Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single-chain variable fragment (scFv) derived from the humanized murine mAb clone J591 as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFN-γ production, and anti-tumor cell activity in vitro. Using two clinically relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer.
Molecular therapy. Advances. 2026 Apr 02*** epublish ***
Lupita S Lopez, Ziyou Cui, Yukiko Yamaguchi, John P Murad, Zhiyuan Yang, Ke Zou, Jason Yang, Wen-Chung Chang, Stephen J Forman, Vivien W Chan, Saul J Priceman
Division of Medical Oncology, Department of Medicine, Keck School of Medicine (KSOM) of USC, Los Angeles, CA 90033, USA., Eureka Therapeutics, Inc., Emeryville, CA 94608, USA., Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.