tumor effect was shown in various in vivo cancer models using the validated anti-mouse SIRPα mAbs surrogate as single agent. The effect was more pronounced in combination with T checkpoint inhibitors (Gauttier V et al, 2018). BI 765063 mechanism of action includes promotion of tumor-antigen-presentation while preserving T-cell activation and increasing tumor phagocytosis.
This study comprises a dose escalation (step 1) to determine the Dose-Limiting Toxicities, Maximum Tolerated Dose (MTD), and Recommended phase II Dose (RP2Ds) of BI 765063 monotherapy and with BI 754091, and dose-confirmation expansion cohorts (step 2). In Step 1, ascending doses of BI 763063 every 3 weeks intravenously (iv) using a Bayesian approach with overdose control are tested. When MTD determined, BI 763063 will be tested with BI 754091, a PD-1 mAb inhibitor. In step 2, 2 parallel randomized, non-comparative mono and combination cohorts will further confirm the RP2Ds and assess the safety and preliminary efficacy (RECIST 1.1 and iRECIST). Patients ≥ 18 years, PS:0-1, with advanced solid tumor who failed or are not eligible to standard therapy will be included. V1/V1 and V1/V2 patients (central testing) are evaluated in separate cohorts in step 1. In step 2 selected population of V1/V1 patients with selected advanced-stage cancers will be included. Pharmacokinetics (PK), SIRPα receptor occupancy (RO) and a comprehensive translational program (in blood and tumour) will assess PK/PD profile and biomarkers of activity. The trial is currently active and will include 116 patients (56 in step 1 and 60 in step 2).
EudraCT: 2018-003830-34; Release date 1 October 2018.
OSE Immunotherapeutics.
OSE Immunotherapeutics in collaboration with Boehringer Ingelheim.
A. Marabelle: Advisory / Consultancy: Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daiichii Sankyo, Imaxio, Sanofi, BioNTech, Corvus, GLG, Deerfield, Guidepoint Global, Edimark, System Analytics, imCheck, Sotio, Bioncotech, Molecular Partners, Pillar Partners, Boehringer Inge; Advisory / Consultancy: Innate Pharma, Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, Bristol-Myers Squibb, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE immunotherapeutics, Transgene, Gritstone, M; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi ; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Merck (MSD), Roche; Speaker Bureau / Expert testimony: Roche/Genentech, Bristol-Myers Squibb, Merck (MSD), Merck Serono, AstraZeneca/Medimmune, Amgen, Sanofi. P. Cassier: Honoraria (self): Novartis, Roche/Genentech, Blueprint Medicines, Amgen; Honoraria (institution): Novartis , Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme, Taiho Pharmaceutical, Toray Industries, Transgene, Loxo, GlaxoSmithKline, Innate Pharma, Janssen ; Travel / Accommodation / Expenses: Roche, Amgen, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme. S. Champiat: Honoraria (self): Amgen, Bristol-Myers Squibb, AstraZeneca, Janssen, MSD, Novartis and Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck , Novartis, Pfizer, Roche and Sanofi; Non-remunerated activity/ies: AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. A. Vinceneux: Advisory / Consultancy: UBS. R. Huhn: Full / Part-time employment: Boehringer-Ingelheim. N. Poirier: Shareholder / Stockholder / Stock options: Ose Immunotherapeutics; Full / Part-time employment: Ose Immunotherapeutics. B. Vasseur: Full / Part-time employment: Ose Immunotherapeutics. All other authors have declared no conflicts of interest.
CD137 (4-1BB) is widely considered a comprehensive marker of T cell activation, and it is largely used in cancer immunology to determine the proportion of tumor-reactive T cells. However, CD137 detection does not provide specific information regarding the functions of activated T cells. Hence, in this study we tried to determine whether the simultaneous detection of CD137 plus common antitumor immune functions (type 1 functions such as production of cytokines TNFα and IFN-γ, or upregulation of CD107a) was feasible and provided advantages over using both methods separately.
The influence of common protein transport inhibitors used to allow cytokine detection, such as Brefeldin A (BFA) or Monensin (MN), on surface and intracellular expression of CD137 was tested in vitro. Activation of tumor infiltrating lymphocytes (TILs) was achieved with unspecific stimuli (PMA and Ionomycin) or naturally presented tumor-antigens (autologous tumor cells). TIL activation was defined as the proportion of CD4+ or CD8+ TILs staining for either CD137 (CD137+ TILs) and/or at least one of TNFα, IFNγ and CD107a (Type 1 function+ TILs) via flow cytometry.
Our results showed that MN had minimal impact on the ability to detect surface CD137, whereas BFA had a much larger effect regardless of the stimulus employed. Nonetheless, robust results could be obtained when type 1 functions detection was combined with intracellular staining of CD137 in the presence of both BFA and MN. Using this method, we identified three tumor-antigen specific T cell subpopulations, characterized by combined expression of CD137 and type 1 functions or CD137 without type 1 functions and vice-versa. The combined method allowed the identification of a much larger proportion of tumor-reactive T cells, over either of the two methods used alone. Indeed, CD137 alone identified 46% of the total tumor-reactive CD8+ TILs, while 86% of the total tumor-reactive CD8+ TILs were positive for type 1 functions.
Combined detection of CD137 and common type 1 functions represents a more comprehensive method to identify and characterize the total repertoire of tumor-antigen specific, activated T lymphocytes, regardless of the antigen recognized.
Herlev and Gentofte Hospital.
Research grant A11806 and A12535, The Danish Cancer Society; Research grant R233-2016-3728 and R286-2018-991 Lundbeck Foundation; Clinician-Scientist Grant from the Herlev and Gentofte Hospital Research Council.
All authors have declared no conflicts of interest.
Cancer immunotherapy has revolutionized treatment options for patients suffering from immunogenic tumors, among them melanoma, bladder and lung cancer. In the context of colorectal cancer (CRC), the administration of checkpoint inhibitors (CPIs) was shown to induce durable clinical responses in patients with mismatch repair deficient and microsatellite instable tumors, a though very small fraction of all CRC subtypes. To ameliorate response rates in metastatic CRC, various therapeutic strategies are currently being investigated to increase the immunogenicity of mismatch repair proficient (pMMR)/ microsatellite stable (MSS) CRC tumors and to set the ground for immunotherapy. Several conventional therapies approved for treating CRC patients are classified as immunogenic cell death inducers and may aid in priming cytotoxic T cells to the patient’s tumor.
At 2cureX, we aim to pre-therapeutically measure the potential responsiveness of a CRC patient to various drug therapy options to support the oncologists in identifying the best suitable treatment regimen. Our functional IndiTreat® assay system allows for testing of chemotherapeutic agents, targeted therapies and combinations thereof against micro-tumors (tumoroids), which we derive from CRC tissue or liver metastases. To broaden the applicability of the IndiTreat® test, the present study aims to adapt the assay system to functional testing of checkpoint inhibitors in the context of pMMR/MSS CRC, subsequent to standard of care therapy.
To assess the potential efficacy of IO interventions for individual patients, we co-culture tumoroids and (in vitro expanded) autologous PBMCs and monitor immune-mediated killing of tumoroids in the presence of CPIs. Tumoroids recapitulate the highly individual disease of cancer patients and constitute a valuable platform for evaluating different aspects of immune-mediated tumor cell recognition and killing.
In vitro testing of individual responses to CPIs will be of key relevance for stratifying pre-treated pMMR/MSS CRC patients according to their likelihood to benefit from IO therapy and holds the potential to make these powerful drugs available to more patients suffering from CRC.
The authors.
2cureX, BMBF KMU-innovativ.
T. Sturmheit: Full / Part-time employment: 2cureX. T. Sutus Temovski: Full / Part-time employment: 2cureX. J. Thastrup: Full / Part-time employment: 2cureX. W. Fiedler: Advisory / Consultancy, Research grant / Funding (self), Licensing / Royalties: Amgen; Advisory / Consultancy: ARIAD/ Incyte; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Jazz Pharmaceuticals; Research grant / Funding (self): Pfizer. J. Wellbrock: Licensing / Royalties: Amgen. J. Kupper: Full / Part-time employment: 2cureX. A. Block: Research grant / Funding (self): 2cureX . All other authors have declared no conflicts of interest.
CD3 bispecific antibodies are a very potent means to re-activate the immune system against tumour cells targeting cancer-associated antigens and CD3 on T cells and acting as direct immune activators. The aim of this study was to investigate the early changes occurring in the tumour and peripheral blood in tumour bearing mice treated with a T cell Bispecific (TCB) antibody designed to elicit T cell activation upon simultaneously binding to T cells and to a tumour-specific target.
C57Bl/6 mice bearing a B16 metastatic lung murine melanoma were treated with a single dose iv of a TCB targeting murine CD3 and an antigen highly expressed in the B16 tumour. At 2h, 4h, 7h, 24h, 48h after treatment blood was collected for hematology, serum chemistry, cytokines, flow cytometry and pharmacokinetic analysis and the tumour-bearing lung was collected and analyzed for cytokines, flow cytometry and histopathology.
Treatment with the targeted TCB induced, starting from two hours post single dose administration, a transient marked drop in lymphocytes, an increase in neutrophils and monocytes and an increase in acute phase proteins (haptoglobin, SAA1, a1-AGP and SAP) in the peripheral blood, correlating with the histopathological changes at the tumour site. Histopathology, immunohistochemistry and flow cytometry of the tumour showed that acute inflammation was already present at two to four hours after treatment in the form of neutrophilic infiltrate, while CD3+ T lymphocytes started to accumulate in the tumour 24h after treatment. These changes were accompanied by an increase of some cytokines in the tumour (e.g. IL-6, MCP1, IL-1b) and in the peripheral blood.
Changes observed in tumour bearing mice upon treatment with a tumour-targeted TCB suggest an early engagement of tumour resident T cells resulting in cytokine release locally and systemically within 2h after treatment, with homing and extravasation of inflammatory cells into the tumour progressively increasing 24h to 48h after treatment. This course of events is believed to be translatable to patients treated with TCBs.
Roche Glycart AG.
Roche Glycart AG.
A.M. Giusti: Full / Part-time employment: Roche Glycart AG. J. Sam: Full / Part-time employment: Roche Glycart AG. M. Karagianni: Full / Part-time employment: Roche Glycart AG. A. Schneider: Full / Part-time employment: Roche Glycart AG.
A combination therapy based on chemotherapy (CT) and Anti-PD1 is the new standard FDA-approved first-line treatment for (R/M) HNSCC PD-L1 negative pts. The addition of pembrolizumab to cetuximab has been proved feasible in a recent Phase II trial for anti-PD-1/PD-L1 and cetuximab naïve HNSCC pts. The efficacy of cetuximab-based CT regimens in the post-IT setting, has not been assessed.
We analyzed 27 R/M HNSCC pts treated at the Vall d´Hebron Hospital from 2015-2019 with CT post-IT, including cetuximab-based CT (CT+cetu post-IT) and non-cetuximab CT regimens (CT post-IT). Clinicopathological features and treatment modalities were correlated with outcomes. Overall survival (OS) was calculated from the first cycle of CT post-IT until death or last follow-up with Kaplan-Meier method.
Out of 27 pts, median age was 62y, all ECOG ≤1, treated with CT+cetu post-IT 20 pts (74%) or CT post-IT 7 pts (26%). P16 immunohistochemistry was present in 3 pts (17%). Median prior lines was 1 (range 1 - 4) and median follow-up was 6 months (m). Median OS was 8 m (CI95% 5 - 23) and median progression free survival (PFS) 5 m (CI95% 3 - 7). No significant differences were found in OS according to cetuximab addition (P = 0.252 log-rank test). In the CT post-IT cohort, 2 pts (29%) had a partial response (PR) and 5 (71%) had progressive disease. Clinical benefit rate (CBR, defined as complete + partial + stable disease) was 29%. Among pts treated with CT+cetu post-IT, 2 pts (11%) achieved a complete response (CR), 10 (52%) achieved a PR and 2 (11%) stable disease (CBR= 74%). A significantly higher CBR was observed for cetuximab based CT regimens following IT (P = 0.036 chi-square test). Among CR pts in the CT+cetu post-IT cohort, all were cetuximab naïve. Interestingly, both pts achieving a CR had PD as best response on previous IT.
In our cohort, the addition of cetuximab to CT post-IT was associated with promising CBR. These results suggest that CT+cetu post-IT regimens may have a role in (R/M) HNSCC pts. Future prospective trials are needed to assess the sensitization effect of IT on cetuximab-based CT and the optimal sequence of treatments in (R/M) HNSCC.
Vall d´Hebron Institute of Oncology.
Has not received any funding.
All authors have declared no conflicts of interest.
The first approval of a checkpoint inhibitor was granted in 2011.
We retrospectively examined all approvals of checkpoint inhibitors (CPIs) granted until January 2019 by FDA. Data regarding the type of approval, cancer type, treatment indication, and endpoints were extracted from the FDA website and from publications.
Fifteen therapeutic indications, including agnostic approvals, among seven CPIs have been approved for solid and hematologic malignancies. Of a total of 41 FDA approvals, nine (21.95%) were approved for the first-line of therapy and 32 (78.05%) for subsequent lines. Fourteen (34.15%) approvals, six (14.63%) in the first-line and eight (19.51%) in the subsequent lines, were granted approval based on overall survival (OS). Twenty-seven (65.85%) approvals (regular and accelerated) were granted based on surrogate endpoints: two (4.88%) using the response rate (RR), 20 (48.78%) using RR and the duration of rsponse (DOR); two (4.88%) using RR, progression-free survival (PFS) and DOR; two (4.88%) using relapse-free survival (RFS), and one (2.44%) using PFS alone. Table shows the distribution of these approvals in the first or subsequent lines. 168PFDA approvals Lines of treatment # for RR (%) # for RR and DOR (%) # for RR, PFS, and DOR (%) # for RFS (%) # for PFS (%) # for OS (%) Total (%) First-line 0 (0) 1 (2.44) 2 (4.88) 0 (0) 0 (0) 6 (14.63) 9 (21.95) Subsequent lines 2 (4.88) 19 (46.34) 0 (0) 2 (4.88) 1 (2.44) 8 (19.51) 32 (78.05) Total 2 (4.88) 20 (48.78) 2(4.88) 2 (4.88) 1 (2.44) 14 (34.15) 41 (100)
Of the total of 41 FDA approvals, 23 (56.10%) were accelerated and 18 (43.90%) regular. Three (7.32%) and 20 (48.78%) were accelerated approvals for the first and subsequent lines, respectively. Six (14.63%) and 12 (29.27%) were regular approvals in the first and subsequent lines, respectively.
RR and DOR were the most frequently approved surrogate endpoints, most often for use in later lines of therapy. The majority of CPI approvals need to confirm the real impact on the patients’ survival, since approximately one third of these approvals were based on the OS. Accelerated approvals based on surrogate endpoints were also preferentially granted for later lines of therapy, where such decisions may have a modest impact on the patients’ survival.
The authors.
Has not received any funding.
The author has declared no conflicts of interest.
The unblinded nature of open-label clinical trials may bias patient assessments of treatment efficacy and PRO measures. In this context, we conducted a SLR of IO trials across indications, to assess and quantify the potential impact of open-label vs. double-blind designs on treatment effects of PROs.
Independent reviewers conducted a systematic search of indexed literature published from January 2009 to May 2019, using PubMed/MEDLINE, Cochrane Library, EMBASE databases and manual search. A detailed search algorithm identified all randomized clinical trials of IO therapies focused on advanced or metastatic cancer patients reporting PRO data. We conducted descriptive analyses quantifying differences at baseline and over time according to the type of studies (open vs. blinded) in terms of PRO questionnaire completion rates and on obtained PRO measures. We determined frequencies, percentages and 95% confidence intervals of the estimated differences when comparing open-label vs. blinded trials. Complementary analyses also assessed the concordance between PRO results and efficacy.
Overall, we identified 8,285 references. After duplicates were removed, 5,888 papers were screened and finally 28 papers were identified according to our predefined criteria, corresponding to a total of 24 studies. Among them, 15 (62.5%) were open-label studies. The main cancer sites were melanoma (N = 10, 41.7%) and non-small cell lung cancer (N = 7, 29.2%). The principal IO-drugs investigated, alone or as part of a combination therapy regimen, were nivolumab (N = 12, 50.0%), ipilimumab (N = 8, 33.3%), and pembrolizumab (N = 5, 20.8%). Descriptive analyses are ongoing and will be presented at the conference.
To our knowledge, this SLR is the first one to focus on the impact of open-label design on PROs in randomized clinical trials of IO agents using a large search algorithm in the 3 most relevant scientific literature databases. Future research should use patient-level data to investigate potential differences in PROs between open-label and blinded trials.
Bristol-Myers Squibb.
Bristol-Myers Squibb.
A. Anota: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb. C. Lefevre: Full / Part-time employment: Bristol-Myers Squibb. H. Lemasson: Full / Part-time employment: Bristol-Myers Squibb. F-E. Cotte: Full / Part-time employment: Bristol-Myers Squibb. G. Mouillet: Honoraria (self): Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
Gut microbiome plays a role in the development and clinical course of colorectal cancer (CRC). Natural antibodies against galactose-α-1,3-galactose (α-gal) are highly abundant in humans due to regular stimulation from gut bacteria. Similarly, Abs against AB0 blood group antigens are produced as cross-reacting with intestinal bacteria and α-gal epitope has similar structure to blood group B Ag. Blood group antigens may be associated with an expansion families of gut bacteria.
CRC patients (n = 114) were sampled for stool, tumour tissue swab and blood prior to anti-cancer pharmacotherapy. The level of anti-α-gal Ig was quantified by ELISA in CRC patients and age-matched healthy subjects. 16S rDNA sequencing was analyzed on genus level and data were treated as composition and normalized using centered log-ratio transformation. Anti- α-gal Ig and microbiome composition was tested using linear model and differences between blood groups using ANOVA and post-hoc Tukey HSD test.
1/ The level of anti-α-gal IgA, but not IgG or IgM, is higher in colorectal cancer patients compared to healthy individuals. 2/ There was no association between CRC stage and anti-α-gal Abs level. 3/ The level of anti-α-gal IgG and IgM is lower in CRC patients with blood group B Ag. 4/ The level of anti-α-gal IgG is positively associated with abundance of Tyzzerella and negatively with Eubacterium ruminantium group and Lachnospiraceae UCG-001 in both patient stool and tumour swabs. 5/ The level of anti-α-gal IgA is positively associated with abundance of Collinsella, Barnesiella and Dorea and negatively with Filifactor and Acinetobacter in CRC tumour swabs. 6/ The level of anti-α-gal IgM is positively associated with abundance of Fusicatenibacter and Megamonas and negatively with Lactobacillus and Coprococcus in both stool and tumour swabs. 7/ Prevotella and Victivallis were less and Bacteroides more abundant in tumour swabs from CRC patients with blood group 0.
The level of anti-α gal antibodies CRC patients is related with various metabolism influencing bacteria. Blood group antigen B is related to reduced IgM and IgG but not specific microbiome composition.
Czech Ministry of Health.
Project AZV 16-31966A (Czech Ministry of Health).
All authors have declared no conflicts of interest.
Personalised tx is key in aRCC. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model determines prognosis of aRCC patients treated with systemic tx, helping guide treatment choice. This study examined real-world tx patterns and outcomes of 1L aRCC patients with differing IMDC status in the US.
Real-world data were drawn from the RCC Disease Specific ProgrammeTM; a cross-sectional study administered to oncologists, nephrologists and urologists in the US. Physicians completed patient record forms (PRFs) for up to the next 8 consulting RCC patients receiving active drug tx, from February - September 2019, plus additional optional PRFs for patients receiving/who had received either 1L nivolumab/ipilimumab combination tx or cabozantinib tx, where these patients were available. Study variables included patient demographics, background clinical information and tx patterns.
Physicians (n = 82) provided data on 687 patients. 445 patients were receiving 1L tx at time of data abstraction. Of those receiving 1L tx, mean age was 64.2 years, and 69% of patients were male. 34% (n = 151) did not have a physician-assessed IMDC prognostic risk score, and 5% (n = 23) reported unknown. Of the 61% (n = 271) that had a physician-assessed IMDC prognostic risk score, 15% had a low risk, 63% had an intermediate risk and 21% had a high risk. In the intermediate and high risk group, tyrosine kinase inhibitor (TKI) monotherapy was the most common 1L therapy (45%, n = 103), followed by IO-IO combination (29%, n = 66).
ASCO and NCCN guidelines recommend IO-IO combination in patients with an intermediate or high IMDC risk. However, at the time of data collection, more patients meeting these criteria received TKI monotherapy than IO-IO combination; moreover, almost a third of 1L tx aRCC patients were not even assessed. Newly introduced IO-TKI combination tx, approved during the fieldwork period, could enable clinicians to offer patients personalised tx, irrespective of risk profile.
Pfizer Inc.
Pfizer Inc. (part of an alliance between Pfizer Inc. and Merck KGaA, Darmstadt, Germany).
G. Zanotti: Shareholder / Stockholder / Stock options: Pfizer; Full / Part-time employment: Pfizer. R. Kim: Full / Part-time employment: Pfizer; Shareholder / Stockholder / Stock options: Exelixis. S.P. Krulewicz: Shareholder / Stockholder / Stock options: Pfizer; Full / Part-time employment: Pfizer. J.P. Hall: Full / Part-time employment: Adelphi Real World. A. Leith: Full / Part-time employment: Adelphi Real World. A. Bailey: Full / Part-time employment: Adelphi Real World. F. Liu: Full / Part-time employment: EMD Serono, Inc. M. Kearney: Full / Part-time employment: Merck KGaA, Darmstadt, Germany; Shareholder / Stockholder / Stock options: Novartis Pharma; Shareholder / Stockholder / Stock options: UCB Pharma; Shareholder / Stockholder / Stock options: SPRL.
Triple Negative Breast Cancer (TNBC) is the most belligerent subtype of BC. Yet, it is considered the best candidate for immunotherapy. As TNBC microenvironment is rich in CD8+ T lymphocytes (CTLs) and Natural Killer cells (NKs), the main key players in BC immune surveillance. During the antitumor immune-response, CTLs and NKs recognize and eliminate BC cells through an array of activating receptors expressed on their surface. CD226 and NKG2D are among the most vital activating receptors present on CTLs, NKs and NKT cells. The rate limiting step in tumor eradication is the binding of the aforementioned receptors to their respective ligands (Major histocompatibility complex class I chain-related proteins A and B (MICA/B) and CD155). Unfortunately, recent studies highlight the extensive shedding of MICA/B and CD155 in TNBC patients. Lately, our group nominated miR-486-5p as an immuno-activating miRNA. However, its impact on TNBC immune ligands has never been investigated. Therefore, our aim is to investigate the impact of miR-486-5p on MICA/B and CD155 in an attempt to alleviate the immune-suppressive nature of TNBC cells.
TNBC patients (n = 25) were recruited. Bioinformatics were performed to verify the binding of miR-486-5p to MICA/B and CD155. MDA-MB-231 and MCF7 cells were cultured and transfected with miR-486-5p oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular viability and clonogenicity were performed using MTT and colony forming assays, respectively.
TNBC patients showed a significant down-regulatory pattern of miR-486-5p, MICA, MICB and CD155 compared to its normal counterparts. In a similar pattern, miR-486-5p, MICA, MICB and CD155 were found to be markedly down-regulated in MDA-MB-231 cells. In-silico results proved that miR-486-5p potentially targets MICA, MICB and CD155. Ectopic expression of miR-486-5p (>1000 folds) resulted in a marked induction of MICA/B (2 folds) and CD155 (5 folds) thus potentiating NKs and CTLs cytotoxicity. Functionally, miR-486-5p mimics resulted in a significant repression of TNBC cellular viability and colony forming ability.
miR-486-5p is an immunomodulatory tumor suppressor miRNA acts by alleviating the immunesuppressive profile of TNBC cells.
German University in Cairo.
Has not received any funding.
All authors have declared no conflicts of interest.
Cancer evades immune detection and destruction via upregulation of immune checkpoint molecules, such as programmed death-1 (PD-1). Signalling from these molecules can be inhibited by antibodies targeting them or their ligands (e.g. PD-L1). Durable responses have been demonstrated, for example, in subsets of patients with melanoma or non-small cell lung cancer (NSCLC). Identifying potential ‘responders’ remains challenging, with immunohistochemical PD-L1 expression the only validated biomarker to date. Biopsies are however invasive, do not account for intratumoural heterogeneity nor are practical for serial measurement, and therefore cannot be used to measure response to immunotherapy reliably. Radioisotope labelling and imaging of PD-L1 antibodies has been shown in preclinical (indium-111) and phase I clinical trials (technetium-99m (99mTc)) to demonstrate PD-L1 expression in tumours. It has the potential to capture heterogenous expression, as well as spatiotemporal variance which would permit quantitative assessment of expression and serve as a companion diagnostic and monitoring tool to improve patient stratification and outcomes.
The PECan (PD-L1 Expression in Cancer) study aims to determine whether PD-L1 expression measured using 99mTc-labelled PD-L1 single-domain antibody single photon emission computed tomography (SPECT) in melanoma and NSCLC correlates with, and thus can predict treatment response in those having anti-PD1/PD-L1 immunotherapy. 99mTc-PD-L1 SPECT will be compared with standard FDG-PET/CT at 0, 12 and 24 weeks in 15 patients with melanoma and FDG-PET/CT and standard CT at 0, 9 and 18 weeks in 15 patients with NSCLC. Imaging will be analysed centrally by an experienced nuclear medicine physician and correlated with clinical data. PD-L1 expression, assessed using SPECT, will also be correlated with baseline immunohistochemistry to determine intertumoural PD-L1 heterogeneity. Patients will require confirmed histological status, PD-L1 assessment and not have received any prior systemic anti-cancer therapy nor radiotherapy. This study is now open to recruitment with reporting expected late 2020.
UK IRAS ID 256684.
King\'s College London and Guy\'s and St Thomas\' NHS Foundation Trust.
Department of Cancer Imaging, King\'s College London, UK with funding from NanoMab Technology Limited, China.
G. Chand: Advisory / Consultancy, Shareholder / Stockholder / Stock options: NanoMab Technology Limited. H.H. Ting: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NanoMab Technology Limited. G. Cook: Research grant / Funding (institution): NanoMab Technology Limited. All other authors have declared no conflicts of interest.