BCMA-targeted immunotherapy for multiple myeloma

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Abstract

B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

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Most cited references 89

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Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

Henk Lokhorst, Torben Plesner, Jacob Laubach … (2015)

Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy.

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Targeting mTOR for cancer therapy

Hui Hua, Qingbin Kong, Hongying Zhang … (2019)

Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

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BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

Brian O'Connor, Vanitha Raman, Loren D. Erickson … (2004)

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this α-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA−/− mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

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Author and article information

Contributors

Bo Yu: boyu051988@gmail.com

Tianbo Jiang: tjiang@nymc.edu

Delong Liu:

ORCID: http://orcid.org/0000-0003-4502-4949

delong_liu@nymc.edu

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 17 September 2020

Publication date PMC-release: 17 September 2020

Publication date Collection: 2020

Volume: 13

Electronic Location Identifier: 125

Affiliations

[1 ]GRID grid.415933.9, ISNI 0000 0004 0381 1087, Department of Medicine, , Lincoln Medical Center, ; Bronx, NY USA

[2 ]GRID grid.260917.b, ISNI 0000 0001 0728 151X, Department of Medicine, , New York Medical College and Westchester Medical Center, ; Valhalla, NY USA

Author information

Delong Liu http://orcid.org/0000-0003-4502-4949

Article

Publisher ID: 962

DOI: 10.1186/s13045-020-00962-7

PMC ID: 7499842

PubMed ID: 32943087

SO-VID: 62661189-de3f-45e3-b0c1-ca0b1ef43e4b

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Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 2 May 2020

Date accepted : 7 September 2020

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: b cell maturation antigen,bcma,belantamab mafodotin,car-t,antibody-drug conjugate,bispecific t cell engager

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: b cell maturation antigen, bcma, belantamab mafodotin, car-t, antibody-drug conjugate, bispecific t cell engager

BCMA-targeted immunotherapy for multiple myeloma

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Cancer Immunotherapy

Most cited references 89

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.

Targeting mTOR for cancer therapy

BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

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