Collagen-binding IL-12 expressing STEAP1 CAR-T cells reduce toxicity and eradicate mouse prostate cancer in combination with checkpoint inhibitors

Sasaki, K.; Bhatia, V.; Asano, Y.; Bakhtiari, J.; Kaur, P.; Wang, C.; Matsuo, T.; Nikolaidi, M.; Chiu, P.-C.; Dubois, O.; Chong, T.; Javier, G.; Priceman, S. J.; Chapuis, A. G.; Lee, J. K.; Ishihara, J.

doi:10.1101/2025.03.19.644145

bioRxiv · 10.1101/2025.03.19.644145

Collagen-binding IL-12 expressing STEAP1 CAR-T cells reduce toxicity and eradicate mouse prostate cancer in combination with checkpoint inhibitors

Sasaki, K.·Bhatia, V.·Asano, Y.·Bakhtiari, J.·Kaur, P.·Wang, C.·Matsuo, T.·Nikolaidi, M.·Chiu, P.-C.·Dubois, O.·Chong, T.·Javier, G.·Priceman, S. J.·Chapuis, A. G.·Lee, J. K.·Ishihara, J.

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Abstract

Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose significant challenges for chimeric antigen receptor (CAR)-T cell therapies to tackle solid tumors. CAR-T cells were armed with immunostimulatory payloads, such as interleukin-12 (IL-12), to overcome this issue, but faced intolerable toxicity during clinical development. Here, we show that collagen-binding domain-fused IL-12 (CBD-IL-12) was retained within syngeneic murine prostate tumors, after secretion from CAR-T cells targeting human six transmembrane epithelial antigen of the prostate 1 (STEAP1). This led to equivalently high intratumoral interferon-{gamma} levels without hepatotoxicity and infiltration of T cells into non-target organs, compared with unmodified IL-12. Both innate and adaptive immune compartments were dramatically activated and recognized diverse tumor antigens after CBD-IL-12 CAR-T cell treatment. Combination immunotherapy of CBD-IL-12 CAR-T cells and immune checkpoint inhibitors eradicated large tumors in an established prostate cancer model, without pre-conditioning chemotherapy. The therapy generated anti-tumor immunological memory. CBD-fusion to potent yet toxic payloads of CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumors.

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Sasaki, K., Bhatia, V., Asano, Y., Bakhtiari, J., Kaur, P., Wang, C., Matsuo, T., Nikolaidi, M., Chiu, P.-C., Dubois, O., Chong, T., Javier, G., Priceman, S. J., Chapuis, A. G., Lee, J. K., Ishihara, J.. 2025-03-19. Collagen-binding IL-12 expressing STEAP1 CAR-T cells reduce toxicity and eradicate mouse prostate cancer in combination with checkpoint inhibitors. https://doi.org/10.1101/2025.03.19.644145

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