Novel PSCA-Targeting Adapter Molecules for Late-Stage RevCAR-T Cell Therapy in Prostate Cancer.

Chimeric antigen receptor (CAR) therapies are emerging as promising strategies, particularly for metastatic castration-resistant prostate cancer (PCa), as they can act independently of the androgen receptor axis. Adapter CAR-T cell platforms, such as the RevCAR system, offer precise therapeutic control and tumor targeting via small, rapidly eliminated tumor-specific adapters. To enable more convenient late-stage RevCAR-T therapy in PCa patients, allowing for discontinuous reverse target module (RevTM) infusion, we developed novel, larger 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 antigen-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 a short-term mouse model. Preliminary PET studies further indicate slow blood elimination and tumor-specific accumulation of novel IgG4-RevTMs. Together, these data position PSCA-IgG4 RevTMs as promising candidates for stepwise RevCAR-T treatment in PCa, in which short-lived scFv-RevTMs are initially used to ensure a rapid safety switch, followed by larger IgG4-RevTMs once the risk profile is known.