PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CART cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805.

Tanya B. Dorff, M. Suzette Blanchard, Lauren N. Adkins, Laura Luebbert, Neena Leggett, Stephanie N. Shishido, Alan Macias, Marissa M. Del Real, Gaurav Dhapola, Colt Egelston, John P. Murad, Reginaldo Rosa, Jinny Paul, Ammar Chaudhry, Hripsime Martirosyan, Ethan Gerdts, Jamie R. Wagner, Tracey Stiller, Dileshni Tilakawardane, Sumanta Pal, Catalina Martinez, Robert E. Reiter, Lihua E. Budde, Massimo D'Apuzzo, Peter Kuhn, Lior Pachter, Stephen J. Forman, Saul J. Priceman