BCMA CAR T Approaches in B-Cell Malignancies

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for B-cell malignancies, particularly multiple myeloma. By leveraging the immune system to selectively target BCMA-expressing cells, these therapies have demonstrated significant clinical responses in patients with relapsed or refractory disease. However, challenges such as resistance, durability of response, and toxicity management remain areas of ongoing research.

Advancements in CAR T-cell engineering, dual-target strategies, and optimized manufacturing processes continue to refine efficacy and safety. Understanding the key components of BCMA CAR T therapy is essential to improving patient outcomes and expanding its application across B-cell malignancies.

Biology Of BCMA In B-Cell Malignancies

B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), plays a central role in plasma cell survival and differentiation. Expressed predominantly on mature B cells and plasma cells, BCMA is activated by its ligands, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), which help maintain long-lived plasma cells in the bone marrow. Unlike CD19 or CD20, BCMA expression is largely restricted to terminally differentiated B cells, making it an attractive therapeutic target, particularly in multiple myeloma.

In multiple myeloma, BCMA is consistently expressed on malignant plasma cells, with higher levels correlating with disease progression and treatment resistance. Inflammatory cytokines within the bone marrow microenvironment further upregulate BCMA expression, reinforcing its role in tumor survival. Soluble BCMA (sBCMA), a cleaved extracellular fragment, is often elevated in patients and can act as a decoy receptor, reducing the efficacy of BCMA-targeted therapies.

Beyond multiple myeloma, BCMA is detected in certain subtypes of non-Hodgkin lymphoma and chronic lymphocytic leukemia, though at lower levels. Its restricted expression minimizes off-target effects, distinguishing it from other B-cell antigens. This selectivity has driven the development of BCMA-targeted therapies, including CAR T cells, bispecific antibodies, and antibody-drug conjugates, all designed to exploit the dependency of malignant plasma cells on BCMA signaling.

CAR T Construct Design For BCMA

The structural design of BCMA-directed CAR T cells defines their therapeutic efficacy, persistence, and safety. Each component—the extracellular antigen-binding domain, hinge and spacer region, transmembrane domain, costimulatory domain, and intracellular signaling domain—must be optimized to enhance recognition of BCMA-expressing cells while mitigating antigen escape and T-cell exhaustion.

The antigen-binding domain, typically derived from a single-chain variable fragment (scFv) of an anti-BCMA monoclonal antibody, recognizes and binds BCMA on malignant plasma cells. Variations in scFv affinity affect CAR T-cell function, as overly strong binding may induce exhaustion, while insufficient affinity reduces target engagement. Some constructs incorporate fully human or humanized scFvs to minimize immunogenicity. The hinge and spacer region, often derived from CD8α, IgG1, or IgG4, ensures effective BCMA recognition even in the presence of high levels of soluble BCMA.

The transmembrane domain anchors the CAR to the T-cell membrane and influences receptor stability. Commonly sourced from CD8α or CD28, this region ensures proper signal transduction upon antigen engagement. The costimulatory domain plays a key role in CAR T-cell expansion, persistence, and cytotoxic activity. CD28-based CARs induce robust early expansion but may have shorter persistence, whereas 4-1BB-based constructs promote sustained proliferation and durability.

The intracellular signaling domain, derived from CD3ζ, drives T-cell activation upon BCMA engagement, triggering cytokine release, cytotoxic granule exocytosis, and target cell apoptosis. Modifications to this domain, such as additional costimulatory motifs or alternative signaling pathways, are being explored to enhance potency while minimizing exhaustion. Some experimental constructs incorporate inducible safety switches to allow selective depletion of CAR T cells in case of severe toxicity.

Dual-Target Concepts With BCMA And CD19

Targeting both BCMA and CD19 in CAR T-cell therapy is an emerging strategy to enhance response durability and prevent antigen escape in B-cell malignancies. While BCMA is associated with plasma cell disorders, CD19 is broadly expressed in B-cell malignancies, including non-Hodgkin lymphoma and acute lymphoblastic leukemia. Dual-targeting aims to address tumor heterogeneity and reduce relapse due to antigen-negative escape variants.

One challenge in BCMA-directed therapy is the emergence of malignant clones that downregulate or lose BCMA expression, rendering single-target CAR T cells ineffective. Dual-targeting approaches leverage CD19 as a secondary antigen to maintain cytotoxic activity against resistant subpopulations. Bispecific CAR constructs incorporating scFvs for both BCMA and CD19 have demonstrated enhanced tumor clearance. Alternatively, co-administration of separate BCMA- and CD19-specific CAR T-cell products has been explored to achieve complementary coverage.

Dual-targeting may also improve CAR T-cell persistence and expansion. CD19-directed therapies have shown prolonged survival in lymphoma and leukemia, suggesting that incorporating CD19 recognition into BCMA-directed CAR T cells could enhance persistence in multiple myeloma. Some studies suggest that CD19-positive B-cell populations within the bone marrow may support CAR T-cell longevity, leading to more sustained disease control. Ongoing clinical trials are evaluating the safety and efficacy of dual-target constructs in relapsed or refractory multiple myeloma.

T-Cell Isolation And Transduction Steps

The manufacturing of BCMA-directed CAR T cells begins with isolating autologous T cells from a patient’s peripheral blood via leukapheresis. This process selectively collects mononuclear cells while returning other blood components, minimizing disruption to the patient’s overall blood volume. The leukapheresis product undergoes further processing to enrich for T cells, typically through magnetic bead-based selection or density gradient centrifugation. CD4+ and CD8+ T-cell subsets are often isolated in defined ratios to optimize therapeutic efficacy, as a balanced composition supports robust expansion and long-term persistence.

Following isolation, T cells are activated to promote proliferation and enhance susceptibility to genetic modification. This is commonly achieved using CD3/CD28 beads or artificial antigen-presenting cells, which provide necessary costimulatory signals. Activation primes the cells for transduction, where the CAR construct is introduced into the T-cell genome. Lentiviral or retroviral vectors are the most frequently used delivery systems, enabling stable integration of the CAR transgene for sustained expression. The transduction efficiency varies based on vector design, multiplicity of infection, and the activation state of the T cells, requiring careful optimization to maximize yield without compromising functionality.

Key Interactions In The Immune Microenvironment

The effectiveness of BCMA-directed CAR T-cell therapy is influenced by interactions within the immune microenvironment. The bone marrow niche, where multiple myeloma and other BCMA-expressing malignancies primarily reside, contains stromal cells, immunosuppressive cytokines, and regulatory immune populations that can either support or hinder CAR T-cell activity.

Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) inhibit CAR T-cell responses by releasing transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), which impair T-cell proliferation and function. Tumor-associated macrophages (TAMs) contribute to immune evasion by secreting anti-inflammatory cytokines and expressing checkpoint ligands like PD-L1, which inhibit CAR T-cell activation. Strategies to counteract these suppressive forces, including checkpoint inhibitors and myeloid-targeting agents, are being explored to enhance CAR T-cell persistence and cytotoxicity.

The metabolic landscape of the bone marrow also affects CAR T-cell function. Hypoxia impairs T-cell metabolism and reduces cytotoxic activity, while high levels of adenosine and lactate create an immunosuppressive milieu. Efforts to modify CAR T-cell metabolism, such as engineering resistance to hypoxia-induced dysfunction or incorporating metabolic reprogramming, may improve therapeutic outcomes. Addressing both direct tumor targeting and the broader suppressive landscape is critical to optimizing CAR T-cell therapy.

B-Cell Malignancy Indications

BCMA-directed CAR T-cell therapy has been most extensively studied in multiple myeloma, but its potential extends to other B-cell malignancies where BCMA expression is present.

In multiple myeloma, BCMA-targeted CAR T-cell therapies have demonstrated high response rates in heavily pretreated patients, with clinical trials such as KarMMa and CARTITUDE showing deep and durable remissions. However, antigen escape and relapse due to residual BCMA-negative clones remain challenges. Researchers are exploring dual-targeting approaches and CAR modifications to improve long-term efficacy.

Beyond multiple myeloma, BCMA expression has been detected in subsets of non-Hodgkin lymphoma and chronic lymphocytic leukemia. Early-phase trials are assessing whether BCMA-directed CAR T cells can achieve meaningful clinical activity in these diseases. Given the heterogeneity of BCMA expression, patient selection and biomarker-driven approaches may help identify those most likely to benefit from this therapy.