Immunotherapeutic strategies targeting B cell maturation antigen in multiple myeloma

AbstractMultiple myeloma (MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel therapeutic agents and stem cell transplantation, all patients eventually relapse due to clone evolution. B cell maturation antigen (BCMA) is highly expressed in and specific for MM cells, and has been implicated in the pathogenesis as well as treatment development for MM. In this review, we will summarize representative anti-BCMA immune therapeutic strategies, including BCMA-targeted vaccines, anti-BCMA antibodies and BCMA-targeted CAR cells. Combination of different immunotherapeutic strategies of targeting BCMA, multi-target immune therapeutic strategies, and adding immune modulatory agents to normalize anti-MM immune system in minimal residual disease (MRD) negative patients, will also be discussed.

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

Journal of Clinical Oncology ◽

10.1200/jco.2018.77.8084 ◽

2018 ◽

Vol 36 (22) ◽

pp. 2267-2280 ◽

Cited By ~ 212

Author(s):

Jennifer N. Brudno ◽

Irina Maric ◽

Steven D. Hartman ◽

Jeremy J. Rose ◽

Michael Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cells ◽

Partial Response ◽

B Cell ◽

Residual Disease ◽

Cell Maturation ◽

B Cell Maturation ◽

Minimal Residual ◽

B Cell Maturation Antigen

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.

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B-Cell Maturation Antigen (BCMA) As a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

10.20944/preprints202007.0016.v1 ◽

2020 ◽

Author(s):

Hanley N. Abramson

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

T Cell ◽

B Cell ◽

Plasma Cells ◽

Cell Types ◽

Cell Maturation ◽

New Drug ◽

B Cell Maturation ◽

B Cell Maturation Antigen

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

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Belantamab mafodotin in the treatment of relapsed or refractory multiple myeloma

Future Oncology ◽

10.2217/fon-2020-0521 ◽

2020 ◽

Vol 16 (34) ◽

pp. 2783-2798 ◽

Cited By ~ 2

Author(s):

Semira Sheikh ◽

Eyal Lebel ◽

Suzanne Trudel

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Plasma Cells ◽

Safety Data ◽

Unmet Need ◽

Cell Maturation ◽

Antibody Drug Conjugate ◽

Refractory Multiple Myeloma ◽

B Cell Maturation ◽

B Cell Maturation Antigen

Multiple myeloma remains an incurable disease, with a large proportion of patients in the relapsed/refractory setting often unable to achieve durable responses. Novel, well-tolerated and highly effective therapies in this patient population represent an unmet need. Preclinical studies have shown that B-cell maturation antigen is nearly exclusively expressed on normal and malignant plasma cells, thereby identifying it as a highly selective target for immunotherapeutic approaches. Belantamab mafodotin (GSK2857916, belamaf) is a first-in-class antibody–drug conjugate directed at B-cell maturation antigen and has shown promising activity in clinical trials. In this review, we provide an overview of belantamab mafodotin as a compound and present the available clinical efficacy and safety data in the treatment of relapsed/refractory multiple myeloma.

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B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

International Journal of Molecular Sciences ◽

10.3390/ijms21155192 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5192 ◽

Cited By ~ 4

Author(s):

Hanley N. Abramson

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

T Cell ◽

B Cell ◽

Plasma Cells ◽

Cell Types ◽

Cell Maturation ◽

New Drug ◽

B Cell Maturation ◽

B Cell Maturation Antigen

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

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Chimeric antigen receptor T-cell therapies for multiple myeloma

Blood ◽

10.1182/blood-2017-06-793869 ◽

2017 ◽

Vol 130 (24) ◽

pp. 2594-2602 ◽

Cited By ~ 85

Author(s):

Lekha Mikkilineni ◽

James N. Kochenderfer

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

B Cell ◽

Plasma Cells ◽

Cell Maturation ◽

Cell Therapies ◽

B Cell Maturation ◽

Car T ◽

B Cell Maturation Antigen

Abstract Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte–activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.

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B-cell maturation antigen (BCMA) in multiple myeloma: the new frontier of targeted therapies

Therapeutic Advances in Hematology ◽

10.1177/2040620721989585 ◽

2021 ◽

Vol 12 ◽

pp. 204062072198958

Author(s):

Larysa Sanchez ◽

Alexandra Dardac ◽

Deepu Madduri ◽

Shambavi Richard ◽

Joshua Richter

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

B Cell ◽

Targeted Therapies ◽

Safety Data ◽

Cell Maturation ◽

Treatment Modalities ◽

Cell Therapies ◽

B Cell Maturation ◽

B Cell Maturation Antigen

Outcomes of patients with multiple myeloma (MM) who become refractory to standard therapies are particularly poor and novel agents are greatly needed to improve outcomes in such patients. B-cell maturation antigen (BCMA) has become an important therapeutic target in MM with three modalities of treatment in development including antibody–drug conjugates (ADCs), bispecific T-cell engagers (BITEs), and chimeric antigen receptor (CAR) T-cell therapies. Early clinical trials of anti-BCMA immunotherapeutics have demonstrated extremely promising results in heavily pretreated patients with relapsed/refractory MM (RRMM). Recently, belantamab mafodotin was the first anti-BCMA therapy to obtain approval in relapsed/refractory MM. This review summarizes the most updated efficacy and safety data from clinical studies of BCMA-targeted therapies with a focus on ADCs and BITEs. Additionally, important differences among the BCMA-targeted treatment modalities and their clinical implications are discussed.

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