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 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 4

Serum cytokines associated with CRS severity and neurotoxicity.

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Serum cytokines associated with CRS severity and neurotoxicity. Serum cy...
Serum cytokine concentrations (in pg/ml) through day 28 were measured by Luminex assay. (A–D) The median peak fold-increase over baseline for each cytokine was compared between subjects with no CRS, grade 1 CRS, or grade 2 CRS not receiving tocilizumab (CRS grade 0–2) and those with grade 3–4 CRS or grade 2 CRS receiving tocilizumab (CRS grade 3–4 or grade 2 + toci). The cytokines most significantly associated with CRS severity were (A) IFN-γ, (B) IL-2Rα, (C) MIP-1α, and (D) IL-15. (E–G) Median peak fold-increase over baseline for each cytokine was compared between subjects with no neurotoxicity (No Ntx) and those with any grade of neurotoxicity (Any Ntx). The cytokines most significantly associated with neurotoxicity were (E) IFN-γ, (F) IL-1RA, and (G) MIP-1α. (H–I) Peak fold-increase in IL-6 was less significantly associated with severe CRS (H) or neurotoxicity (I) when only pretocilizumab/siltuximab values were included. Stars depict subjects with grade 3–4 neurotoxicity. Exact P value by Mann-Whitney test is shown. Because the statistical analyses performed here are exploratory and hypothesis-generating in nature, no adjustment of the P values was made for multiple comparisons. Horizontal lines depict medians. IFN-γ, interferon gamma; IL-1RA, interleukin 1 receptor antagonist; IL-2Rα, interleukin 2 receptor alpha; IL-6, interleukin 6; IL-15, interleukin 15; MIP-1α, macrophage inflammatory protein 1 alpha.