The clinical significance of B-cell maturation antigen as a therapeutic target and biomarker

Sanchez, Eric; Tanenbaum, Edward J; Patil, Saurabh; Li, Mingjie; Soof, Camilia; Vidisheva, Aleksandra; Waterman, Gabriel N.; Hekmati, Tara; Tang, George; Wang, Cathy S.; Chen, Haiming; Berenson, James R.

doi:10.1080/14737159.2018.1448269

Cited by 22 publications

(14 citation statements)

References 43 publications

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“…sBCMA may also serve as a valuable biomarker in select patient populations that are otherwise difficult to monitor. The levels of sBCMA are independent of renal function, which permits its use as a biomarker in patients with renal insufficiency, and sBCMA is detectable in the serum of patients with nonsecretory disease as well as in nonsecretory murine xenograft models [7,21,29].…”

Section: Resultsmentioning

confidence: 99%

“…BCMA is also expressed at much lower concentrations (9-to 50-fold lower) by plasmacytoid dendritic cells, which are known to help promote MM PC survival in the bone marrow environment [13,17]. Additional details regarding the role of BCMA in B-cell biology and in MM, including illustrations, can be found in other reviews [18][19][20][21].…”

Section: Biology Of Bcma In MMmentioning

confidence: 99%

“…It has been demonstrated that sBCMA can bind to and interfere with anti-BCMA antibodies [38]. In this case, drugs that inhibit γsecretase could enhance the efficacy of BCMA-targeted therapy by reducing shedding of BCMA from the cell surface and subsequent interference of BCMA-targeted therapies by sBCMA [20,21,38]. An additional approach could be to use anti-BCMA monoclonal antibodies (mAbs) with higher specificity for membrane-bound BCMA than sBCMA [39].…”

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

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B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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Section: Resultsmentioning

confidence: 99%

Section: Biology Of Bcma In MMmentioning

confidence: 99%

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

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B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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“…At present BCMA is being targeted by several immunotherapeutic strategies including antibodies (naked antibodies, antibodies-drug conjugates, and bispecific antibodies) and cellular therapies (chimeric antigen receptor T-cells), with promising clinical results even in relapsed refractory MM. 27–31 In addition, serum soluble BCMA is elevated among patients with MM and chronic lymphocytic leukemia and can served as a prognostic marker and monitor of clinical response. Finally, most recent studies indicate that BCMA is expressed in non-hematopoietic tissue: BCMA is abnormally expressed in non-small cell lung cancer cell lines and may play a role in the tumors through the ERK1/2 signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Selective targeting of multiple myeloma by B cell maturation antigen (BCMA)-specific central memory CD8+ cytotoxic T lymphocytes: immunotherapeutic application in vaccination and adoptive immunotherapy

et al. 2019

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To expand the breadth and extent of current multiple myeloma (MM)-specific immunotherapy, we have identified various antigens on CD138+ tumor cells from newly diagnosed MM patients (n=616) and confirmed B-cell Maturation Antigen (BCMA) as a key myeloma-associated antigen. The aim of this study is to target the BCMA, which promotes MM cell growth and survival, by generating BCMA-specific memory CD8+ CTL that mediate effective and long-lasting immunity against MM. Here we report the identification of novel engineered peptides specific to BCMA, BCMA72–80 (YLMFLLRKI) and BCMA54–62 (YILWTCLGL), which display improved affinity/stability to HLA-A2 compared to their native peptides and induce highly functional BCMA-specific CTL with increased activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecule expression. Importantly, the heteroclitic BCMA72–80 specific CTL demonstrated poly-functional Th1-specific immune activities [IFN-γ/IL-2/TNF-α production, proliferation, cytotoxicity] against MM, which were correlated with expansion of Tetramer+ and memory CD8+ CTL. Additionally, heteroclitic BCMA72–80 specific CTL treated with anti-OX40 (immune agonist) or anti-LAG-3 (checkpoint inhibitor) display increased immune function, mainly by central memory CTL. These results provide the framework for clinical application of heteroclitic BCMA72–80 peptide, alone and in combination with anti-LAG3 and/or anti-OX40 therapy, in vaccination and/or adoptive immunotherapeutic strategies to generate long-lasting anti-tumor immunity in patients with MM or other BCMA expressing tumors.

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“…The expression of BCMA is restricted to the B-cell compartment, being expressed in clonal and polyclonal plasma cells, as well as in a small subset of normal memory B cells. BCMA is overexpressed in MM preclinical models and patients and has been reported to play a role in myeloma cell growth, chemoresistance, and microenvironment immunosuppression [8,9].…”

Section: Overexpressed In Multiple Myeloma Cellsmentioning

confidence: 99%

CAR T-Cells in Multiple Myeloma Are Ready for Prime Time

Rodríguez‐Otero

Prósper

Alfonso

et al. 2020

JCM

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The survival of patients with multiple myeloma (MM) has been dramatically improved in the last decade thanks to the incorporation of second-generation proteasome inhibitors (PI), immunomodulatory drugs (IMID), and, more recently, anti-CD38 monoclonal antibodies (MoAb). Nevertheless, still, a major proportion of MM patients will relapse, underscoring the need for new therapies in this disease. Moreover, survival in patients failing the current standard of care regimens (including PI, IMIDs, and anti-CD38 MoAb), which is now defined as triple-class refractory, remains dismal, and new drugs with different mechanism of action are needed. B-cell maturation antigen (BCMA)-targeted therapies and in particular chimeric antigen receptor T cell (CAR T-cell) treatment have emerged as promising platforms to overcome refractoriness to conventional drugs. In this manuscript, we review the current available data regarding CAR T-cell therapy for MM, with a special focus on target selection, clinical results, limitations, and future strategies.

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The clinical significance of B-cell maturation antigen as a therapeutic target and biomarker

Cited by 22 publications

References 43 publications

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

Selective targeting of multiple myeloma by B cell maturation antigen (BCMA)-specific central memory CD8+ cytotoxic T lymphocytes: immunotherapeutic application in vaccination and adoptive immunotherapy

CAR T-Cells in Multiple Myeloma Are Ready for Prime Time

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