title: T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma.
abstract: Therapies with novel mechanisms of action are needed for multiple myeloma (MM). B-cell maturation antigen (BCMA) is expressed in most cases of MM. We conducted the first-in-humans clinical trial of chimeric antigen receptor (CAR) T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. Twelve patients received CAR-BCMA T cells in this dose-escalation trial. Among the 6 patients treated on the lowest 2 dose levels, limited antimyeloma activity and mild toxicity occurred. On the third dose level, 1 patient obtained a very good partial remission. Two patients were treated on the fourth dose level of 9 × 10(6) CAR(+) T cells/kg body weight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM, making up 90% of bone marrow cells. After treatment, bone marrow plasma cells became undetectable by flow cytometry, and the patient's MM entered a stringent complete remission that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T cells, bone marrow plasma cells were undetectable by flow cytometry, and the serum monoclonal protein had decreased by >95%. This patient is in an ongoing very good partial remission. Both patients treated on the fourth dose level had toxicity consistent with cytokine-release syndrome including fever, hypotension, and dyspnea. Both patients had prolonged cytopenias. Our findings demonstrate antimyeloma activity of CAR-BCMA T cells. This trial was registered to www.clinicaltrials.gov as #NCT02215967.
authors.affiliation: Center for Cancer Research, and.
authors.forename: Syed Abbas
authors.initials: SA
authors.lastname: Ali
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;
authors.forename: Victoria
authors.initials: V
authors.lastname: Shi
authors.affiliation: Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD;
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD;
authors.forename: David F
authors.initials: DF
authors.lastname: Stroncek
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Rose
authors.affiliation: Center for Cancer Research, and.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Brudno
authors.affiliation: Laboratory of Pathology, and.
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, MD.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;
authors.forename: Brenna G
authors.initials: BG
authors.lastname: Hansen
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;
authors.forename: Vicki S
authors.initials: VS
authors.lastname: Fellowes
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;
authors.forename: Frances T
authors.initials: FT
authors.lastname: Hakim
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD;
authors.forename: James N
authors.initials: JN
authors.lastname: Kochenderfer
mesh_terms: D053301:B-Cell Maturation Antigen / Q000097:blood / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000097:blood; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D007970:Leukopenia / Q000209:etiology; D009101:Multiple Myeloma / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D009194:Myeloma Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000276:immunology; D012074:Remission Induction; D013601:T-Lymphocytes / Q000276:immunology*; D013921:Thrombocytopenia / Q000209:etiology; D047368:Tumor Burden / Q000276:immunology
chemical_list: D053301:B-Cell Maturation Antigen; D016207:Cytokines; D009194:Myeloma Proteins; D011993:Recombinant Fusion Proteins; C086966:TNFRSF17 protein, human