Characterization of T cell responses induced following checkpoint inhibition therapy across multiple malignancies with a high tumor mutational burden

Abstract

Abstract Cancer vaccination has been idealized for the past two decades but has suffered from the lack of relevant and specific target antigens. Neoantigens, harboring neoepitopes, represent patient-specific mutated antigens which could potentially serve as immunotherapeutic targets. In the recent years, it has been observed that patients with a higher tumor-mutational burden (TMB) have better clinical responses to checkpoint inhibition therapy. TMB may become a potential criterion for the inclusion of patients in such immunotherapeutic trials. However, this observed correlation between TMB and improved clinical response has yet to be fully substantiated, especially in a pan-cancer setting. This work presents preliminary data from a basket trial that has been undergoing at Rigshospitalet, Denmark. This trial contains patients presenting malignant tumors with a high TMB across multiple cancer types, those of which are undergoing various immunotherapies. Preliminary data indicates that neoepitope-specific CD8+ T cells can be detected in patient-derived tumor-infiltrating lymphocytes and PBMCs with the use DNA barcode labeled peptide-MHC (pMHC) multimers. Through FACS and NGS sequencing, immunogenic neopeptides may be identified from a library of personalized in silico predicted peptides. Thus, providing further support to the notion that high-throughput methods of antigen-specific T cell detection may be utilized to interrogate the contribution of TMB to clinical outcome in checkpoint inhibition therapy.