Article
Author: Tilakawardane, Dileshni ; Dorff, Tanya B ; Reiter, Robert E ; Luebbert, Laura ; Gerdts, Ethan ; Pachter, Lior ; Del Real, Marissa M ; D'Apuzzo, Massimo ; Chaudhry, Ammar ; Martinez, Catalina ; Leggett, Neena ; Forman, Stephen J ; Budde, Lihua E ; Rosa, Reginaldo ; Priceman, Saul J ; Paul, Jinny ; Dhapola, Gaurav ; Stiller, Tracey ; Macias, Alan ; Martirosyan, Hripsime ; Wagner, Jamie R ; Murad, John P ; Adkins, Lauren N ; Blanchard, M Suzette ; Pal, Sumanta ; Kuhn, Peter ; Egelston, Colt ; Shishido, Stephanie N
Abstract: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 CAR T 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.