B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.
OBJECTIVE
Multiple myeloma is a usually incurable malignancy of plasma cells. New therapies are urgently needed for multiple myeloma. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies, but an ideal target antigen for CAR-expressing T-cell therapies for multiple myeloma has not been identified. B-cell maturation antigen (BCMA) is a protein that has been reported to be selectively expressed by B-lineage cells including multiple myeloma cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells.


METHODS
We conducted an assessment of BCMA expression in normal human tissues and multiple myeloma cells by flow cytometry, quantitative PCR, and immunohistochemistry. We designed and tested novel anti-BCMA CARs.


RESULTS
BCMA had a restricted RNA expression pattern. Except for expression in plasma cells, BCMA protein was not detected in normal human tissues. BCMA was not detected on primary human CD34(+) hematopoietic cells. We detected uniform BCMA cell-surface expression on primary multiple myeloma cells from five of five patients. We designed the first anti-BCMA CARs to be reported and we transduced T cells with lentiviral vectors encoding these CARs. The CARs gave T cells the ability to specifically recognize BCMA. The anti-BCMA-CAR-transduced T cells exhibited BCMA-specific functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. Importantly, anti-BCMA-CAR-transduced T cells recognized and killed primary multiple myeloma cells.


CONCLUSIONS
BCMA is a suitable target for CAR-expressing T cells, and adoptive transfer of anti-BCMA-CAR-expressing T cells is a promising new strategy for treating multiple myeloma.
Experimental Transplantation and Immunology Branch; Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892, USA.
Robert O
RO
Carpenter
Moses O
MO
Evbuomwan
Stefania
S
Pittaluga
Jeremy J
JJ
Rose
Mark
M
Raffeld
Shicheng
S
Yang
Ronald E
RE
Gress
Frances T
FT
Hakim
James N
JN
Kochenderfer
D000818:Animals; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D020014:K562 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D053301:B-Cell Maturation Antigen; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D011948:Receptors, Antigen, T-Cell