Abstract 643: Non-classical sources of tumour specific antigen in checkpoint inhibitor response

Abstract

Abstract A large-scale meta-analysis of over 1000 CPI (immune checkpoint blockade) treated patients across multiple cancer types broadly categorised biomarkers into four categories: sources of antigen leading to T-cell responses, host-derived factors, immune evasion and infiltration mechanisms. Our analyses established tumour mutation burden (TMB) as the strongest predictor of CPI response, alongside clonal TMB and CXCL9 expression. However, over half of the patients in our cohort who responded to CPI treatment did not have high-TMB and showed no evidence of oncogenic viral infections, hence suggesting alternative sources of antigen could be driving the immune response. As well as this, data from the CPI1000 cohort suggested that the biomarkers identified in an extensive systematic review only accounted for ~60% of the variance in CPI response, promoting the search for non-classical sources of antigen. Extending the cohort to encompass 2500+ patients, using available genomic and transcriptomic data from checkpoint inhibitor trials and industry partners, the previously published multivariate predictor will be further validated in a larger patient cohort inclusive of more cancer types. The CPI1000 cohort utilised primarily whole exome-sequencing therefore, had limited ability to discern non-coding sources of tumour antigen and cell-type specific predictors of response. The CPI2500+ cohort will incorporate several additional cohorts as well as single-cell and T-cell reactivity data. The raw data will be harmonised across studies and processed using a robust bioinformatics pipeline. As well as this, alternative (non-classical) sources of tumour specific antigen will be studied. Alternative sources of antigen can originate from a diverse range of biological processes including retained introns, stop codon loss mutations and cancer associated bacterial/viral epitopes. Data from this exploratory analysis will be coupled with peptide reactivity assays from local UCL patient TIL (tumour infiltrating lymphocyte) and PMBC (peripheral blood mononuclear cells) samples to validate immunogenicity. Current analysis has identified a novel subgroup of CPI-responders with low-TMB who have significantly higher rates of microbial diversity, consistent with a diverse tumour microbiome providing a source of immunogenic antigens in the absence of high-TMB. Here we will present insights from CPI2500+ and highlight the importance of emerging non-classical sources of tumour specific antigen. Citation Format: Krupa Thakkar, Danwen Qian, Hongui Cha, Thomas B. Watkins, Charles Swanton, Kevin Litchfield. Non-classical sources of tumour specific antigen in checkpoint inhibitor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 643.