Abstract B82: Identification of tumor neoantigens for combination therapy in murine tumor models

Abstract

Abstract The adoption of anti-CTLA-4 and anti-PD-1/PD-L1 blockade has dramatically changed the treatment approaches in multiple cancer types, and has demonstrated the power of the immune system to control the outgrowth of neoplastic lesions. Accumulating evidence suggests these successes are mediated by T cells targeting nonsynonymous mutations unique to the patient’s tumor. When used in combination with checkpoint inhibition, or other standard of care treatment modalities, vaccines targeting tumor neoantigens have the potential to greatly enhance patient survival. Recent advances in DNA/RNA sequencing and bioinformatic analysis have made it possible to rapidly identify nonsynonymous mutations being expressed in patient tumors. As the number of nonsynonymous mutations detected in patient samples can range from less than 10 to several thousand, it is necessary to develop strategies to identify and rank neoantigens with a greater probability of being immunogenic and mediating regression of established tumors. In the present study, we harvested tumors from mice bearing syngeneic tumors, and performed DNA/RNA sequencing to identify nonsynonymous mutations to use as tumor specific neoantigens. These potential neoantigens were ranked based upon their proposed in-silico MHC binding affinity, and the relative abundance of each transcript as determined by RNA-seq. Top ranking 9-mer neoantigens peptides were synthesized and evaluated. We assessed neoantigens for their ability to bind MHC in vitro, and expand antigen-specific T cells in vivo. To further augment the immunogenicity of our neoantigen 9-mer peptides, we used them in combination with an IL-15 super-agonist (ALT-803) and an anti-PD-L1 antibody. When used in combination with these immune-modulators, we observed a dramatic increase in the magnitude of the immune response generated against our neoantigens, which associated with increased tumor therapy. This study provides the rational for the combination of neoantigen vaccines with immune modulators to slow tumor growth and extend survival. Citation Format: Karin L. Lee, Andrew T. Nguyen, Steven C. Benz, Shahrooz Rabizadeh, James W. Hodge, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton. Identification of tumor neoantigens for combination therapy in murine tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B82.