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 6

Predictors of in vivo CART-BCMA expansion and response.

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Predictors of in vivo CART-BCMA expansion and response. (A) Peak blood C...
(A) Peak blood CART-BCMA expansion, as measured by qPCR, as well as (B) total CART-BCMA expansion over first 28 days (calculated as AUC), were both associated with clinical response. Greater peak CART-BCMA expansion (C) and response (D) were also associated with more severe CRS, defined as grade 3–4 or grade 2 requiring tocilizumab. A higher ratio of CD4+ to CD8+ T cells (CD4/CD8 ratio) within the leukopheresis product, as determined by flow cytometry, also correlated with both peak expansion (E) and response (F), while in vitro proliferation, measured as fold-increase of seeded cells during manufacturing, correlated only with peak expansion (G), but not response (P = 0.54, Mann-Whitney test, data not shown). (H–I) A higher proportion of CD8+ T cells within the leukapheresis product with a CD45RO–CD27+ phenotype was significantly associated with peak CART-BCMA expansion (H) and to a lesser degree, response (I). For A, B, C, F, and I, analysis was performed using Mann-Whitney test; lines represent median values. For D, analysis was by Fisher’s exact test. For E, G, and H, analysis was done using Spearman correlation.