Abstract 3544: Synergistic efficacy of a PSMA DNA vaccine and PD-1 inhibition in anti-tumor immunity against prostate cancer

Abstract Prostate cancer (PCa) remains one of the leading causes of cancer-related morbidity and mortality in men. A promising target for immunotherapy is prostate-specific membrane antigen (PSMA), a transmembrane protein predominantly overexpressed in PCa, with expression levels correlating with tumor aggressiveness and invasiveness. In this study, we evaluated the prophylactic and therapeutic potential of a plasmid DNA vaccine targeting PSMA for the treatment and prevention of prostate cancer using the RM-1 mouse PCa cell line engineered to overexpress human PSMA. A DNA plasmid which encoded the human PSMA antigen, was administered prophylactically, prior to tumor challenge, or therapeutically, following tumor establishment using electroporation. In the prophylactic approach, vaccination resulted in significant tumor volume reduction and marked tumor growth inhibition. Moreover, the immune response was robust, characterized by increased infiltration of tumor-infiltrating lymphocytes (TILs), including CD8+ cytotoxic T cells, CD4+ helper T cells, B cells, NK cells, neutrophils, macrophages, and dendritic cells within the tumor microenvironment. Immune cell activation was also observed in the spleens, indicating systemic immune priming. Peptide-MHC tetramer staining revealed a significant increase in PSMA-specific CD8+ T cells in the spleen of vaccinated mice, confirming the induction of a targeted immune response against PSMA-expressing tumor cells. Additionally, PSMA-specific antibodies were significantly increased in the serum of vaccinated mice, suggesting humoral immunity in response to the vaccine. In the therapeutic approach, vaccination with the PSMA DNA vaccine alone slowed tumor growth. Like the prophylactic approach, therapeutic vaccination resulted in increased TILs and immune activation in the spleen. Upon the addition of PD-1 antibody, tumor growth was significantly inhibited, resulting in a greater reduction in tumor volume. The combination of PSMA vaccination and PD-1 blockade led to a more potent anti-tumor immune response, characterized by further activation and expansion of PSMA-specific CD8+ cytotoxic T cells, increased production of PSMA-specific antibodies, and enhanced infiltration of immune cells. These findings underscore the potential of PSMA-targeted DNA vaccines in combination with immune checkpoint blockade (e.g., anti-PD-1) as a promising preventive and therapeutic strategy for PCa, highlighting their ability to enhance immune surveillance and induce more effective anti-tumor immunity Citation Format: Perry Ayn Mayson Maza, Leslie Flores, Dana Rae Cyril-Ramirez, Dafei Chai, Delana Bui, Dan Zhao, Junhao Wang, Yifei Wang, Haiwei Ni, Xiaohui Xie, Xinfang Yu, Yong Li. Synergistic efficacy of a PSMA DNA vaccine and PD-1 inhibition in anti-tumor immunity against prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3544.