Abstract B055: Enhanced detection of T-cells targeting unique neoantigens and shared mutated oncogenes for personalized cancer immunotherapy

Abstract

Adoptive cell transfer (ACT) of selected tumor-infiltrating lymphocytes (TILs) targeting neoantigens can mediate tumor regression in selected patients with metastatic epithelial cancer. However, effectively identifying and harnessing neoantigen-reactive T-cells for patient treatment remains a challenge and it is unknown whether current methods to detect neoantigen-reactive T-cells are missing potentially clinically relevant neoantigen reactivities. We thus investigated whether the detection of tumor-neoantigen reactive TILs in epithelial cancers could be enhanced by enriching T-cells that express PD-1 and/or T-cell activation markers (CD134, CD137) followed by microwell culturing at limiting dilution cell concentrations to avoid overgrowth of non-reactive T-cells. Using this approach, in six patients with metastatic epithelial cancer including stomach, colon pancreatic and ovarian cancers, this method led to the detection of CD4 and CD8 T-cells targeting 19 neoantigens compared to only eight neoantigens recognized using our standard TIL fragment screening approach. In two patients, no recognition of mutated peptides was observed using our conventional screen, while our high-throughput approach led to the identification of five neoantigen reactive-TCRs against five different mutations from one patient and a highly potent MHC-II-restricted KRASG12V reactive TCR from a second patient. In addition, in a metastatic tumor sample from a patient with serous ovarian cancer, we isolated three MHC class-II-restricted TCRs targeting the TP53G245S “hot-spot” mutation. In conclusion, this approach provides a highly sensitive and specific platform to isolate clinically relevant neoantigen-reactive T-cells or their TCRs for cancer treatment. Citation Format: Rami Yossef, Eric Tran, Alena Gros, Drew Deniger, Gal Cafri, Steven A. Rosenberg. Enhanced detection of T-cells targeting unique neoantigens and shared mutated oncogenes for personalized cancer immunotherapy [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 B055.