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B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.

ABSTRACT: PURPOSE: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. EXPERIMENTAL DESIGN: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.

SUBMITTER: Carpenter RO

PROVIDER: S-EPMC3630268 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.

Carpenter Robert O RO Evbuomwan Moses O MO Pittaluga Stefania S Rose Jeremy J JJ Raffeld Mark M Yang Shicheng S Gress Ronald E RE Hakim Frances T FT Kochenderfer James N JN

Clinical cancer research : an official journal of the American Association for Cancer Research 20130123 8

<h4>Purpose</h4>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 inclu ...[more]

PMID: 23344265

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Project description:Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA-CARTx) is an emerging treatment for relapsed or refractory multiple myeloma (R/R MM). Here we characterize the epidemiology of infections, risk factors for infection, and pathogen-specific humoral immunity in patients receiving BCMA-CARTx for R/R MM. We performed a retrospective cohort study in 32 adults with R/R MM enrolled in 2 single-institution phase 1 clinical trials of BCMA-CARTx administered after lymphodepleting chemotherapy alone (n = 22) or with a gamma secretase inhibitor (GSI). We tested serum before and up to approximately 180 days after BCMA-CARTx for measles-specific IgG and for any viral-specific IgG using a systematic viral epitope scanning assay to describe the kinetics of total and pathogen-specific IgG levels pre- and post-BCMA-CARTx. We identified microbiologically documented infections to determine infection incidence and used Poisson regression to explore risk factors for infections within 180 days after BCMA-CARTx. Most individuals developed severe neutropenia, lymphopenia, and hypogammaglobulinemia after BCMA-CARTx. Grade ≥3 cytokine release syndrome (CRS; Lee criteria) occurred in 16% of the participants; 50% of the participants received corticosteroids and/or tocilizumab. Before BCMA-CARTx, 28 of 32 participants (88%) had an IgG <400 mg/dL, and only 5 of 27 (19%) had seropositive measles antibody titers. After BCMA-CARTx, all participants had an IgG <400 mg/dL and declining measles antibody titers; of the 5 individuals with baseline seropositive levels, 2 remained above the seroprotective threshold post-treatment. Participants with IgG MM (n = 13) had significantly fewer antibodies to a panel of viral antigens compared with participants with non-IgG MM (n = 6), both before and after BCMA-CARTx. In the first 180 days after BCMA-CARTx, 17 participants (53%) developed a total of 23 infections, of which 13 (57%) were mild-to-moderate viral infections. Serious infections were more frequent in the first 28 days post-treatment. Infections appeared to be more common in individuals with higher-grade CRS. Individuals with R/R MM have substantial deficits in humoral immunity. These data demonstrate the importance of plasma cells in maintaining long-lived pathogen-specific antibodies and suggest that BCMA-CARTx recipients need ongoing surveillance for late-onset infections. Most infections were mild-moderate severity viral infections. The incidence of early infection appears to be lower than has been reported after CD19-directed CARTx for B cell neoplasms, possibly due to differences in patient and disease characteristics and regimen-related toxicities.

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B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.

Publications

B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.

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