Background: CART-PSMA-02 is a multi-center, open-label, phase 1 trial evaluating the safety and feasibility of CART-PSMA-TGFβRDN T-cells (PSMA-CART) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). PSMA-CART are engineered to express a chimeric antigen receptor with specificity to PSMA and a dominant negative form of TGFβRII which renders PSMA-CART resistant to TGFβ-mediated immunosuppression. Herein, preliminary safety and efficacy results from this trial are reported. Methods: This is a 3+3 dose escalation study to determine the recommended phase 2 dose and schedule of PSMA-CART cells following lymphodepleting chemotherapy (LD) with cyclophosphamide and fludarabine. Results: As of October 2021, 9 pts were dosed. Two pts received 1-3x10⁷ cells, 4 pts received 1-3x10⁸ cells, and 3 pts received 0.7-1x10⁸ cells with anakinra prophylaxis. Grade 1-2 CRS was observed in all pts receiving 1-3x10⁸ cells and 2/3 pts who received anakinra prophylaxis. No pts developed CRS > G2. Two events of immune-effector cell associated neurotoxicity syndrome (ICANS) were observed (1 G2, 1 G5). Two pts experienced DLTs at dose level of 1-3x10⁸, one of whom developed G5 events of ICANS and multi-organ failure (MOF) after receiving 30% of his fractionated dose (total dose = 0.9x10⁸). This pt’s clinical course and autopsy findings were consistent with macrophage activation syndrome. The trial continued with a modified dose of 0.7-1x10⁸ and the incorporation of prophylactic anakinra (100mg SC daily x7 doses). Another G5 event was observed, likely related to immune toxicity, with ferritin levels peaking at >100,000 ng/mL prior to death. Cause of death on autopsy was equivocal and contributing factors included metastatic prostate cancer, MOF and coagulopathy. Cytokine levels from both pts experiencing G5 events were elevated compared to all other pts (e.g., IL-6, sIL2RA, MIG/CXCL9, MIP1b/CCL4, IP-10/CXCL19, IL2 and IL1b). In pts receiving ≥ 0.9x10⁸ cells (n=7), preliminary efficacy results demonstrated stable disease by RECIST v1.1 at day 28 (D28) in 4/5 evaluable pts. Decreases in serum PSA occurred in 4/7 pts with >50% decreases observed in 2/5 evaluable pts at D28. Conclusions: PSMA-CART has shown preliminary evidence of biological activity in the absence of clear indications of on-target/off-tumor toxicity. The exact mechanisms driving the severe immune-mediated toxicities in this study are currently unclear. While this study has been closed to further enrollment, ongoing research efforts are aimed at exploring patient specific factors, tumor microenvironment factors, and the PSMA-CART construct (including both functional components and armored modules) to design future constructs of PSMA-CART that will enhance the efficacy/safety profile and allow for continued study of this novel therapy in the clinic. Clinical trial information: NCT04227275.