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 5

Soluble BCMA (sBCMA), BAFF, and APRIL concentration, and BCMA expression on MM cells before and after CART-BCMA infusions.

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Soluble BCMA (sBCMA), BAFF, and APRIL concentration, and BCMA expression...
(A) Baseline peripheral blood serum concentration of sBCMA and APRIL for subjects (sub) were significantly increased and decreased, respectively, compared with a panel of healthy donors (HD, n = 6) (P = 0.017, and P < 0.001, respectively, Mann-Whitney). Baseline BAFF concentrations were not significantly different. Median concentrations are depicted by red lines. (B) Serial sBCMA concentrations decline after CART-BCMA infusions more significantly in hematologic responders (PR/VGPR/CR/sCR) than in nonresponders (MR/SD/PD) before day 28 (P < 0.001). After day 28 the slopes of the curves are not significantly different between groups (P = 0.429). The estimation was based on a linear random intercept mixed effects model on log10-transform sBCMA that included 2 piecewise linear splines connected at day 28; P values were determined based on z test for the regression coefficient of interest or a linear combination of the coefficients. Mean concentration (ng/ml) + SEM are depicted. (C) Representative examples of BCMA expression on MM cells by flow cytometry. See Supplemental Figure 9 for gating strategy. FMO, fluorescence minus one. (D) BCMA mean fluorescence intensity (MFI) on MM cells over time in 18 subjects with evaluable serial bone marrow aspirates. Median MFI was significantly different between pretreatment (pre-tx) and day 28 (D28) for responders (4000 vs. 944, P = 0.02, paired t test) but not for nonresponders (2704 vs. 2140, P = 0.19). Median MFI was not significantly different between pre-tx and day 90 (D90) for responders (4000 vs. 2022, P = 0.26). *Subject 15 had no detectable MM cells at D28. #Subject 03 had no detectable MM cells at D45 (D28 not done) and too few MM cells to characterize at D90. D164 marrow is depicted at D90 time point.