Abstract B120: Therapeutic cancer vaccine targeting the endogenous retroviral envelope protein ERVMER34-1 facilitates expansion of neoepitope specific T cells and improves responsiveness to PD-L1 blockade

Abstract Purpose: Endogenous retroviruses (ERVs) are remnants of retrovirus germline infections that occurred over the course of evolution and constitute between 5-8% of the human genome. While ERVs tend to be epigenetically silenced in normal adult human tissues, they are often overexpressed in carcinomas and may represent novel immunotherapeutic targets. However, therapeutic cancer vaccines targeting ERVs have not been assessed clinically. For the first time, this study characterizes the ERV envelope protein ERVMER34-1 as target for a therapeutic cancer vaccine. Experimental Design: The expression of ERVMER34-1 in multiple healthy adult and cancer tissues was assessed, as was its immunogenicity to ascertain whether specific T-cells could lyse human carcinoma cell lines expressing ERVMER34-1. Furthermore, the ability of a rationally designed ERVMER34-1 targeted therapeutic vaccine to induce tumor clearance in two murine carcinoma models expressing ERVMER34-1 was examined either as a monotherapy or in combination with immune-oncology agents. Results: The ERVMER34-1 protein is overexpressed in several types of human carcinomas while being absent in most healthy adult tissues. ERVMER34-1 specific T-cells were detected in PBMCs of cancer patients but not healthy donors following an overnight stimulation. However, reactive T-cells are readily expanded from both healthy donor and cancer patient PBMCs following a 7-day in-vitro stimulation. Furthermore, specific T-cells selectively kill human carcinoma cell lines expressing ERVMER34-1. A novel, rationally designed, therapeutic cancer vaccine targeting ERVMER34-1 mediated tumor control in established syngeneic murine tumors expressing ERVMER34-1 and promoted expansion of neoepitope-reactive T cells, which was enhanced when combined with rationally selected immune-oncology agents. Conclusions: This study supports the potential clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1, which would represent a new class of therapeutic cancer vaccine targeting ERVs. Citation Format: Duane H Hamilton, Maria Maldonado, Maria Gracia-Hernandez, Renee N Donahue, Claudia M Palena, Jeffrey Schlom. Therapeutic cancer vaccine targeting the endogenous retroviral envelope protein ERVMER34-1 facilitates expansion of neoepitope specific T cells and improves responsiveness to PD-L1 blockade [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B120.