177Lu-PSMA-617 + PSCA CAR-T cell therapy

177Lu-PSMA-617 + PSCA CAR-T cell therapy is an investigational combination regimen for metastatic castration-resistant prostate cancer (mCRPC) that pairs lutetium-177 vipivotide tetraxetan, a β-emitting small-molecule radioligand targeting prostate-specific membrane antigen (PSMA), with autologous T cells engineered to express a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA). 177Lu-PSMA-617 delivers targeted radiation to PSMA-expressing tumor cells and their microenvironment, improving overall survival and radiographic progression-free survival in mCRPC in phase 3 trials and is approved as Pluvicto for PSMA-positive mCRPC.[3][5][11] PSCA CAR-T cell therapy, developed and clinically tested at City of Hope, uses second-generation 4-1BB–costimulated CAR T cells targeting PSCA, a surface antigen highly expressed in advanced prostate cancer, and has shown early safety and bioactivity in a first-in-human phase 1 study in men with mCRPC, with PSA declines, radiographic improvements, and manageable cytokine release syndrome but on-target cystitis as a dose-limiting toxicity.[4][6] The rationale for combining these modalities is to integrate radiopharmaceutical tumor debulking and modulation of the tumor microenvironment with targeted cellular immunotherapy to enhance depth and durability of response in heavily pretreated PSMA/PSCA-expressing prostate cancer.