PSCA-IgG4 RevTMs enhance RevCAR-T activity in prostate cancer; eliminates need for continuous RevTM infusions

Novel PSCA-targeting adapter molecules for prolonging therapeutic effects of RevCAR-T cells in prostate cancer

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Arndt, C. ; García de Andres, I.; Bergmann, R.; Mitwasi, N.; Neuber, C. ; Soto, K. E. G.; Jones Cifuentes, N. A. ; Jutrzenka-Trzebiatowski, A. ; Rodrigues Loureiro, L. R.; Mathé, D.; Bachmann, M.; Feldmann, A.

Metastatic prostate cancer (PCa) remains lethal with limited treatment options, especially after progression to castration-resistant disease. Targeted therapies, including chimeric antigen receptor (CAR) therapies, are emerging as promising strategies that can act inde-pendent of the androgen receptor axis. Here, we employ the adapter CAR-T cell platform “RevCAR” for targeted PCa therapy, offering precise therapeutic control and tumor tar-geting via tumor-specific reverse target modules (RevTMs). To prolong and intensify RevCAR-T activity, we developed novel IgG4-based RevTMs targeting prostate stem cell antigen (PSCA) and benchmarked them against previously described smaller adapter formats. Within the RevCAR system, PSCA-IgG4 RevTMs effectively mediated PCa killing at low effector-to-target ratios and low RevTM concentrations in a strictly anti-gen-dependent manner. Oncolytic activity was accompanied by a rapid and pronounced release of proinflammatory cytokines across a broad RevTM concentration range, which is particularly advantageous for immunologically cold PCa. Finally, anti-tumor activity was confirmed in immunodeficient mice. Further PET studies demonstrated improved phar-macokinetics, as evidenced by slow blood elimination and accumulating tumor uptake over time. Together, these data position PSCA-IgG4 RevTMs as promising candidates for enhancing and prolonging RevCAR-T effects in PCa, while eliminating the need for con-tinuous RevTM infusions. This eases applicability to patients without compromising safety control.

International Journal of Molecular Sciences 27(2026)14, 6407 DOI: 10.3390

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