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J Clin Oncol. 2018 Aug 1;36(22):2267-2280. doi: 10.1200/JCO.2018.77.8084. Epub 2018 May 29.

T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma.

Author information

1
Jennifer N. Brudno, Irina Maric, Steven D. Hartman, Jeremy J. Rose, Norris Lam, Maryalice Stetler-Stevenson, Dalia Salem, Constance Yuan, Steven Pavletic, Jennifer A. Kanakry, Lekha Mikkilineni, Steven A. Feldman, David F. Stroncek, Brenna G. Hansen, Rashmika Patel, Frances Hakim, Ronald E. Gress, and James N. Kochenderfer, National Institutes of Health, Bethesda; Syed Abbas Ali, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore; Judith Lawrence, Leidos Biomedical Research, Frederick, MD; Michael Wang, University of Texas MD Anderson Cancer Center, Houston, TX; and Dalia Salem, Mansoura University, Mansoura, Egypt.

Abstract

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease-negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

PMID:
29812997
PMCID:
PMC6067798
[Available on 2019-08-01]
DOI:
10.1200/JCO.2018.77.8084

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