Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

Researchers at Memorial Sloan Kettering Cancer Center and City of Hope, together with a multicenter U.S. team and Poseida Therapeutics, have reported early clinical activity for a prostate-specific membrane antigen (PSMA)-directed CAR T-cell therapy in metastatic castration-resistant prostate cancer (mCRPC). In this phase I study, published in Clinical Cancer Research, the autologous product P-PSMA-101 was engineered using a nonviral piggyBac transposon platform designed to enrich stem cell–like memory T cells (TSCM) and included an inducible caspase-9 safety switch. Overall, this approach resulted in anti-tumor response in patients with mCRPC, despite toxicity.

Normally an immunologically “cold” solid tumor, mCRPC cancer remains difficult to treat with immunotherapy, with prior CAR T-cell efforts demonstrating limited durability. To address this, the investigators tested P-PSMA-101 in a first-in-human, multicenter 3+3 dose-escalation trial enrolling patients who had already received an androgen receptor pathway inhibitor and taxane chemotherapy, or were ineligible for those treatments. Between March 2020 and December 2022, 74 patients were consented, 51 underwent apheresis, manufacturing was successful in 47 (92%), and 33 ultimately received treatment. Patients received fludarabine/cyclophosphamide lymphodepletion followed by P-PSMA-101, with intensive inpatient monitoring, serial cytokine testing, qPCR-based CAR kinetics, and standard radiographic and PSA response assessment.

Among 33 treated patients, 18% developed dose-limiting toxicities, CRS occurred in 61% and grade 3 or higher CRS in 9%, while 15% developed HLH-like toxicity and 24% required activation of the inducible safety switch with rimiducid. Antitumor activity was observed with 21% achieving a PSA50 response, 33% achieving a PSA30 response, 1 of 13 RECIST-evaluable patients had a partial response, and 61% had stable disease, including 21% with stability for at least 3 months. Two patients had remissions lasting more than 12 months with PSA declines greater than 90%. In one representative bone-only case, PSMA-PET SUV fell from 28.5 at baseline to 8.3 at 4 weeks and 2.8 at 12 weeks, with biopsy confirming CD4 and CD8 infiltration and detectable CAR transgene at the tumor site. These findings are important because they show that PSMA CAR T cells can traffic to bone metastases and induce meaningful tumor regression in prostate cancer, but also make clear that future development will depend on improving safety while preserving persistence and response durability.

Reference:

Slovin S, Gao X, Wei XX, et al. Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC). Clin Cancer Res. Published online March 4, 2026. http://doi.org/10.1158/1078-0432.CCR-25-3052