Abstract B010: Targeting Metastatic Prostate Cancer with STEAP1 CAR T Cells and Tumor-Localized Immunomodulation

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is a major cause of cancer-related deaths among men in the United States, with limited effectiveness from current cancer immunotherapies due to prostate cancer’s immunologically ‘cold’ nature. Chimeric antigen receptor (CAR) T cell therapies have transformed treatment paradigms in hematologic cancers, but achieving similar success in solid tumors like prostate cancer remains challenging. Most current CAR T cell therapies for prostate cancer target prostate-specific membrane antigen (PSMA) or prostate stem cell antigen (PSCA); however, the heterogeneous expression of these antigens in mCRPC underscores the need for new, more widely expressed targets. Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) presents a promising alternative target, with more consistent expression in mCRPC compared to PSMA. Here, we report the development of a second-generation STEAP1 CAR T cell therapy optimized for activity even at low antigen densities. Our STEAP1 CAR T cells demonstrated potent anti-tumor efficacy and prolonged persistence in preclinical mCRPC models, including human-in-mouse (C4-2B, 22Rv1) and mouse-in-mouse (RM9) systems. Safety was confirmed using a human STEAP1 knock-in mouse model, where no significant toxicities were observed. Despite this efficacy, antigen escape mechanisms remain a barrier to sustained response. To counter this, we explored the combination of STEAP1 CAR T therapy with tumor-localized interleukin-12 (IL-12) therapy. We engineered an “armored” variant by combining STEAP1 CAR T cells with a tumor-localized collagen binding domain (CBD)-IL-12 fusion protein, which promotes anti-tumor immunity, remodels the immunosuppressive tumor microenvironment, and reduces antigen escape through enhanced host immunity and epitope spreading. Our develpoed STEAP1 CAR T cell therapy has entered clinical trials, supported by the NCI NExT Program, with open enrollment now underway. These trials will explore CAR T cell persistence, expansion, trafficking, tumor microenvironment interactions, and mechanisms of resistance. In parallel, research is underway to further optimize metabolic fitness and efficacy through innovative strategies, including armored CARs with pro-inflammatory cytokines, and dual antigen targeting next-generation CAR T designs. This comprehensive approach aims to overcome the current limitations of CAR T cell therapy in treating mCRPC and enhance durable responses in this challenging disease. Citation Format: Vipul Bhatia, Sasaki Koichi, Ishihara Jun, John K Lee. Targeting Metastatic Prostate Cancer with STEAP1 CAR T Cells and Tumor-Localized Immunomodulation [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 B010.