B cell maturation antigen–specific CAR T cells are clinically active in multiple myeloma

• Published in: The Journal of clinical investigation Vol. 129; no. 6; pp. 2210 - 2221
• Main Authors: Cohen, Adam D., Garfall, Alfred L., Stadtmauer, Edward A., Melenhorst, J. Joseph, Lacey, Simon F., Lancaster, Eric, Vogl, Dan T., Weiss, Brendan M., Dengel, Karen, Nelson, Annemarie, Plesa, Gabriela, Chen, Fang, Davis, Megan M., Hwang, Wei-Ting, Young, Regina M., Brogdon, Jennifer L., Isaacs, Randi, Pruteanu-Malinici, Iulian, Siegel, Don L., Levine, Bruce L., June, Carl H., Milone, Michael C.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2019
• Subjects: Adult; Aged; Antigens; Autografts; B-Cell Maturation Antigen - immunology; Chemotherapy; Clinical Medicine; Cyclophosphamide; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Disease-Free Survival; Encephalopathy; Female; Humans; Immunotherapy, Adoptive; Lymphocyte Depletion; Male; Middle Aged; Multiple Myeloma - genetics; Multiple Myeloma - immunology; Multiple Myeloma - mortality; Multiple Myeloma - therapy; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Pharmaceutical industry; Receptors, Chimeric Antigen - genetics; Receptors, Chimeric Antigen - immunology; Survival Rate; T cells; T-Lymphocytes - immunology; T-Lymphocytes - pathology; T-Lymphocytes - transplantation; Toxicity; Transduction, Genetic; Switzerland; Cancer immunotherapy; Oncology; Clinical Trials
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI126397

Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required. CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product. CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients. NCT02546167. University of Pennsylvania-Novartis Alliance and NIH.