Abstract 3964: Chemotherapeutic drug-induced tumor neoantigen discovery

Checkpoint inhibitors have shown significant efficacy against a variety of cancers, changing the way many cancers are treated. However, only a subset of patients can benefit from these therapies currently, and finding ways to increase the number of patients who can is a primary interest. Tumor mutational burden is one biomarker for checkpoint inhibitor efficacy, which may point to effective strategies for increasing tumor response to therapy. Combination of checkpoint inhibitors with existing chemotherapy is being pursued in several clinical trials, and has been shown to have synergistic effects in a mouse tumor model. Chemotherapeutic drugs work in many ways to kill tumor cells, notably by attacking DNA and its replication machinery to prevent proliferation. These DNA-targeting drugs can cause mutations in cells that are not killed outright. We hypothesize that some chemotherapeutics can cause DNA mutations that are translated into proteins and peptides that make their way into the HLA class I peptide presentation pathway. If these neoantigens are seen by CD8+ T cells as foreign, T cells will attack these tumor cells. This could provide one mechanism of action for an increase in therapeutic efficacy in tumors treated with combinations of chemotherapeutics and checkpoint inhibitors. We test the ability of two drugs, SN-38 (an active metabolite of irinotecan) and oxaliplatin to induce neoantigens by sequencing peptides from class I molecules in a colon cancer cell line. Citation Format: Julie M. Rumble, James L. Mobley, Richard Jones, Michael Ford, Michael Pisano. Chemotherapeutic drug-induced tumor neoantigen discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3964.