Abstract PR12: Functional identification and therapeutic targeting of tumor neoantigens

Accurate identification of tumor-specific neoantigens (NeoAg) is essential for the development of effective personalized cancer vaccines and cellular immunotherapies. The success rates for purely computational approaches which rely on predicted HLA-binding have been disappointing, as these generally ignore 85-90% of total mutations and find less than 5% of those selected can be confirmed as T-cell targets. We have developed a novel NeoAg identification platform in which WES and RNAseq metadata is used to nominate mutations for subsequent functional T-cell analysis using autologous PBMC and/or TIL. Applying this platform to tumors of low mutational burden including PDAC, HNSCC, and MSS-CRC, we report that an average of 35% of expressed mutations selected for functional testing can be verified as neoantigens, and that a significant number of these would be missed by HLA-binding algorithms. Responses comprise both type I and type 2 CD4+ and CD8+ effector T-cells recognizing both “passenger” mutations and known activating mutations in driver oncogenes such as KRAS, PIK3CA, and NRAS. Additionally, we have established a single-cell platform for isolation of T-cell receptors (TCR) against these shared recurrent mutations, and have opened a phase 1b clinical trial to evaluate the efficacy of personalized NeoAg vaccination in solid tumors. Citation Format: Stephen Phillip Schoenberger, Aaron M. Miller, Luise A. Sternberg, Leslie Montero Cuencac, Milad Bahmanof, Zeynep Koasaloglu-Yalcin, Manasa Lanka, Ashmitaa Premlal, Pandurangan Vijayanand, Jason Greenbaum, Allesandro Seatte, Ezra E.W. Cohen, Bjoern Peters. Functional identification and therapeutic targeting of tumor neoantigens [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 PR12.