Abstract 2052: LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses, tumor inhibition, and provides rationale for first-in-human trial

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 thus making LT an attractive target for therapeutic cancer vaccines. We designed a cancer vaccine that promotes potent, antigen-specific CD4+ T cell responses to MCPγV-LT. To activate antigen-specific CD4+ T cells in vivo, we utilized our nucleic acid platform, UNITE࣪ (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 MCPγV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE࣪ platform. In pre-clinical studies, vaccination with LTS220A-UNITE࣪ (ITI-3000) induced antigen-specific CD4+ T cells that were sufficient to delay tumor growth, and this effect was dependent on their ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including significantly enhanced numbers of CD4+ and CD8+ T cells as well as NK and NKT cells. These findings strongly suggest that in pre-clinical studies, DNA vaccination using the UNITE࣪ platform enhances CD4+ T cell responses to MCPγV-LT that result in significant anti-tumor immune responses. We are planning a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC. Patients will receive up to four intramuscular vaccinations of 4mg of ITI-3000 using the PharmaJet Stratis® needle-free injection system. The primary objectives will be safety and tolerability, observing dose-limiting toxicities, serious adverse events, standard clinical assessments, and safety laboratory parameters. Immunogenicity of the vaccine will be measured by peripheral blood assessments of T cell activation using ELISpot and flow cytometry assays. Citation Format: Claire Buchta Rosean, Mohan Karkada, David M. Koelle, Paul Nghiem, Teri Heiland. LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses, tumor inhibition, and provides rationale for first-in-human trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2052.