This study aims to translate tumor-specific mutations identified by next-generation sequencing techniques into an effective anti-tumor vaccine for a classically non-immunogenic tumor, pancreatic ductal adenocarcinoma (PDA). Pancreatic ductal adenocarcinomas develop an average of 63 mutations during tumorigenesis, collectively referred to as the “mutome.” Of these, approximately 45 are amino acid point mutations. These mutations are not present in normal cells and provide a source of tumor-specific neoepitopes for targeted immunotherapy. Next-generation sequencing technologies allow for rapid identification of mutations present in patient tumors; however, methods for rapid identification of immunogenic neoepitopes which can be effectively targeted for tumor clearance, and optimized vaccination strategies for targeting them, still need to be developed.

In this study, we are using a transplantable murine PDA model, Panc02, to develop vaccination strategies for inducing neoepitope-specific T cell antitumor responses, and to define parameters for selecting appropriate targets. Exome sequencing identified 878 nonsynonymous mutations in the Panc02 cell line. Three immunological epitope prediction servers identified 878 potentially immunogenic peptides in the Panc02 model, 29 of which were strong candidates (scores <50) and another 240 candidate epitopes within the limits of prediction (scores <1000). Panc02 neoepitope peptide vaccinations in mice confirmed 14% of the predicted epitopes to be immunogenic by IFNγ ELISPOT, which may include both CD8+ and CD4+ T cell responses. Tumor transplant experiments demonstrate that therapeutic vaccination against neoepitopes in combination with a human STING-activating cyclic dinucleotide adjuvant is capable of inducing a temporary regression of implanted tumors. After tumor escape and regrowth, flow cytometry reveals a large population of infiltrating lymphocytes, the majority of which are co-expressing the checkpoint molecules PD-1, Tim3, and Lag3, indicating that treatment of vaccinated animals with checkpoint blockade therapy may potentiate infiltrating lymphocytes and ultimately result in permanent tumor regression. Thus, a broad and unbiased approach for screening vaccine targets will allow for the evaluation of predictive algorithms and ultimately the development of more effective vaccination approaches for targeting the tumor mutome.

Citation Format: Heather Kinkead, Eric Lutz, Thomas W. Dubensky, Elizabeth Jaffee. Exploiting the pancreatic cancer mutome for immune interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1695. doi:10.1158/1538-7445.AM2017-1695