• 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, and Michael C Milone.
• Abramson Cancer Center.
• J. Clin. Invest. 2019 Mar 21; 129 (6): 2210-2221.

BackgroundChimeric 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).MethodsWe 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.ResultsCART-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.ConclusionCART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients.Trial RegistrationNCT02546167.FundingUniversity of Pennsylvania-Novartis Alliance and NIH.

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