Dataset Information

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

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 .

SUBMITTER: Dorff TB

PROVIDER: S-EPMC11186768 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Dorff Tanya B TB Blanchard M Suzette MS Adkins Lauren N LN Luebbert Laura L Leggett Neena N Shishido Stephanie N SN Macias Alan A Del Real Marissa M MM Dhapola Gaurav G Egelston Colt C Murad John P JP Rosa Reginaldo R Paul Jinny J Chaudhry Ammar A Martirosyan Hripsime H Gerdts Ethan E Wagner Jamie R JR Stiller Tracey T Tilakawardane Dileshni D Pal Sumanta S Martinez Catalina C Reiter Robert E RE Budde Lihua E LE D'Apuzzo Massimo M Kuhn Peter P Pachter Lior L Forman Stephen J SJ Priceman Saul J SJ

Nature medicine 20240612 6

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 po ...[more]

PMID: 38867077

Similar Datasets

Project description:Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, 'on-target, off-tumor' immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets