Browsing Over 346 Presentations
34P - Development of LAG-3 nanobodies as potent cancer imaging tracers
- Q. Lecocq (Brussels, Belgium)
- Q. Lecocq (Brussels, Belgium)
- R. Awad (Jette, Belgium)
- K. Zeven (Jette, Belgium)
- Y. De Vlaeminck (Jette, Belgium)
- W. De Mey (Jette, Belgium)
- P. Debie (Jette, Belgium)
- J. Puttemans (Jette, Belgium)
- C. Goyvaerts (Jette, Belgium)
- G. Raes (Jette, Belgium)
- M. Keyaerts (Jette, Belgium)
- N. Devoogdt (Jette, Belgium)
- K. Breckpot (Jette, Belgium)
Abstract
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Legal entity responsible for the study
Geert Raes.
Funding
Kom op tegen kanker and FWO flanders.
Disclosure
All authors have declared no conflicts of interest.
71P - Correlation between toxicities and outcomes during treatment with immune checkpoint inhibitors in non-small cell lung cancer patients
- P. Ayala de Miguel (Caceres, Spain)
- P. Ayala de Miguel (Caceres, Spain)
- S. Arnáiz Díez (Cáceres, Spain)
- I. Gorospe García (Cáceres, Spain)
- J. López Gallego (Cáceres, Spain)
- A. Illán Varella (Cáceres, Spain)
- P. Borrega García (Cáceres, Spain)
Abstract
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Cell therapies against cancer
- M. Donia (Herlev, Denmark)
- M. Donia (Herlev, Denmark)
109P - Phase I clinical study for validation of fimaporfin-based photochemical internalisation: A novel technology for enhancing cellular immune responses important for therapeutic effect of peptide-and protein-based vaccines
- P. Selbo (Oslo, Norway)
- P. Selbo (Oslo, Norway)
- S. Janetzki (Fort Lee, NJ, United States of America)
- M. Welters (Leiden, Netherlands)
- M. Håkerud (Oslo, Norway)
- A. Nedberg (Oslo, Norway)
- V. Edwards (Oslo, Norway)
- H. Olivecrona (Oslo, Norway)
- S. Van der Burg (Leiden, Netherlands)
- T. Otterhaug (Oslo, Norway)
- A. Hogset (Oslo, Norway)
Abstract
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Clinical trial identification
NCT02947854.
Legal entity responsible for the study
PCI Biotech AS.
Funding
PCI Biotech AS.
Disclosure
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.
Artificial intelligence for digital tissue biomarker discovery in immune oncology
- G. Schmidt (Munich, Germany)
- G. Schmidt (Munich, Germany)
144P - Loss of BAP-1 influences the activation of p52 and RelB proteins in the Inflammatory microenvironment of uveal melanoma
- M. Singh (Delhi, India)
- M. Singh (Delhi, India)
- S. Kashyap (New Delhi, India)
- L. Singh (New Delhi, India)
- N. Pushker (New delhi, India)
- S. Bakhshi (New Delhi, India)
- S. Sen (Delhi, India)
Abstract
Background
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.
Methods
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.
Results
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).
Conclusion
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.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Exploring and exploiting the tumor microenvironment
- J. Joyce (Lausanne, Switzerland)
- J. Joyce (Lausanne, Switzerland)
Q&A and closing remarks (ID 512)
Intra-arterial therapies and immune response
- R. Duran (Lausanne, Switzerland)
- R. Duran (Lausanne, Switzerland)
DOI session
2O - Biomarkers of immune switch induced by a novel anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) in MATINS trial patients with advanced solid tumours
- M. Hollmén (Turku, Finland)
- M. Hollmén (Turku, Finland)
- R. Virtakoivu (Turku, Finland)
- P. Jaakkola (Helsinki, Finland)
- A. Minchom (London, United Kingdom)
- S. Jalkanen (Turku, Finland)
- M. Karvonen (Turku, Finland)
- J. Mandelin (Turku, Finland)
- J. Koivunen (Oulu, Switzerland)
- P. Bono (Helsinki, Finland)
Abstract
Background
A scavenger receptor CLEVER-1 is highly expressed on tumor associated macrophages (TAMs) and mediates the clearance of “unwanted” self-components. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8+ T cell responses with robust anti-tumor activity (Viitala et al., 2019). Targeting CLEVER-1 could overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody.
Methods
MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients with advanced, IO-refractory melanoma, cholangiocarcinoma, hepatocellular, colorectal, and pancreatic ductal adenocarcinoma. Biomarker analysis included CLEVER-1 determination, immune cell profiling by mass cytometry and analysis of cytokine production.
Results
11 patients (median age 57) were enrolled in four cohorts (0.3, 1.0, 3.0 or 10 mg/kg) and received 1-8 cycles (median 3) of FP-1305 every three weeks. FP-1305 has been well tolerated without dose-limiting toxicities and maximum tolerated dose (MTD) has not been reached. Promising early efficacy results have recently been reported (ESMO 2019, LBA19). FP-1305 dosing led to increased Th1 skewing (CXCR3+CCR6-) of CD4 and CD8 T cell populations with downregulation of several inhibitory immune checkpoint molecules. Increase in circulating IFN gamma was detected but it was most prominent in the patient showing durable partial response.
Conclusion
FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response against cold tumors.
Clinical trial identification
NCT03733990.
Legal entity responsible for the study
Faron Pharmaceuticals.
Funding
Finnish Academy, Finnish Cancer Foundations, Sigrid Juselius Foundation, Faron Pharmaceuticals.
Disclosure
M. Hollmén: Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. P. Jaakkola: Advisory / Consultancy: Faron Pharmaceuticals. A. Minchom: Advisory / Consultancy: Faron Pharmaceuticals. S. Jalkanen: Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. M. Karvonen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Mandelin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Koivunen: Advisory / Consultancy: Faron Pharmaceuticals; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: KaikuHealth. P. Bono: Advisory / Consultancy, Travel / Accommodation / Expenses, Spouse / Financial dependant: Faron Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: OrionPharma. All other authors have declared no conflicts of interest.
25P - Analysis of NGS-based blood immune cell RNA signatures for colorectal cancer detection
- S. Morgenthaler (Lausanne, Switzerland)
- S. Morgenthaler (Lausanne, Switzerland)
- H. Lindsay (Lausanne, Switzerland)
- L. Ciarloni (Epalinges, Switzerland)
- P. Angelino (Lausanne, Switzerland)
- G. Dorta (Lausanne, Switzerland)
- M. Delorenzi (Lausanne, Switzerland)
- S. Hosseinian Ehrensberger (Epalinges, Switzerland)
Abstract
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Legal entity responsible for the study
Novigenix.
Funding
Novigenix.
Disclosure
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.