Vijetha Karen Kitchley, M.Sc.
Editorial Office, The ACTO Times
International PhD Program in Cell Therapy & Regenerative Medicine, Taipei Medical University, Taipei, Taiwan

Introduction

Autoimmune disorders arise when immune tolerance breaks down, leading the immune system to mistakenly recognize self-tissues as foreign. These conditions collectively affect roughly 5–10% of individuals worldwide and include diseases such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, and inflammatory myopathies. Standard management typically involves corticosteroids, biologic agents, and other immunosuppressive drugs aimed at controlling inflammation and limiting tissue injury. While these approaches can reduce disease activity, they rarely eradicate the autoreactive immune populations that drive pathology, which allows disease flares and cumulative organ damage to persist over time (1,2).

In recent years, cellular immunotherapy has introduced a fundamentally different therapeutic concept. Chimeric antigen receptor T-cell (CAR-T) therapy, initially developed for hematologic malignancies, is now being explored as a treatment option for severe and refractory autoimmune diseases (2–4). Rather than broadly suppressing immune function, this strategy selectively eliminates disease-driving B-cell populations responsible for autoantibody production. Among the most studied targets are CD19 and B-cell maturation antigen (BCMA), which are expressed at distinct stages of B-cell differentiation.

Role of B Cells in Autoimmune Pathogenesis

B lymphocytes normally play a protective role in adaptive immunity by generating antibodies against pathogens. However, in autoimmune conditions, a subset of these cells becomes dysregulated and produces antibodies that target self-antigens. These autoantibodies contribute to chronic inflammation through immune complex deposition, complement activation, and recruitment of inflammatory mediators, ultimately resulting in tissue injury (2,6).

Conventional B-cell depletion strategies such as rituximab primarily eliminate CD20-positive mature B cells. Despite their effectiveness, these therapies do not fully eradicate early B-cell precursors or long-lived plasma cells, allowing autoantibody production to persist and disease relapse to occur after immune reconstitution (2,6). CAR-T therapy has therefore been proposed as a more durable strategy capable of sustained elimination of pathogenic B-cell subsets and long-term immune reprogramming (3,7).

CD19-Directed CAR-T Therapy

CD19 is broadly expressed across most stages of B-cell development, including early precursors, naïve cells, and memory B cells, but is not present on fully differentiated plasma cells (2,3). The production of CD19 CAR-T cells involves harvesting patient T cells, genetically engineering them to express a CD19-specific receptor, expanding them ex vivo, and reinfusing them after lymphodepleting conditioning (7).

Once administered, these modified T cells recognize CD19-positive cells and eliminate them through cytotoxic mechanisms involving perforin release, granzymes, and cytokine-mediated effects. Unlike antibody-based therapies, CAR-T cells can expand in vivo and persist for extended periods, enabling continuous surveillance and removal of newly emerging autoreactive B cells (3,7).

Clinical experience has shown promising outcomes in patients with refractory autoimmune diseases. In severe systemic lupus erythematosus, a single infusion has been associated with rapid remission, reduction of autoantibody titers, restoration of immune balance, and discontinuation of immunosuppressive therapy (1,2).

Similar therapeutic responses have been reported in systemic sclerosis, inflammatory myopathies, vasculitis, and anti-synthetase syndrome, supporting the concept that CD19 CAR-T therapy may induce a long-lasting immune reconfiguration rather than temporary suppression (2,3).

BCMA-Targeted CAR-T Therapy

Although CD19-directed therapy effectively depletes most B-cell populations, it has limited impact on long-lived plasma cells, which typically lose CD19 expression but retain BCMA expression (2,6). These plasma cells are a major source of persistent autoantibody production and therefore represent a critical therapeutic target.

BCMA serves as a key survival receptor for plasma cells, interacting with BAFF and APRIL signaling pathways to support their longevity (6). CAR-T cells engineered to target BCMA can selectively eliminate these antibody-secreting cells, thereby reducing chronic autoantibody levels and potentially improving long-term disease control (3,6).

The established efficacy of BCMA CAR-T therapy in multiple myeloma has encouraged its investigation in autoimmune diseases (5). Ongoing studies are evaluating its role in conditions such as lupus nephritis, myasthenia gravis, and autoimmune neurological disorders. Early clinical data suggest meaningful reductions in pathogenic antibodies and sustained clinical improvement in selected patients (3,6).

Combined CD19/BCMA CAR-T Strategy

Because CD19 and BCMA are expressed on different stages of B-cell maturation, simultaneous targeting of both antigens may provide a more complete depletion of autoreactive immune cells than single-target approaches (3).

This dual-target strategy aims to eliminate:

• Immature and mature autoreactive B cells via CD19 targeting
• Memory B-cell populations expressing CD19
• Long-lived plasma cells expressing BCMA

By addressing both precursor and antibody-secreting compartments, this approach may enhance immune system rebalancing and reduce the likelihood of relapse. Early clinical findings are encouraging, showing acceptable safety and promising efficacy, although larger controlled trials are still required to confirm long-term outcomes (2,3,8).

Limitations and Challenges

Despite its therapeutic potential, CAR-T therapy faces several important limitations. Each treatment is patient-specific, requiring individualized manufacturing from autologous T cells, which increases cost and production time.

Additionally, patients must undergo lymphodepleting chemotherapy and require close clinical monitoring after infusion (3,7).

The most frequently observed toxicities include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Notably, patients with autoimmune diseases often experience less severe CRS compared to oncology patients, likely due to a lower overall burden of target cells (2,3).

Prolonged depletion of B cells may also increase infection risk and, in some cases, necessitate immunoglobulin replacement therapy (3). To overcome these challenges, next-generation approaches are being developed, including fully human CAR constructs, allogeneic “off-the-shelf” CAR-T products, and CAR-engineered natural killer (CAR-NK) cells, all of which aim to improve safety, scalability, and accessibility (3,7).

Future Outlook

The emergence of CD19- and BCMA-directed CAR-T therapies represents a major shift in autoimmune disease management. Instead of continuous immunosuppression, these therapies aim to remove the underlying cellular drivers of disease and allow immune system reconstitution with restored tolerance (2,3).

Although further randomized clinical trials are necessary to confirm durability and safety, early clinical evidence suggests that CAR-T therapy may enable long-term, treatment-free remission in patients with severe, refractory autoimmune diseases (1–3). As manufacturing processes improve and costs decrease, CAR-T-based strategies are expected to become an increasingly important component of precision medicine for autoimmune disorders.

References

• Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124–2132.
• Mackensen A, Müller F, Lorenz HM, et al. Anti-CD19 CAR T cell therapy for autoimmune disease. N Engl J Med. 2024;390(8):687–700.
• Schett G, Mougiakakos D, Mackensen A. CAR T-cell therapy in autoimmune diseases. Nat Rev Rheumatol. 2023;19(5):289–303.
• Kansal R, Richardson N, Neeli I, et al. Sustained B-cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Nat Commun. 2019;10:3932.
• Zhao WH, Liu J, Wang BY, et al. A phase 1, open-label study of LCAR-B38M, a BCMA-directed CAR-T cell therapy in relapsed or refractory multiple myeloma. J Hematol Oncol. 2018;11:141.
• Dörner T, Lipsky PE. Beyond B-cell depletion: emerging B-cell-targeted therapies in autoimmune diseases. Nat Rev Rheumatol. 2024;20:1–17.
• June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73.
• Mougiakakos D, Krönke G, Völkl S, et al. CD19 CAR T cells in autoimmune diseases: mechanisms and clinical perspectives. Nat Rev Immunol. 2024;24:289–304.