Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS).
P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells.
Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data.
Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2026 Mar 04 [Epub ahead of print]
Susan Slovin, Xin Gao, Xiao X Wei, David Y Oh, Rana R McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A Spear, Devon J Shedlock, Tanya B Dorff
Memorial Sloan Kettering Cancer Center New York, NY United States., Massachusetts General Hospital Boston, Massachusetts United States., Dana-Farber Cancer Institute Boston, MA United States., University of California, San Francisco San Francisco, CA United States., University of California, San Diego La Jolla, CA United States., Sarah Cannon Denver, Colorado United States., University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center Baltimore, MD United States., Sarah Cannon Nashville, TN United States., Poseida Therapeutics (United States) San Diego, CA United States., Poseida Therapeutics (United States) United States., Poseida Therapeutics (United States) San Diego United States., City Of Hope National Medical Center Duarte, CA United States.