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bioRxiv · 10.64898/2026.03.05.709907

IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer

Lopez, L.·Cui, Z.·Yamaguchi, Y.·Murad, J. P.·Yang, Z.·Zou, K.·Yang, J.·Chang, W.-C.·Forman, S.·Chan, V.·Priceman, S. J.
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Abstract

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, IFNy 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.

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Lopez, L., Cui, Z., Yamaguchi, Y., Murad, J. P., Yang, Z., Zou, K., Yang, J., Chang, W.-C., Forman, S., Chan, V., Priceman, S. J.. 2026-03-08. IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer. https://doi.org/10.64898/2026.03.05.709907

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