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- Title
B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma.
- 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; Fang Chen; Davis, Megan M.; Wei-Ting Hwang; Young, Regina M.; Brogdon, Jennifer L.; Isaacs, Randi; Pruteanu-Malinici, Iulian; Siegel, Don L.; Levine, Bruce L.
- Abstract
<bold>Background: </bold>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).<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients.<bold>Trial Registration: </bold>NCT02546167.<bold>Funding: </bold>University of Pennsylvania-Novartis Alliance and NIH.
- Subjects
T cells; B cells; MULTIPLE myeloma; CANDIDEMIA; MANUFACTURING cells; HEMATOLOGIC malignancies; MULTIPLE myeloma treatment; PROTEINS; RESEARCH; IMMUNIZATION; GENETICS; CLINICAL trials; RESEARCH methodology; IMMUNOSUPPRESSION; PROGNOSIS; CELL receptors; EVALUATION research; MEDICAL cooperation; AUTOGRAFTS; COMPARATIVE studies; CYCLOPHOSPHAMIDE; RESEARCH funding
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 6, p2210
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI126397