Tumor Neoantigen Profiling With Validated Patient-Specific Tcr Characterization To Improve Neoepitope Prediction.

Abstract PACT Pharma has developed an ultra-sensitive approach to validate predicted neoantigens and the cognate T cell receptors (neoTCRs) from tumor specific somatic mutations by capturing neoantigen-specific T cells from peripheral blood. This process is used in clinical trials (NCT03970382) of personalized neoTCR-T therapy for persons with solid cancers. Using the state of the art prediction pipeline and screening process, more than one hundred twenty neoantigens were predicted from 5 type of solid cancers that were validated by characterizing cognate T cells and their close to 200 unique TCRs captured from the blood of the same individual. These validated neoepitopes of 8 to 11 amino acids represent broad HLA class I coverage with >30 alleles to date. Our analysis revealed that mutations can occur in all positions within the epitopes. Epitope immunogenicity is potentially affected by different mechanisms including mutation position, agretopicity, as well as HLA interacting positions and/or by interactions between mutated residues and its cognate TCRs. It was observed that these validated neoepitopes comprise broad ranges of predicted HLA binding affinities, stability, and neoantigen expression levels. The analysis presented here offers insights to enable machine learning to advance rules for epitope selection and prioritization that may be important for immunological approaches to address a broad range of diseases, including cancer. Citation Format: Zheng Pan, Olivier Dalmas, Songming Peng, Kyle Jacoby, Barbara Sennino, Yan Ma, Chad Smith, Amin Momin, Allison Xu, Katharine Heeringa, Jonathan Johnston, Duo An, Boi Quach, William Lu, Diana Nguyen, Andrew Conroy, Bhamini Purandare, Eva Huang, Eric Stawiski, Alex Franzusoff, Stefanie Mandl. Tumor neoantigen profiling with validated patient-specific TCR characterization to improve neoepitope prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2177.