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Abstract
BACKGROUND. Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS. Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS). RESULTS. ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently. CONCLUSION. CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells. TRIAL REGISTRATION. Clinicaltrials.gov identifier NCT02135406. FUNDING. Novartis, NIH, Conquer Cancer Foundation.
Authors
Alfred L. Garfall, Edward A. Stadtmauer, Wei-Ting Hwang, Simon F. Lacey, Jan Joseph Melenhorst, Maria Krevvata, Martin P. Carroll, William H. Matsui, Qiuju Wang, Madhav V. Dhodapkar, Kavita Dhodapkar, Rituparna Das, Dan T. Vogl, Brendan M. Weiss, Adam D. Cohen, Patricia A. Mangan, Emily C. Ayers, Selene Nunez-Cruz, Irina Kulikovskaya, Megan M. Davis, Anne Lamontagne, Karen Dengel, Naseem D.S. Kerr, Regina M. Young, Donald L. Siegel, Bruce L. Levine, Michael C. Milone, Marcela V. Maus, Carl H. June
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