595 A phase I clinical trial evaluating the safety and preliminary efficacy of PAP CAR-T cells for the treatment of desmoplasia-resistant prostate cancer

<h3>Background </h3> Castration-resistant prostate cancer (CRPC) represents a challenge in the treatment of prostate cancer with relatively limited treatment options. Prostate-specific acid phosphatase (PAP) is a secreted glycoprotein with a molecular weight of 100 kDa that is primarily synthesized in the lysosomes of prostate epithelial cells. Its expression level positively correlates with prostate cancer progression and is closely associated with disease staging. PAP CAR-T cells were generated using lentiviral vectors encoding an anti-prostatic acid phosphatase (PAP) CAR molecule. Immunohistochemistry (IHC) results showed PAP expression in approximately 97.3% of prostate cancer patients, making it an ideal tumor-specific target antigen. After characterizing the antitumor activity and cytotoxicity of PAP CAR-T cells by pharmacokinetics and pharmacodynamics, we conducted a Phase I clinical trial at Shanghai Tenth People’s Hospital affiliated with Tongji University to evaluate the safety and efficacy of PAP CAR-T cells in patients with advanced metastatic prostate cancer. Three patients received a single infusion of CAR-T cells after lymphodepletion, with the longest survival time reaching 26 months. <h3>Methods</h3> This is an open-label, single-arm, single-center Phase I clinical trial enrolling patients with CRPC. Patients underwent leukapheresis half a month prior to infusion, followed by lymphodepletion with cyclophosphamide 300mg/m² + fludarabine 30mg/m². Subsequently, PAP CAR-T cells were administered by intravenous injection at a dose range of 1.85*10^5 - 2.10*10^5 PAP CAR-T cells/kg. Safety and efficacy were evaluated in patients who received one dose of CAR-T therapy. <h3>Results</h3> A total of three patients were evaluated and enrolled between November 2021 and March 2022. All three patients developed fever. Two patients developed cytokine release syndrome (CRS). We observed that patients with significant side effects had better treatment outcomes. According to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines, all three patients were considered PSA responsive with biochemical PSA response rates of 82.70%, 48.22% and 85.50% for P1, P2 and P3, respectively. The overall objective response rate (ORR) was 100%. Details are shown in table 1. <h3>Conclusions</h3> This Phase I clinical trial, which included three patients with advanced CRPC, demonstrated that PAP CAR-T cells are safe, feasible and effective in the treatment of CRPC patients. The potential impact of PAP CAR-T cell therapy on the long-term survival of CRPC patients will continue to be monitored. <h3>Trial Registration</h3> Clinical trial information: ChiCTR2200055854.