CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond

Abstract

Significant progress has been achieved in the realm of therapeutic interventions for multiple myeloma (MM), leading to transformative shifts in its clinical management. While conventional modalities such as surgery, radiotherapy, and chemotherapy have improved the clinical outcomes, the overarching challenge of effecting a comprehensive cure for patients afflicted with relapsed and refractory MM (RRMM) endures. Notably, adoptive cellular therapy, especially chimeric antigen receptor T-cell (CAR-T) therapy, has exhibited efficacy in patients with refractory or resistant B-cell malignancies and is now also being tested in patients with MM. Within this context, the B-cell maturation antigen (BCMA) has emerged as a promising candidate for CAR-T-cell antigen targeting in MM. Alternative targets include SLAMF7, CD38, CD19, the signaling lymphocyte activation molecule CS1, NKG2D, and CD138. Numerous clinical studies have demonstrated the clinical efficacy of these CAR-T-cell therapies, although longitudinal follow-up reveals some degree of antigenic escape. The widespread implementation of CAR-T-cell therapy is encumbered by several barriers, including antigenic evasion, uneven intratumoral infiltration in solid cancers, cytokine release syndrome, neurotoxicity, logistical implementation, and financial burden. This article provides an overview of CAR-T-cell therapy in MM and the utilization of BCMA as the target antigen, as well as an overview of other potential target moieties.

Keywords: B-cell maturation antigen (BCMA); CAR-T-cell therapy; multiple myeloma (MM).

Figure 1

Basic structures and generations of CAR T cells: First-generation CARs have only one signal structure domain (CD3ζ) and no co-stimulatory domain and are the initiators of T-cell receptor intracellular signaling. Second-generation CARs are engineered to contain one co-stimulatory domain to enhance cytotoxicity and persistence. Third-generation CARs contain two co-stimulatory domains: CD28 4-1BB or OXO40. Fourth-generation CARs, which are also called TRUCKs, possess a cytokine-induced domain IL-12 (cytokine inducer). Fifth-generation CARs have an additional intracellular domain, creating a truncated cytoplasmic IL-2 receptor β-chain domain with a binding site for transcription factor STAT3.

Figure 2

Significance of BCMA signaling pathway in plasma cells: BAFF and APRIL are two natural ligands for BCMA. APRIL can bind with both TACI and BCMA and has a higher binding affinity with BCMA than BAFF. BAFF is a ligand for BAFF-R and can also bind with BCMA. The binding of APRIL and BAFF with BCMA results in the activation of different pathways in MM cells, like AKT, P38, NF-kβ, and JNK. γ-secretase can cleave the BCMA membrane and release sBCMA, which can also bind with BAFF and APRIL.

Figure 3

Limitations of CAR-T-cell therapy: (A) On-target/off-tumor attacking of the normal cell by CAR T cell if the same target antigen is present on the tumor cell. (B) The immunosuppressive microenvironment of the tumor cell consists of chemokines, and growth factors that lead to the infiltration of immune cells in the tumor. (C) CAR-T-cell toxicities: the pathogeneses of immune effector cell-associated neurotoxicity syndrome and cytokine release syndrome occur after the interaction of the tumor cell with the target antigen on the tumor cell.