CELL INTELLIGENCE · 肿瘤细胞治疗研究

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapies have shown potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR T-cell products could enhance engraftment, persistence, and prolong immune activity. This phase I trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich, bone-tropic CAR T-cell therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castrate-resistant prostate carcinoma (mCRPC). Secondary endpoints included objective response rate, prostate-specific antigen (PSA) response, and radiographic progression-free survival. PATIENTS AND METHODS: The final P-PSMA-101 product was produced from leukapheresis using the piggyBac DNA transposon-based platform, which integrates a multicistronic transgene encoding an inducible caspase 9 (iCasp9) safety switch in addition to the CAR, generating TSCM-rich CAR T cells. RESULTS: Among 33 treated patients, 18% (n = 6) had dose-limiting toxicities. Cytokine release syndrome (CRS) occurred in 61% (n = 20), with grade 3 CRS seen in 9% (n = 3). Activation of the iCasp9-based safety switch was required in 24% (n = 8) of cases, including one toxicity that was ultimately fatal and successful resolution of symptoms in the other seven. P-PSMA-101 demonstrated antitumor activity, with 21% (n = 7) of patients achieving a 50% PSA decline (PSA50 response). Among 13 RECIST-evaluable patients, one partial response was observed. Stable disease was observed in 61% (n = 20) of patients, with 21% (n = 7) maintaining disease stability for 3 months. Two patients experienced sustained remissions exceeding 12 months, characterized by PSA declines of more than 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. CONCLUSIONS: 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 therapy may be informed by the results of this nonviral engineering, TSCM cell-enriched approach. See related commentary by Lee et al., p. 3417.