Abstract 4585: LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses and prevents tumor growth

Abstract

Abstract The majority of Merkel cell carcinomas (MCC), a rare and highly-aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of a truncated form of the viral large T antigen (LT) in infected cells and making LT an attractive target for therapeutic cancer vaccines. While induction of tumor-reactive CD8+ T cells is a major goal of cancer therapy, CD4+ T cells provide essential support to CD8+ T cells by promoting their expression of cytotoxic effector molecules and increasing their migratory capacity. Cytokines secreted by CD4+ T cells, such as IFNγ, can also exert desirable effects on the tumor microenvironment. Therefore, we set out to design a cancer vaccine that promotes potent, antigen-specific CD4+ T cell responses to MCPyV-LT. To activate antigen-specific CD4+ T cells in vivo, we utilized our nucleic acid platform, UNITE (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and a balanced T cell response. LTS220A, encoding a mutated form of MCPyV-LT that abrogates its pro-oncogenic properties, was introduced into the UNITE platform. Intradermal vaccination with LTS220A-UNITE promoted a potent, antigen-specific CD4+ T cell response to MCPyV-LT. Additionally, prophylactic vaccination with LTS220A-UNITE prevented growth of B16F10 tumors expressing LTS220A in 100% of mice. Therefore, we find that DNA vaccination using the UNITE platform enhances CD4+ T cell responses to MCPyV-LT and prevents tumor growth when given prophylactically. Future studies will test the efficacy of LTS220A-UNITE for use as a therapeutic cancer vaccine. Citation Format: Claire Buchta Rosean, Pratima Sinha, David M. Koelle, Paul Nghiem, Teri Heiland. LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses and prevents tumor growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4585.