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Overview of BCMA-targeted CAR Cell Therapies

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Background of BCMA

B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor (TNFR) family, is also known as TNFR superfamily member 17 (TNFRSF17). It is a non-glycosylated type III integral membrane protein consisting of 185 amino acid residues with a 1.2-kb mRNA and plays a critical role in managing B-cell maturation and B-cell differentiation into plasma cells. In human and murine BCMA proteins, it contains a conserved 6 cysteine motif at the N-terminal end. These conserved regions were verified by hydrophobic analysis and sequence analysis, showing similarity to the extracellular 6 cysteine repeats of the TNFR family, confirming that BCMA is somewhat conserved. It was found that BCMA proteins are not expressed on the cell surface but are localized within the Golgi. BCMA does not maintain the dynamic homeostasis of normal B cells but is necessary for the survival of long-lived plasma cells. In patients with multiple myeloma (MM), BCMA mRNA is commonly highly expressed in malignant plasma cells.

Fig.1 Structure of BCMA

BCMA Signaling Pathways

BCMA binding to ligands activates the corresponding signal transduction pathways, which are essential survival signals to maintain myeloma cell survival, differentiation, and maturation. There is a common signaling pathway associated with BCMA, namely the nuclear factor kappa-B (NF-κB) signaling pathway.

The binding of BCMA and its ligand can activate the classical NF-κB signaling pathway, which can activate the IκB kinase (IKK) when using the intracellular tumor necrosis factor receptor-associated factor (TRAF) as the second messenger, thus further phosphorylating IκB and releasing the cytosolic factor p50/p65, which can bind to each other with the target genes in the nucleus, and by regulating the transcription of their target genes, the translation process which results in the upregulation of anti-apoptotic proteins Bcl-2, Bcl-xL, Mcl-1, Bcl-w, and A1, and the downregulation of pro-apoptotic proteins such as Bax and Bak, ultimately increasing the proliferation and survival of B cells. This is essential for the survival of many B-cell malignancies, including MM. In addition, BCMA may also play a role in plasma-like dendritic cells, further promoting the survival and development of drug resistance in MM cells.

BCMA is also involved in the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signaling pathways and plays an important role in cell proliferation and survival. B-cell activating factor (BAFF) binding to BCMA activates JAK enzymes and further activates STAT transcription factors. The activated STAT enters the nucleus and regulates the transcription of several genes, including IL-6 and Mcl-1, to promote cell proliferation and survival, etc. Overexpression of BCMA induces enhanced protein kinase B, mitogen-activated protein kinase, and NF-κB signaling cascades to promote MM cell growth and survival, resulting in accelerated MM progression. At the same time, the downregulation of BCMA expression significantly reduces MM colony formation and decreases MM cell survival.

Clinical Status of BCMA-Targeted CAR Cell Therapies

BCMA, due to its restricted expression in plasma cells and not in natural and memory B cells, has been used as a new drug target for the diagnosis and treatment of MM. In April 2017, BCMA jumped to become a star target of the American Association for Cancer Research. Currently, tumor immunotherapies targeting BCMA, mainly through chimeric antigen receptor T cell (CAR-T) therapy, have shown promising efficacy in preclinical and clinical trials, which involves genetically modifying one's T cells in vitro and then infusing them back into the patient to kill tumor cells in the body. In March 2019, the U.S. Food and Drug Administration (FDA) approved the first BCMA-targeted CAR-T cell therapy—a cell therapy drug with the commercial name Yescarta (axicabtagene ciloleucel)—for the treatment of MM. Subsequently, in March 2020, the FDA approved a second BCMA-targeted CAR-T cell therapy, commercially known as Abecma, also for the treatment of MM.

Table 1. Approved BCMA -Targeted CAR Cell Therapies

Ongoing clinical trials of BCMA-targeted CAR-T cell therapy mainly include advanced MM and other hematological malignancies, such as lymphoma and acute lymphoblastic leukemia. Among them, the majority of trials are for advanced MM, which is due to the poor therapeutic effect of current treatments for relapsed and refractory patients with MM and the need to find new treatment strategies.

Ongoing clinical trials of BCMA-targeted CAR-T cell therapies are currently divided into two phases: Phase I/II trials, which are designed to evaluate the safety and efficacy of BCMA-targeted CAR-T cell therapy regimens and usually involve a smaller number of patients, and Phase III trials, which are more extensive to validate and compare treatment regimens. All of the above trials involved CAR-T cells that recognized and attacked BCMA-positive tumor cells by modifying the patient's T cells to express BCMA-targeted CARs. Preliminary results from these trials showed that BCMA-targeted CAR-T cell therapy achieved significant therapeutic effects in a subset of patients, and no serious treatment-related adverse effects were observed. However, further studies are needed to confirm these preliminary results and to identify more optimal treatment regimens.

Table 2. Ongoing BCMA -Targeted CAR Cell Therapy Clinical Trials

References

1. Oden, Felix, et al. "Potent anti-tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma." Molecular Oncology 9.7 (2015): 1348-1358.
2. Mullard, Asher. "The BCMA bonanza." Nature reviews. Drug Discovery 18.7 (2019): 481-484.
3. Mullard, Asher. "FDA approves first BCMA-targeted therapeutic." Nature Reviews Drug Discovery 19.10 (2020): 659-660.
4. Da Vià, Matteo C., et al. "Homozygous BCMA gene deletion in response to anti-BCMA CAR-T cells in a patient with multiple myeloma." Nature medicine 27.4 (2021): 616-619.
5. Mailankody, Sham, et al. "Allogeneic BCMA-targeting CAR-T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results." Nature Medicine 29.2 (2023): 422-429.