Abstract 5332: Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody

Perforin secreted from cytotoxic T cells and natural killer cells play important roles in anti-tumor immunoreaction leading to cancer cell apoptosis. The aim of this study is to investigate whether perforin-rich tumor microenvironment could inhibit tumor growth. Advanced prostate cancer (PC) expresses high amount of prostate-specific antigen (PSA) that is a possible therapeutic target, therefore, we constructed a PSA promoter-driven perforin expression vector for its predominant expression in tumor microenvironment of PC. Prostate membrane-specific antigen (PSMA) expressed on PC cell surface is also an attractive therapeutic target. To deliver perforin expression vector to PC, it was encapsulated in liposomes conjugated with anti-PSMA antibody (PSMA-pLipo), then the anti-tumor effect of PSMA-pLipo was evaluated using docetaxel-resistant PC cell line, 22Rv1DR, expressing both PSA and PSMA. The conjugated anti-PSMA antibody on PSMA-pLipo recognized recombinant PSMA protein, and incubation with PSMA-pLipo induced perforin expression in 22Rv1DR cells but not in PC-3 cells not expressing both PSA and PSMA. Growth of 22Rv1DR and PC-3 cells was barely inhibited by PSMA-pLipo alone. Perforin functions in concert with cytotoxic lymphocytes, therefore anti-tumor effect of PSMA-pLipo was analyzed in the presence of human peripheral blood mononuclear cells (PBMCs). Low concentration of PSMA-pLipo with human PBMCs significantly inhibited growth of 22Rv1DR cells but not PC-3 cells. High concentration of PSMA-pLipo with human PBMCs showed nearly complete inhibition of 22Rv1DR cell growth. In a mouse xenograft model implanted with 22Rv1DR cells, PSMA-pLipo was intravenously administrated via tale vein and tumor volume was monitored. PSMA-pLipo inhibited growth of 22Rv1DR cells compared to injection of anti-PSMA antibody alone. The data presented here suggest that gene therapy expressing perforin specifically in PC cells could be a novel therapy for advanced PC. Citation Format: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Taku Kato, Manabu Takai, Daiki Kato, Koji Iinuma, Takuya Koie, Masafumi Ito. Prostate cancer targeting therapy using PSA promoter-driven perforin expression vector encapsulated in liposomes conjugated with anti-PSMA antibody [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 5332.