B cell maturation antigen–specific CAR T cells are clinically active in multiple myeloma
Adam D. Cohen, … , Carl H. June, Michael C. Milone
Adam D. Cohen, … , Carl H. June, Michael C. Milone
Published June 3, 2019; First published March 21, 2019
Citation Information: J Clin Invest. 2019;129(6):2210-2221. https://doi.org/10.1172/JCI126397.
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Clinical Medicine Clinical trials Oncology

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

Abstract

BACKGROUND. CAR T cells are a promising therapy for hematologic malignancies. B cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS. 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 as follows: cohort 1, 1 × 108 to 5 × 108 CART-BCMA cells alone; cohort 2, cyclophosphamide (Cy) 1.5 g/m2 plus 1 × 107 to 5 × 107 CART-BCMA cells; cohort 3, Cy 1.5 g/m2 plus 1 × 108 to 5 × 108 CART-BCMA cells. No prespecified BCMA expression level was required. RESULTS. 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 cytokine release syndrome and encephalopathy. Responses (based on treated subjects) were seen in 4 of 9 (44%) in cohort 1, 1 of 5 (20%) in cohort 2, and 7 of 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 premanufacturing leukapheresis product. CONCLUSION. CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily pretreated patients with MM. TRIAL REGISTRATION. NCT02546167. FUNDING. University of Pennsylvania-Novartis Alliance and NIH.

Authors

Adam D. Cohen, Alfred L. Garfall, Edward A. Stadtmauer, J. Joseph Melenhorst, Simon F. Lacey, Eric Lancaster, Dan T. Vogl, Brendan M. Weiss, Karen Dengel, Annemarie Nelson, Gabriela Plesa, Fang Chen, Megan M. Davis, Wei-Ting Hwang, Regina M. Young, Jennifer L. Brogdon, Randi Isaacs, Iulian Pruteanu-Malinici, Don L. Siegel, Bruce L. Levine, Carl H. June, Michael C. Milone

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Figure 2

Clinical outcomes.

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Clinical outcomes. (A) Swimmer’s plot showing best response and progress...
(A) Swimmer’s plot showing best response and progression-free survival (PFS) for each subject in cohort 1 (1 × 108 to 5 × 108 CART-BCMA cells alone), cohort 2 (Cy plus 1 × 107 to 5 × 107 CART-BCMA cells), and cohort 3 (Cy plus 1 × 108 to 5 × 108 CART-BCMA cells). Arrow indicates ongoing response. Blue bars represent PR or better; red bars, MR; black bars, no response (SD or PD). *Minimal residual disease (MRD), negative by flow cytometry (estimated sensitivity 1 in 10–5 cells). **Has negative serum and urine immunofixation and negative bone marrow biopsy but residual retroperitoneal lymph nodes (LN), known to contain myeloma by prior biopsy, that decreased in size by more than 50% and became FDG-negative on PET/CT but did not disappear. Repeat LN biopsy not performed. (B) PET/CT scan images for subject 03 showing resolution of extramedullary disease (arrows) and malignant pleural effusion after treatment. (C) Overall survival (OS) based on cohort, Kaplan-Meier plot. CR, complete response; MR, minimal response; PR, partial response; VGPR, very good partial response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.