Data from Phase I Trial of P-PSMA-101 CAR T Cells in Patients with Metastatic Castration-Resistant Prostate Cancer

<jats:p>&lt;div&gt;Abstract Purpose:&lt;p&gt;Chimeric antigen receptor (CAR) T-cell therapies have shown potential in solid tumors. A higher proportion of stem cell–like memory T cells (T&lt;sub&gt;SCM&lt;/sub&gt;) 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 T&lt;sub&gt;SCM&lt;/sub&gt;-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.&lt;/p&gt; Patients and Methods:&lt;p&gt;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 T&lt;sub&gt;SCM&lt;/sub&gt;-rich CAR T cells.&lt;/p&gt; Results:&lt;p&gt;Among 33 treated patients, 18% (&lt;i&gt;n&lt;/i&gt; = 6) had dose-limiting toxicities. Cytokine release syndrome (CRS) occurred in 61% (&lt;i&gt;n&lt;/i&gt; = 20), with grade ≥3 CRS seen in 9% (&lt;i&gt;n&lt;/i&gt; = 3). Activation of the iCasp9-based safety switch was required in 24% (&lt;i&gt;n&lt;/i&gt; = 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% (&lt;i&gt;n&lt;/i&gt; = 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% (&lt;i&gt;n&lt;/i&gt; = 20) of patients, with 21% (&lt;i&gt;n&lt;/i&gt; = 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.&lt;/p&gt; Conclusions:&lt;p&gt;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, T&lt;sub&gt;SCM&lt;/sub&gt; cell–enriched approach.&lt;/p&gt;&lt;p&gt;&lt;a target="_blank" href="https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-26-0959"&gt;&lt;i&gt;See related commentary by Lee et al., p. 3417&lt;/i&gt;&lt;/a&gt;&lt;/p&gt;&lt;/div&gt;</jats:p>