042 Tumor neoantigens and a novel hapten vaccine promote immune targeting of wild type tumor antigens and improve response to immune checkpoint blockade

Abstract

In metastatic melanoma, both tumor neoantigen load and development of vitiligo have been associated with favorable response to immunotherapy. We hypothesize that in the context of immune checkpoint blockade (ICB), neoantigens facilitate epitope spreading and immune targeting of tumor-lineage self-antigens. We also aim to harness this process with a hapten-based vaccine to improve ICB response. Previously, our lab demonstrated in a murine model of melanoma that tumors with high neoantigen load respond significantly better to ICB than syngeneic tumors with low neoantigen load. We show that this response is associated with increased immune recognition of a melanocyte self-antigen (gp100) and that long-term survivors develop a durable immune response against tumor-lineage self-antigens. We leverage the understanding that neoantigens can promote epitope spreading into a novel vaccine therapy by exogenously introducing “neoepitopes” into tumor cells with hapten treatment. Mice bearing melanomas with low neoantigen load responded significantly better to hapten vaccine plus anti-PD-1 compared to unhaptenated control vaccine plus anti-PD-1. Bulk tumor RNA-Seq revealed enhanced immune and T cell signatures with hapten vaccine treatment. Immunohistochemistry showed increased CD8+ T cells and decreased Foxp3+ Tregs intratumorally, and flow cytometry demonstrated elevated functional CD8+ T cells targeting the melanocyte self-antigen gp100. Depletion of specific immune cell populations confirmed that CD8+ T cells are required for treatment efficacy. Hapten vaccine treatment also increased the efficacy of combination immunotherapies and improved ICB response in a model of pancreatic ductal adenocarcinoma. This novel hapten-based vaccine may have broad clinical applications as a strategy to enhance ICB response.