학술논문
PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.
Document Type
Academic Journal
Author
Dorff TB; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA. tdorff@coh.org.; Blanchard MS; Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.; Adkins LN; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Luebbert L; Departments of Mathematics and Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.; Leggett N; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Shishido SN; Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer, University of Southern California, Los Angeles, CA, USA.; Macias A; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Del Real MM; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Dhapola G; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Egelston C; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA.; Murad JP; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Rosa R; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Paul J; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Chaudhry A; Department of Radiology, City of Hope, Duarte, CA, USA.; Martirosyan H; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.; Gerdts E; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Wagner JR; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Stiller T; Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.; Tilakawardane D; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Pal S; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.; Martinez C; Department of Clinical and Translational Project Development, City of Hope, Duarte, CA, USA.; Reiter RE; Department of Urology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.; Budde LE; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; D'Apuzzo M; Department of Pathology, City of Hope, Duarte, CA, USA.; Kuhn P; Michelson Center for Convergent Bioscience, Convergent Science Institute in Cancer, University of Southern California, Los Angeles, CA, USA.; Pachter L; Departments of Mathematics and Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.; Forman SJ; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA.; Priceman SJ; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. spriceman@coh.org.; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, USA. spriceman@coh.org.
Source
Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
Subject
Language
English
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 .
(© 2024. The Author(s).)
(© 2024. The Author(s).)