Mutational Analysis and Predicting Response to Immunotherapy最新文献

{"title":"Abstract B092: Tumor infiltrating T-cells from renal cell carcinoma patients recognize neoantigens derived from point and frameshift mutations","authors":"S. Ramskov, U. Hansen, Anne-Mette Bjerregaard, A. Bentzen, M. Donia, R. Andersen, Z. Szallasi, I. Svane, A. Eklund, S. Hadrup","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B092","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B092","url":null,"abstract":"Mutation-derived neoantigens are important targets of T-cell mediated reactivity towards tumors. Their unique tumor-restriction poses an advantage compared to shared tumor antigens in that they are in principle both foreign and tumor specific, hence presumably less impacted by T-cell tolerance and for therapeutic applications less prone to mediate immune-related destruction of noncancerous tissue. Moreover, the mutational burden and predicted number of neoantigens correlate to favorable clinical outcome and benefit from immune checkpoint therapy. Neoantigen-reactive T-cells have been detected across a number of solid cancers, ranging from immunogenic tumors such as melanoma and non-small cell lung cancer to less immunogenic tumors such as breast cancer. Renal cell carcinomas (RCCs) are among medium-range mutational burden tumors and present with the highest pan-cancer number and proportion of frameshift mutations, a mutation type considered to be highly immunogenic. However, to our knowledge, yet no reports have described neoantigen-specific T-cells in this malignancy. In this study, the mutational landscape and HLA (human leukocyte antigen) profile of tumors from six renal cell carcinoma patients were analyzed by whole-exome sequencing (WXS) of DNA from tumor fragments (TFs), autologous tumor cell lines (TCLs) and tumor-infiltrating lymphocytes (TILs, germline reference). Hereafter the online MuPeXi tool was used to predict binding of mutated peptide sequences of 9-11mer length to the HLAs of each patient, using a rank score Citation Format: Sofie Ramskov, Ulla Kring Hansen, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Marco Donia, Rikke Andersen, Zoltan Szallasi, Inge Marie Stentoft Svane, Aron Charles Eklund, Sine Reker Hadrup. Tumor infiltrating T-cells from renal cell carcinoma patients recognize neoantigens derived from point and frameshift mutations [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B092.","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"87 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114545680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B083: Defective transcription elongation in a subset of cancers confers immunotherapy resistance","authors":"V. Modur","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B083","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B083","url":null,"abstract":"Immunogenicity of most cancer types is a result of either neoantigenic mutational load, which stokes up an adaptive immune response, or due to oncogenic stress pathways, which elicit an innate antitumor response. There have been exponential gains made in recent times using numerous strategies to reactivate the host antitumor immunity including the development of immune checkpoint inhibitors. Nonetheless, the promise of a cure and durable response in select patients does not refute the low response rates in advanced cases, most of which also relapse. These observations shore up the possibility of other mechanisms beyond the inactivation of local lymphocyte infiltrates that might also play in tumor cell evasion of antitumor immune response. Through comprehensive computational and follow-up experimental validations, we have found that a subset of cancers (~15-20% of all cancers) are characterized by severe defects in almost the entire epigenetic and transcriptional apparatus. These defects result in genome-wide deregulation of histone modifications, mRNA transcription elongation, and mRNA processing and nuclear export, especially in the long genes which we term as Transcriptional Elongation Deficient: TEdef. As such, cancer cells with TEdef suppressed the expression of the pathways enriched for long genes, such as proinflammatory signaling pathways (FasL response, TNF/NF-kB signaling, interferon signaling) at both mRNA and protein levels, and had diminished response to interferon and TNF stimuli. Remarkably, in renal cell carcinoma and metastatic melanoma patients in four cohorts, the TEdef phenotype significantly correlated with poor response and unfavorable outcome to immunotherapy, but not to chemo- or targeted therapy. Importantly, forced induction of TEdef in tumor cells impaired the expression of, and signaling through, the proinflammatory pathways, and imposed a resistance to the innate and adaptive antitumor immune responses and to immune checkpoint inhibitor therapy in vivo. Tumor lymphocyte infiltration (TIL) and somatic neoepitope load (SNL) are some of the best markers of immunotherapy response in the clinic. However, TEdef tumors were characterized by a higher rate of immune cell infiltration, but paradoxically, less immune-mediated local tumor cell lysis, further supporting the notion that TEdef is a tumor cell-autonomous mechanism of immune resistance. As such, combining TIL or SNL with TEdef had superior power in predicting the progression-free and overall survival of melanoma patients treated with the anti-CTLA4 and anti-PD-1 therapy. Overall, TEdef is a novel epigenetic mechanism of resistance to antitumor immune attack, which warrants its assessment in cancer patients undergoing immunotherapy. Citation Format: Vishnu Modur. Defective transcription elongation in a subset of cancers confers immunotherapy resistance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"39 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116486789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B093: Development of prediction software PrDx, trained on peptide-MHC stability assays, shows new important positions in the binding patterns of the peptides-MHC I and II complexes","authors":"Stephan Thorgrimsen, S. Justesen, N. Rapin","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B093","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B093","url":null,"abstract":"Mutations in cancer cells may lead to the formation of neo-epitopes potentially presented by both major histocompatibility complex (MHC) class I or II. These neo-epitopes may be recognized by CD8+ or CD4+ T-cells, and trigger an immune response. Only a small fraction of the neoepitopes will be displayed by the MHC class I or II. One of the challenges of cancer immunotherapy is therefore to predict which neoepitopes are susceptible to elicit a T-cell response. Software tools such as netMHC, MHC Flury and many others are over-predictive as the bulk part of the data used to train these methods are based on affinity assays. Several publications have indicated that stability assays may provide data that better correlate with epitope presentation by MHC. Prediction tools trained on stability assays may therefore be better at selecting neoepitopes resulting in more effective cancer vaccine design. We performed stability assay measurements for 10 MHC class I and 10 MHC class II alleles using a peptide scan library approach. In brief, random 9-mers where one position is known were used to measure stability of the peptide MHC complex. Next, the data were used to train a prediction tool, PrDx, that relies on a combination of different machine learning methods (random forest, feed forward neural networks and recurrent neural networks), of which the outputs are gathered in an assemble model. The model was then further trained with peptides predicted to bind with high stability, to the MHC alleles, until satisfactory performances were attained. To our surprise, PrDx showed new binding patterns for the alleles we trained. Although mostly similar to the binding patterns seen with affinity data trained method, the stability trained method is able to show new important positions in the binding patterns of the peptide-MHC complexes. Through retrospective analysis, our method seems able to select more accurately peptides susceptible to elicit a T-cell response, compared to state-of-the-art epitope prediction methods. Our results suggest that PrDx may be an attractive prediction tool for neo-epitopes discovery. Citation Format: Stephan Thorgrimsen, Sune Justesen, Nicolas Rapin. Development of prediction software PrDx, trained on peptide-MHC stability assays, shows new important positions in the binding patterns of the peptides-MHC I and II complexes [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B093.","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121987433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B094: Successful identification of neoantigen-specific T-cell responses in low mutation burden colorectal cancers for personalized cancer vaccine development","authors":"Jitske van den Bulk, D. Ruano, M. Ijsselsteijn, Marten Visser, R. V. D. Breggen, K. Peeters, T. Duhen, Rebekka Duhen, A. Weinberg, S. V. D. Burg, E. Verdegaal, N. Miranda","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B094","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B094","url":null,"abstract":"Innovative treatment options are required to improve cure rates in advanced colorectal cancer patients. Immune checkpoint blockade therapy (anti-PD-1) was shown to be effective in colorectal cancers with high mutation burden (e.g., mismatch repair deficient) as antitumor reactivity is largely explained by the recognition of somatically mutated antigens (neoantigens). No immunotherapeutic strategies are currently available for patients diagnosed with low mutation burden colorectal cancer. We hypothesized that if neoantigen-reactive T-cells are present in low mutation burden patients, the latter could benefit from immunotherapeutic interventions that stimulate neoantigen recognition and the onset of a robust antitumor immune response.In order to detect neoantigens, whole exome and RNA next-generation sequencing analyses were performed in cancer and healthy tissues from five colorectal cancer patients. Corresponding neoepitopes were synthesized and tested for their ability to induce immune cell activation in T-cells isolated from the tumor tissue (TIL) and from peripheral blood. Neoantigen-specific T-cell responses were identified in the majority of patients that presented with tumors carrying 25 to 36 transcribed, non-synonymous variants. Up to six different neoantigens were recognized per tumor, which resulted in a higher detection rate than anticipated based on published data. Moreover, we discovered the merits of isolating CD39+CD103+CD8+ T-cells for detection of a broad recognition of HLA class I-restricted neoantigens. This CD39+CD103+CD8+ T-cell subset comprises the majority and a broader repertoire of neoantigen-specific T-cells compared to bulk TIL populations or lymphocytes derived from peripheral blood. In conclusion, we developed a neoantigen screening pipeline to unlock the immunogenic potential of colorectal cancers with low mutation burden. We have detected a relatively high number of neoantigens that are recognized by tumor- and/or PBMC-derived T-cells in mismatch repair proficient, low mutation burden colorectal cancer patients, and show the importance of the CD39+CD103+CD8+ T-cell subset for neoantigen-based immunotherapies. These findings warrant the further exploration of the potential to employ neoantigen-targeted therapies to improve clinical outcomes of colorectal cancer patients. Citation Format: Jitske van den Bulk, Dina Ruano, Marieke E. Ijsselsteijn, Marten Visser, Ruud van der Breggen, Koen C.M.J. Peeters, Thomas Duhen, Rebekka Duhen, Andrew D Weinberg, Sjoerd S.H. van der Burg, Els M.E. Verdegaal, Noel F. de Miranda. Successful identification of neoantigen-specific T-cell responses in low mutation burden colorectal cancers for personalized cancer vaccine development [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B094.","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"47 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127925979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B087: MHC class II on cancer cells—Role in response to BCG therapy of bladder cancer","authors":"Gil Redelman-Sidi, M. Glickman, A. Binyamin, A. Antonelli","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B087","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B087","url":null,"abstract":"BCG, a live mycobacterium also used worldwide as a vaccine against tuberculosis, is one of the first successful immunotherapies of cancer. Despite being in clinical use for the treatment of non-muscle-invasive bladder cancer (NMIBC) for 4 decades, the mechanism by which BCG activates the immune system to destroy cancer cells is poorly understood and there are no reliable methods to predict a patient’s response to BCG treatment. Current data suggest that the efficacy of BCG depends on initial attachment of BCG to bladder cancer cells leading to activation of an immune response that is T-cell dependent. It is not known whether bladder cancer cells have a direct role in activating T-cells. Using an orthotopic mouse model of BCG treatment of bladder cancer we show that: 1) BCG induces tumor-specific immunity; 2) CD4+ T-cells are the main requirement for BCG efficacy and for the tumor-specific immunity engendered by BCG therapy;3) bladder cancer cells can directly activate CD4+ T-cells; 4) the efficacy of BCG depends on MHC class II expression on the surface of bladder cancer cells. These data suggest that bladder cancer cells directly activate and drive a CD4+ T-cell dependent immune response that is required for the efficacy of BCG. Current work in the lab is focused on characterizing MHC class II expression on human NMIBC specimens and determining whether expression of MHC class II on bladder cancer cells predicts clinical outcomes after BCG therapy. Citation Format: Gil Redelman-Sidi, Michael Glickman, Anna Binyamin, Anthony Antonelli. MHC class II on cancer cells—Role in response to BCG therapy of bladder cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B087.","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116625403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA34: Mapping immune recognition of non-self neoantigens in human pancreatic cancer","authors":"M. Luksza, Joanne Leung, Alexander Solovyov, D. Redmond, M. Merad, S. Gnjatic, Christine Iacubuzio-Donohue, R. DeMatteo, T. Chan, J. Wolchock, S. Leach, B. Greenbaum, T. Merghoub, V. Balachandran","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA34","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA34","url":null,"abstract":"Endogenous T-cell responses to cancer-specific mutations (neoantigens) are a common denominator of successful immunotherapies. However, endogenous neoantigen-specific T cell immunity in immunotherapy refractory tumors remains poorly characterized. Pancreatic ductal adenocarcinoma (PDAC) is the prototypical immunotherapy refractory cancer: response rates to single-agent checkpoint blockade are 5 years, T cell immunity has been linked to their exceptional outcome however the relevant antigens remained unknown. We sought to identify the landscape, antigenic potential, and T cell functional states induced by neoantigens in rare long-term pancreatic cancer survivors. Using genetic, immunologic, and computational techniques, we recently reported that tumors with the highest predicted neoantigen number and the greatest density of CD3+CD8+ infiltrates together, but neither parameter alone, could identify long-term survivors, suggesting differential inherent neoantigen immunogenicity. To investigate the specific neoantigen qualities promoting differential immunogenicity, we developed a fitness model that quantifies neoantigen immunogenicity based on estimations of the relative MHC binding affinity of each neoantigen to its wild type counterpart, as well as a nonlinear dependence on sequence similarity of neoantigens to known antigens. Our neoantigen quality fitness model identified long-term survivors in two independent PDAC datasets, as well as predicted survival in anti-CTLA4 treated melanoma patients, and anti-PD-1 treated lung cancer patients. In long-term PDAC survivors, we detected high quality neoantigen-specific intratumoral T cell clones persisting in the blood up to 12 years after primary tumor removal, with both unique clonal and phenotypic profiles. Our results identify neoantigens with unique qualities as T cell targets in both endogenous and immunotherapy treated cancers. Neoantigen quality can therefore inform rational neoantigen immunogenicity predictions that may guide patient and target selection for immunotherapies. Citation Format: Marta Luksza, Joanne P. Leung, Alexander Solovyov, David Redmond, Miriam Merad, Sacha Gnjatic, Christine Iacubuzio-Donohue, Ronald P. DeMatteo, Timothy A. Chan, Jedd Wolchock, Steven D. Leach, Benjamin D. Greenbaum, Taha Merghoub, Vinod P. Balachandran. Mapping immune recognition of non-self neoantigens in human pancreatic cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA34.","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"68 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126341385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR11: CX3CR1+CD8+ T-cells are responsible to the clinical benefit of chemoimmunotherapy in metastatic melanoma patients after disease progression on PD-1 blockade","authors":"Yiyi Yan, Haidong Dong, R. Dronca, S. Markovic","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-PR11","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-PR11","url":null,"abstract":"Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains a challenge and lacks a standard of care. Immunotherapy or chemotherapy alone provides limited benefit in this setting. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. Our preclinical study in MM has shown that the addition of chemotherapy to PD-1 blockade can reshape a subset of therapy-responsive CD8+ T-cells with resultant enhanced antitumor activities, suggesting the potential clinical benefits of CIT in MM patients whose disease have progressed after anti-PD-1 therapy. Further understanding of the clinical benefits and immunoregulatory mechanisms of CIT in this setting is crucial for the development of optimal combinatorial chemo-immunotherapeutic strategies to improve clinical outcomes in patients with advanced cancer. Methods: MM patients (n=22) who have failed PD-1 blockade therapy were subsequently treated with CIT (paclitaxel and carboplatin in combination with pembrolizumab). The overall survival (OS), objective response rate (ORR), time-to-next therapy (TTNT), and toxicities were assessed. Using peripheral blood (PB) from MM patients, the phenotypic and functional changes induced by chemotherapy in therapy-responsive T-cells, in the setting of anti-PD1 therapy, were examined. The immunoregulatory effects of CIT were also examined in melanoma mouse model. Results: MM patients who have received subsequent CIT had a median OS of 5 years (95% CI: 2-NR) (median follow up of 3.9 years), with ORR of 61% (CR of 23%). The median TTNT was 8 months (95% CI: 6-15). No additional toxicities were identified. CX3CR1+CD8+ therapy-responsive T-cells are low in MM patients who have failed to respond to anti-PD-1 monotherapy. However, in MM patients who responded to subsequent CIT, this subset of therapy-responsive T-cells survived the chemotherapy with increased frequency and enhanced function. The clinical benefit of CIT is only observed in CX3CR1 wild type mice, not in KO mice, and ongoing PD-1 blockade is necessary to improve its anti-tumor activities. Conclusion: In MM patients who have failed anti-PD-1 therapy, the chemo-immunotherapy combination showed favorable clinical outcomes and an acceptable toxicity profile. CX3CR1+ CD8+ effector T-cells are responsible for the clinical benefit of CIT. This novel therapy-responsive population underlies the key cellular and molecular immunoregulatory mechanisms of chemotherapy. It serves as a meaningful marker to measure these collaborative effects and to develop the optimal chemo-immunotherapy strategy to improve clinical responses to current immune checkpoint blocking agents. Citation Format: Yiyi Yan, Haidong Dong, Roxana Dronca, Svetomir Markovic. CX3CR1+CD8+ T-cells are responsible to the clinical benefit of chemoimmunotherapy in metastatic melanoma patients after disease progression on PD-1 blockade [abstract]. In: Proceedings of the F","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130848537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B076: Pan-cancer analysis to identify which cancers may benefit most from LAG-3 blockade","authors":"S. Ganesan, Anshuman Panda, G. Bhanot","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B076","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B076","url":null,"abstract":"Immune checkpoint blockade using antibodies that target programmed-cell-death-1 (PD-1) or its ligand programmed-cell-death-ligand 1 (PD-L1), and/or cytotoxic-T-lymphocyte-associated-protein-4 (CTLA-4) have led to dramatic responses, but only in a subset of human cancers. An antibody targeting lymphocyte-activation-gene-3 (LAG-3), relatlimab (BMS-986016), recently showed significant clinical activity in melanoma, and early clinical data showed that LAG-3 expression is a biomarker of response to this agent. We performed a pan-cancer analysis of The Cancer Genome Atlas data to identify genomic and immunologic correlates of LAG-3 expression. Hyper-mutation, and exogenous (Epstein-Barr virus, human papillomavirus) or endogenous (endogenous retrovirus group 3 member 2) viral expression in tumor were associated with increased expression of LAG-3 in multiple cancer types. LAG-3 expression was also correlated with CD8A and PD-L1 expression in most cancer types; however, there were notable exceptions, including head-neck squamous-cell cancer (HNSC), renal cell cancer (RCC) and glioblastoma. In HNSC, LAG-3 expression, but not PD-L1, was significantly increased in HPV+ cancers. In RCC and gliobastoma, LAG-3 was more strongly associated with CD8A expression than PD-L1. These results may have implications on the design of future clinical trials of LAG-3 blockade. Citation Format: Shridar Ganesan, Anshuman Panda, Gyan Bhanot. Pan-cancer analysis to identify which cancers may benefit most from LAG-3 blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B076.","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"34 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134524820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B071: Validating sequence similarity-driven neoepitope fitness models via immunogenomics on TCGA and multiregional tumor data","authors":"A. Bubie, N. Akers, A. Villanueva, B. Losic","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B071","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B071","url":null,"abstract":"Clonal fitness and survival models for checkpoint blockade response prediction have recently been proposed on the basis of ranking neoepitopes via an interaction between a proxy of T-cell recognition, a nonlinear function of neoepitope sequence similarity to known antigens, and neoantigen relative MHC binding affinity. In this work we examine the SKCM (n = 337) and NSCLC (n = 305) TCGA datasets to explicitly test if sequence similarity to known antigens from the IEDB is associated with tumor infiltrating lymphocyte (TIL) burden in patients, as measured by TCR sequencing and CDR reconstruction in RNA-seq data. We find that there is no statistically significant association between either the inferred clonality or magnitude of TIL response and neoepitope sequence similarity to known antigens. We do, however, find significant, moderate associations of TIL response to neoepitope burden. Further, we examined the LIHC (n = 193) and UCEC (n = 245) TCGA cohorts to explicitly derive tumor and virally derived epitopes (HepB, HPV respectively) and ranked their relative predicted MHC binding affinity profiles. We find a greater MHC binding affinity bias exists towards neoepitopes compared to virally derived peptides in a natural setting where both viral and tumor antigens are simultaneously present. Moreover, we find low and significant associations between TIL burden and overall neoepitope burden, but no association with overall viral epitope or expression burden. Finally, we used multiregionally sampled data (12 patients, 72 regions) from HepB-positive HCC liver cancer patients to confirm preferential MHC binding affinity and TIL response bias towards neoepitopes still holds and is significant. Our results suggest that neoepitopes dominate in their recruitment potential of, and association with, TIL burden compared to viral-cofactors. They also suggest that neoepitope sequence similarity to known antigens does not recapitulate patient TIL burden to first approximation. Citation Format: Adrian Bubie, Nicholas Akers, Augusto Villanueva, Bojan Losic. Validating sequence similarity-driven neoepitope fitness models via immunogenomics on TCGA and multiregional tumor data [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B071.","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"600 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132481484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B074: A recall antigen-based potency assay for immunomodulatory biologics that could discriminate responders from nonresponders","authors":"M. Delcommenne, E. Kleiman, Wushouer Ouerkaxi, P. Daftarian","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B074","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B074","url":null,"abstract":"The surge of therapeutic regimens involving immune checkpoint antagonists and co-stimulatory pathways (ACP) antagonists used as single agents or in combination necessitates better functional screening assays. In vitro functional screening assays need to be non-invasive and high throughput. The recall antigen assay is arguably the one that, in an antigen specific controlled system, directly assesses the activity of potential immune checkpoint inhibitors (ICI) candidates, in a relatively physiologically relevant manner. The recall antigen assay has been often used in the past to prove the potency of ICI or ACP as indicated in publications and submissions to regulatory bodies. We have conducted a thorough optimization combined with modifications to the recall antigen assay to enable the need for a more effective and efficient assay.Our recall antigen assay has been optimized across multiple parameters including donor selection based on expression of co-inhibitory/co-stimulatory molecules. This facilitates the selection of the right donor for the right candidate. We have optimized both stimulation and readout components to enhance signal to noise ratio. For example, we reduced the duration of in vitro antigen specific CD8+ T-cell clonotype expansion from 2 weeks to 5 to 7 days. To maximize the direct readout, we have used an MHC Tetramer guided analysis, using a cocktail of MHC tetramers made with stimulating peptides. To further empower the tetramer assay with functionality, we also have co-stained tetramer positive cells with activation markers. Finally, we verified the assay using various activity-confirmed ICIs and controls. The assay uses characterized PBMCs stimulated with a pool of peptides with positive and negative treatments (e.g., PD-1 blockades and IgG4) and “test samples,” which are the candidates to be tested. Depending on the donor’s recall responses, a typical assay results in two to 6-fold increase of the antigen specific MHC tetramer positive population. Furthermore, after developing this recall antigen assay, we validated it by performing the assay in different laboratories, using different reagents lots, different instrumentations, and different operators. Recall antigen assay data indicated that not all donors respond to approved immune checkpoint blockades. Healthy donors stimulated with anti CD3 or cytokine cocktails varied showed a wide a wide variability of immune checkpoint molecules (ICM) cell surface levels. Further studies using characterized PBMCs in our recall antigen potency assay revealed that the expression of immune checkpoint molecules may contribute in unresponsiveness to a given ICI. In conclusion, we have developed an improved in vitro recall antigen potency assay for immunomodulatory biologics functional screening including ICIs and APCs. Furthermore, we observed that in our studies this potency assay divides hosts into responders and nonresponders. Interestingly, we also showed significant variation of persons","PeriodicalId":433681,"journal":{"name":"Mutational Analysis and Predicting Response to Immunotherapy","volume":"102 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115893835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}