Browsing Over 191 Presentations
Health-related quality of life (HRQoL) in patients (Pts) with Merkel cell carcinoma (MCC) receiving avelumab
- Murtuza Bharmal
- Murtuza Bharmal
- Paul Williams
- Meliessa Hennessy
- Michael Schlichting
- Matthias Hunger
- Alexia Marrel
- Howard Kaufman
Abstract
Background
In a single-arm, open-label phase 2 trial (NCT02155647 Part A) of avelumab 10 mg/kg q2w, pts with stage IV MCC pretreated with chemotherapy were followed for HRQoL and clinical outcomes. The primary analysis (6 months after enrolment of the last pt) showed nonprogression during avelumab treatment was associated with clinically meaningful improvements in HRQoL. Here we report interim results 12 months after enrollment of the last pt.
Methods
HRQoL was assessed using FACT-Melanoma (FACT-M) and EQ-5D questionnaires at baseline (BL), week 7, every 6 weeks thereafter until disease progression (PD), and at end of treatment (EOT). Linear mixed models (LMM) assessed change from BL until week 49 for FACT-M scales, including covariates of time and PD vs. non-PD. Minimally important differences (MIDs) derived from MCC populations were used to interpret the meaningfulness of changes. Sensitivity analyses (pattern-mixture models) provided estimates assuming missing values were nonrandom. Health utility was assessed by EQ-5D using similar methods.
Results
Overall, no meaningful changes from BL were seen for FACT-M scales during treatment visits up to week 49 in 70 analyzed pts. However, at the final HRQoL assessment before EOT and at EOT, meaningful worsening in HRQoL was observed for all scales, primarily associated with PD at EOT (63.6%). LMM showed significant differences between PD vs non-PD pts in the expected directions in the range of MIDs for (mean change) physical well-being (1.40), emotional well-being (1.52), melanoma (3.07), TOI (5.68), FACT-G total (4.37) and FACT-M total (7.03). The models showed improvement in emotional well-being (1.70) for non-PD pts and worsening in physical well-being (-1.68), TOI (-4.01), FACT-G total (-4.44) and FACT-M total (-5.64) for PD pts. Sensitivity analyses showed outcomes did not differ by timing of dropout. Mean health utility EQ-5D scores based on the US (UK) value set was 0.8024 (0.8269) for non-PD pts and 0.7352 (0.7415) for PD pts.
Conclusions
Consistent with previous findings, nonprogression during avelumab treatment contributed to statistically and clinically meaningful improvements in HRQoL in this longer-term 12-month follow-up analysis.
Clinical trial identification
NCT02155647 Part A
Legal entity responsible for the study
N/A
Funding
This study was funded by and is part of an alliance between Merck KGaA and Pfizer, Inc, NY, USA.
Disclosure
M. Bharmal, M. Schlichting: employee of Merck KGaA, Darmstadt, Germany, P. Williams, M. Hunger, A. Marrel: Mapi employees, consultant for Merck KgaA, M. Hennessy: employee of EMD Serono, H. Kaufman: received research grants from Amgen, Merck. Merck, provided consulting for Amgen, Celldex, EMD Serono, Merck, Prometheus, Sanofi, Turnstone Biologics participated in Speaker’s buereau’s for Merck. Merck, has received honoraria from Amgen, Celldex, EMD Serono, Merck, Prometheus, Sanofi, Turnstone Biologics
ZUMA-1: Engineering new therapies to meet needs in NHL
- Zachary Roberts
- Zachary Roberts
TIM-3 and LAG-3 checkpoints: Into the clinic and back to the bench
- Catherine Sabatos-Peyton
- Catherine Sabatos-Peyton
Approaches to convert immunologically “cold” into “hot” tumours
- Ronald Herbst
- Ronald Herbst
In patients with advanced non-small cell lung cancer (NSCLC) LAG-3 is expressed on activated TILs and predicts resistance to PD-1 axis blockers
- Ila Datar
- Ila Datar
- Miguel F. Sanmamed
- Jungmin Choi
- Jun Wang
- Brian S. Henick
- Ti Badri
- Luis D. Mejias
- Maria Lozano
- Jose Luis Gracia
- Vamsidhar Velcheti
- Roy Herbst
- Ignacio Melero
- Lieping Chen
- Kurt A. Schalper
Abstract
Background
The functional role and clinical utility of measuring PD-1, LAG-3 and TIM-3 in NSCLC tumor tissue remain poorly understood even though corresponding clinical trials with blocking agents are ongoing. We analyzed the expression of these targets in association with key functional immune metrics and outcome after treatment with PD-1 axis blockers in human NSCLC.
Methods
We performed CyTOF on immune cell suspensions from 20 primary human NSCLCs to map the distribution of PD-1, LAG-3 and TIM-3 and explore their function. We analyzed RNA levels of these markers in TCGA NSCLC datasets and their association with CD4/CD8 mRNA and mutational burden. Using multiplex quantitative immunofluorescence (QIF) we measured the levels of CD3, PD-1, LAG-3 and TIM-3 in 66 pre-treatment tumor samples from NSCLC patients receiving PD-1 axis blockers in 2 independent cohorts (Cohort #1, Yale, N = 42 cases [Training set] and cohort #2, Cleveland Clinic/University of Navarra, N = 24 [Validation set].
Results
In primary NSCLCs, PD-1 was predominantly expressed on T- and NKT cells. LAG-3 expression was higher in CD8+, CD4+CD25+FOXP3+ and NKT cell subsets, but low/absent in antigen-presenting cells (APCs). TIM-3 was broadly expressed in adaptive and innate immune cells, with the highest levels in APCs. Expression of all 3 markers in T-cells was associated with lymphocyte activation (CD69/HLA-DR), effector function (Granzyme-B) and proliferation (Ki-67). LAG-3-expressing T-cells showed higher association with early activation and effector function than TILs expressing PD-1 or TIM-3. In TCGA, PD-1 and LAG-3 transcripts strongly correlated with CD8, while TIM-3 was associated with CD4 mRNA. There was limited association between the markers and tumor mutational burden. In pre-treatment specimens from both cohorts of patients treated with PD-1 blockers, elevated LAG-3 but not PD-1 or TIM-3 protein were significantly associated with shorter OS.
Conclusions
PD-1, LAG-3 and TIM-3 show variable expression and are associated with T-cell activation and effector function in NSCLC. Elevated T-cell LAG-3 in baseline tumor samples predicts primary resistance to PD-1-axis blockers.
Legal entity responsible for the study
Kurt A. Schalper- Yale University School of Medicine
Funding
NIH/NCI, DOD-LCRP, SU2C, LCRF
Disclosure
B.S. Henick: Participated in a consulting program for Boehringer Ingelheim. I. Melero: Consultancy: BMS, Roche, Bayer, Lily, AstraZeneca, Genmab, Aliigator, Tusk; Grants: Roche, BMS, Alligator, Pfizer. K.A. Schalper: Merck, Tesaro, Takeda, Onkaido/Moderna, Navigate/Novartis, Surface Oncology, Celgene, Vasculox. All other authors have declared no conflicts of interest.
Combined immunotherapy encompassing intratumoral polyICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients
- Maria E. RodrÍguez-Ruiz
- Maria E. RodrÍguez-Ruiz
- JL Perez-Gracia
- Inmaculada Rodriguez
- Carlos Alfaro
- Carmen Oñate
- Guiomar Perez
- Susana Inoges
- Leyre Resano
- Alberto Benito
- Benigno Barbes
- Mariano Ponz-Sarvisé
- Salvador Martin Algarra
- Alfonso Gurpide
- Miguel F. Sanmamed
- Carlos De Andrea
- Jose Echeveste
- Andres Salazar
- Ignacio Melero
Abstract
Background
Combined tumor immunotherapy interventions have the potential to achieve additive or synergistic effects. Combined local injection of dsRNA analogues (mimicking viral RNA) and repeated vaccination with tumor-lysate loaded dendritic cells shows efficacy against a mouse model of established colon cancer.
Methods
In a pilot phase I clinical trial 16 advanced (stage IV) cancer patients received two cycles of a course consisting of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with polyICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each of each cycle, patients received intratumoral image-guided injections of 0.25 mg of Hiltonol. Each cycle was given 3-4 weeks apart and was preceded on day -7 by 600 mg/m2 of cyclophosphamide. The last six patients were given SABR (stereoatactic ablative radiotherapy) in some of the lesions including that injected with Hiltonol. Expression of a series of 25 inmune-relevant genes was sequentially monitored by RT-PCR on circulating PBMCs and serum concentrations of a cytokine panel were sequentially determined.
Results
Combined treatment was feasible, safe and well tolerated without >grade 2 side effects. No objective responses by RECIST1.1 criteria were observed while nine patients experienced stabilization of disease (five of them in the six-patient radiotherapy cohort). A heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to radiotherapy with responding lesions located far from the irradiated region. Response was associated to an increase of CD8 T cells infiltrating the tumor. In this series of patients post-treatment elevated IFNβ and IFNα mRNA in circulating PBMC following intratumoral Hiltonol was detected, in addition to increases of serum IL-12 and IL-1β following DC vaccination, that occurred more prominently in stable disease cases.
Conclusions
This combination strategy aimed to resembling viral infection in tumor tissue, while on a dendritic-cell vaccine approach and added to radiotherapy is safe for advanced cancer patients and shows indications of immune-associated activity.
Clinical trial identification
NTC01734564
Legal entity responsible for the study
Clinica Universidad de Navarra
Funding
None
Disclosure
All authors have declared no conflicts of interest.
Immune-mediated cystatin A expression in patients with pancreatic ductal adenocarcinoma
- Takuya Komura
- Takuya Komura
- Yoshio Sakai
- Hisashi Takabatake
- Kenichi Harada
- Tetsuo Ohta
- Hirohisa Kitagawa
- Shuichi Kaneko
Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy with an extremely poor prognosis due to the lack of an efficient diagnostic tool and any radical treatments, except surgical removal. Therefore, it is extremely important to understand its pathology including the host inflammatory immune response of PDAC for development of novel diagnostic tool as well as treatment alternative. In this study, we investigated the pathological feature of PDAC in the context of CSTA, a cytein protease inhibitor, excamining the blood and PDAC tissues.
Methods
We assessed transcriptional expression of CSTA in peripheral blood cells of 41 patients with PDAC and 20 healthy volunteers by quantitative real-time PCR. Next, serum CSTA concentrations in 36 patients with PDAC and those in 37 healthy volunteers were measured, and its correlation with PDAC clinical parameters was analysed. Furthermore, we measured cytokine profiles of sera from 6 PDAC patients with elevated CSTA concentration in sera and 9 PDAC patients without elevation. We also examined the expression of CSTA, its substrate, cathepsin B, and cytokines, in tumor tissues in 20 surgically resected PDAC tissues by immunohistochemical staining.
Results
We observed increment of CSTA mRNA expression in CD4+ cells of peripheral blood of 41 patients with PDAC compared with that in 20 healthy volunteers. Correspondingly, serum CSTA concentrations in 36 patients with PDAC were higher than those in 37 healthy volunteers, and this increase was correlated with PDAC clinical stage. We found that IFN-g, TNF-a, and IL-1b concentrations in sera were significantly correlated with those of CSTA in sera of PDAC patients. As for tumor tissue analysis, CSTA expression was detected in some tumor tissues and many tumor-infiltrating immune cells, particularly neutrophils. Cathepsin B expression was observed in most tumor tissues and tumor-infiltrating immune cells, particularly macrophages.
Conclusions
CSTA expression was involved in the PDAC inflammatory condition in local tumor microenvironment. The CSTA concentration in peripheral blood of PDAC patients have a possibility of potential role as a PDAC immunopathological biomarker.
Legal entity responsible for the study
Kanazawa University Ethics Committee
Funding
None
Disclosure
All authors have declared no conflicts of interest.
Novel adaptive designs for immunotherapy trials
- Donald Berry
- Donald Berry
Hepatocellular carcinoma
- Ignacio Melero
- Ignacio Melero
Expansion of tumor specific tumor-infiltrating lymphocytes (TIL) from sarcoma and the potential benefit of anti-CD137 stimulation: A prerequisite for adoptive cell transfer (ACT) immunotherapy
- Morten Nielsen
- Morten Nielsen
- Anders Krarup-Hansen
- Dorrit Hovgaard
- Michael M. Petersen
- Anand C. Loya
- Marie Christine W. Westergaard
- Inge Marie Svane
- Niels Junker
Abstract
Background
Tumor specific TIL can be in vitro expanded and have the ability to induce complete and durable tumor regression in some patients with melanoma following ACT. In this preclinical study, we investigated the feasibility of expanding TIL from sarcomas, as well as performing functional in vitro analyses on these.
Methods
Fresh tumor samples were obtained, and TIL were isolated and expanded in growth medium containing IL-2. In a sub study, we investigated the effect of adding an agonistic CD137 antibody (Urelumab, BMS) and/or an anti-CD3 antibody (OKT3) to the medium. Phenotype and functional analyses was performed using flow cytometry and IFNγ-Elispot. Cytotoxicity analyses were performed using Xcelligence.
Results
Tumor samples from 28 patients with 8 different sarcoma subtypes were obtained, and we were able to expand a minimum of 40 million TILs from 25 of these. Mean expansion times were 32 days (14 - 61). 87,7% (36,4 – 99,1) of these cells were CD3+, and of these, 66,7% (16,3 – 99,1) were CD4+, and 21,8% (0,1 – 50,6) were CD8+. Adding anti-CD137 and/or OKT3 increased total yield of TILs; anti-CD137 skewed the phenotype significantly towards more CD8+ TILs and in some cases NK cells and γδ cells. TILs from 11 of 22 tested tumor samples from 7 of 8 different sarcoma subtypes demonstrated reactivity against autologous tumor cells using IFNγ-Elispot. These results were verified in an intracellular cytokine release assay using flow cytometry, and in cytotoxicity assays. In some cases the fraction of reactive cells was more than 20%. In TILs stimulated with anti-CD137 the reactivity increased in four of four tested samples.
Conclusions
We were able to expand TIL from 90% of tested tumor samples. Expanded TIL were a mix of CD4+ and CD8+ with CD4+ being predominant. Half of the TIL cultures showed in vitro tumor reactivity, which in some cases was as high as previously only seen in melanoma samples. Early analyses suggest that addition of anti-CD137 could influence expansion time, phenotype, and functional capacity of the expanded TIL. Based on these results, we plan to initiate clinical testing of TIL based ACT in sarcoma patients.
Legal entity responsible for the study
Center for Cancer Immune Therapy, Herlev Hospital
Funding
Center for Cancer Immune Therapy, Herlev Hospital
Disclosure
All authors have declared no conflicts of interest.
XIST and TSIX: Novel cancer-immune biomarkers showing differential expression in tumor, PBMCs, serum, nipple discharge and lymph nodes of PD-L1 overexpressing BC patients
- Esraa Atef
- Esraa Atef
- Reda Abdel Tawab
- Hend M. El Tayebi
Abstract
Background
Despite the success of immunotherapies, patients still respond differently. Thus, there is an urge to explore novel predictive biomarkers to understand the complex interactions within cancer immunity. Long non-coding RNAs (lncRNAs) were found to act as biomarkers in breast cancer (BC). X inactive –specific transcript (XIST) has been proved to be an indicator of poor outcome in BC. TSIX is the antisense of XIST and both LncRNAs were shown to have crucial role in breast carcinogenesis. However, no evidences were reported about their role in immune evasion. Our previous data proved that XIST and TSIX were able to paradoxically manipulate PD-L1 expression in BC cell lines. This study aims at investigating the potential role of XIST and TSIX as cancer-immune biomarkers in relation to the PD-L1 expression in different body compartments of BC patients.
Methods
BC biopsies, Lymph nodes (LN), whole blood, serum and nipple discharge(ND) were collected from 35 BC patients (15.7% triple negative BC (TNBC), 36.8% luminal B, 21.05% luminal A, 10.5%Her2+ and 15.78% luminal B Her2+). PBMCs were isolated using Ficoll-Hypaque method. Total RNA extraction was performed using BIOZOL reagent, then the expression profiling of PD-L1, XIST & TSIX was quantified by Taqman Real Time qPCR and normalized to Beta-2-microglobulin.
Results
The relative expression of XIST and TSIX was markedly increased in tumor biopsies (p = 0.0493 and p = 0.0173), PBMCs (p = 0.0414 and p = 0.029), Serum (p = 0.0144 and p = 0.0336) and ND (p = 0.0197 and p < 0.0001) of BC patients compared to their paired controls. XIST and TSIX expression was positively correlated to PD-L1 mRNA expression in these 4 body compartments (p = 0.0468 and p = 0.0362). PD-L1, XIST and TSIX showed a higher expression in TNBC and Luminal B subtypes compared to other subtypes (p = 0.0001, p = 0.0467 and p = 0.0115). In contrast, XIST and TSIX showed a dramatic down regulation in metastatic LNs compared to non-metastatic LNs (p = 0.0061 and P = 0.0028). PD-L1 was abscent in metastatic LNs.
Conclusions
This study introduces XIST and TSIX as novel immune biomarkers that are highly correlated with the expression profile of PD-L1 in different body compartments of BC.
Legal entity responsible for the study
German University in Cairo, Egypt
Funding
None
Disclosure
All authors have declared no conflicts of interest.
Chemokine receptor 2 (CCR2) antagonism with a small molecule enhances the effectiveness of checkpoint inhibition by altering the tumor microenvironment in mouse colorectal tumours: Reducing tumor size and increasing long term survival
- James Campbell
- James Campbell
- Christine Janson
- Linda Ertl
- Chris Li
- Zhenhua Miao
- Vicky Chhina
- Marta Vilalta
- Alice Kumamoto
- Ton Dang
- Shirley Liu
- Simon Yao
- Penglie Zhang
- Thomas J. Schall
- Rajander Singh
Abstract
Background
CT26 tumors are heavily infiltrated by tumor-specific CD8 T cells but nevertheless grow rapidly in Balb/c mice. These tumors are partially responsive to anti-PD-1 monoclonal antibody therapy, suggesting an active suppression of the tumor-specific cytotoxic T cells. As CCR2 is expressed by a potentially suppressive leukocyte subset within these these tumors, we aimed to test whether CCR2 blockade could enhance the anti-tumor effects of anti-PD-1.
Methods
Five days after subcutaneous CT26 implantation into the flanks of 9wk female Balb/c mice (2.5x105/mouse), the recipients were randomized based on tumor size and treatment was begun. Mice received anti-PD-1 by IP injection on days 7, 10, 17 and 21 (200μg/mouse), and received CCR2 antagonist CCX598 (30 or 60mg/kg) or vehicle by oral gavage every 24 hours until day 60.
Results
We have found that the therapeutic effects of anti-PD-1 therapy are appreciably enhanced by specific blockade of chemokine receptor 2 (CCR2) via a small molecule antagonist. This combined anti-PD-1/CCR2i approach significantly decreases tumor size and increases the proportion of long-term survivors, with more than 50% of the mice (up to 73%) showing complete regression of a previously established tumor. The effects of this combined therapy are dependent on the presence of CD8+ T cells, as tumors do not respond to the therapy in CD8-depleted mice. The anti-CT26 tumor response is specific: long term survivors are resistant to re-inoculation with the CT26 tumor (even without further dosing of either drug) but are not resistant to the 4T1 breast tumor. CCR2 antagonism alters the tumor microenvironment by reducing the number of mMDSC per gram of tumor (a CCR2hi population phenotypically defined as CD11b+/Ly6G-/Ly6Chi). Reduction in tumor size is inversely proportional to the ratio of CD8 T cells to mMDSC.
Conclusions
These data are consistent with a hypothesis that CCR2 antagonism enhances anti-PD-1 therapy by preventing mMDSC from accumulating within the tumor, thus reducing their suppressive effects on cytotoxic T cells.
Legal entity responsible for the study
ChemoCentryx, Inc.
Funding
ChemoCentryx, Inc.
Disclosure
J. Campbell, C. Janson, L. Ertl, C. Li, Z. Miao, V. Chhina, M. Vilalta, A. Kumamoto, T. Dang, S. Liu, S. Yao, P. Zhang, T.J. Schall, R. Singh: Full time employee of ChemoCentryx, Inc.