Chimeric antigen receptor (CAR-T cells) are cell-based, "living drug" therapies that merge the physiological properties of immune cells—migration, activation, proliferation—with a genetically encoded, redirected antigen specificity. In autoimmune diseases (AID), most clinical development has focused on targeting B cells via surface antigens such as CD19 or B cell maturation antigen (BCMA). CAR-T cells recognize these B cell markers, bind target cells, and mediate deep depletion of circulating and tissue-resident B cells across secondary lymphoid organs and affected target tissues.
This profound B cell elimination disrupts germinal center architecture, removes follicular dendritic cell networks, and impairs antigen presentation, with downstream effects on T cell and myeloid compartments. Collectively, these changes have been described as an immune reset, often associated with deep and sustained drug-free remission in treated patients.
Autologous CAR-T therapy—where a patient’s own T cells are isolated, transduced with a CAR-encoding vector, expanded ex vivo, and reinfused after lymphodepletion—remains the most established approach and is the focus of much of the current clinical experience in AID.
CD19-directed CAR-T cell therapy was first used in an autoimmune patient with refractory systemic lupus erythematosus in 2021. Since that report, CD19-CAR-T treatment has been applied across a widening range of AIDs including autoimmune rheumatic diseases, neuroinflammatory disorders, immune cytopenias, and inflammatory bowel disease. Published case series and early-phase trials report deep B cell depletion followed by reconstitution of a predominantly naïve B cell repertoire, often correlated with durable remission without ongoing immunosuppression.
Safety observations to date indicate a relatively low incidence of high-grade cytokine release syndrome, severe neurologic events, and hematotoxicity compared with oncology cohorts, supporting feasibility in selected AID populations. Nonetheless, the overall number of treated AID patients in the literature remains limited and consolidation of efficacy and safety findings in larger, controlled studies is needed.
Multiple important questions remain before routine clinical integration. It is uncertain whether eradication of long-lived plasma cells will be required in some patients to achieve lasting immune reset; long-lived plasma cells do not express CD19 and thus are spared by CD19-CAR-T cells. The appropriate intensity and composition of lymphodepletion regimens for AID are not established—current practices are largely adapted from oncology and may be amenable to dose reductions in nonmalignant indications.
Key safety concerns that need further characterization include late-onset neutropenia, persistent B cell aplasia, and long-term risks such as infection, secondary malignancy, and cardiovascular disease, all of which may be heightened in AID populations. Structured, long-term follow-up is necessary to delineate these outcomes.
CARs targeting BCMA permit depletion of plasma cells, including long-lived cells responsible for established humoral immunity. BCMA-directed CAR-T cells have been used in AID and offer a means to remove antibody-secreting cells that are refractory to CD19-directed approaches; however, they raise additional challenges. Elimination of immune memory may necessitate immunoglobulin replacement and planned re-vaccination because existing vaccine-induced humoral responses can be lost.
Vaccination responsiveness after CAR-T therapy depends on timing relative to B cell depletion. During B cell aplasia, humoral responses to vaccination are not expected. Preliminary reports indicate that after reconstitution, humoral responses to vaccination may normalize as the B cell compartment repopulates with mostly naïve cells; nonetheless, comprehensive assessment of primary and recall vaccine responses after both CD19 and BCMA approaches is required.
Barriers to wide adoption of autologous CAR-T therapy include high manufacturing costs and the limited number of specialized treatment centers. Oncology experience has shown several strategies to mitigate access issues—better patient selection, regulatory hospital exemption pathways, and improved production methods. Similar adaptations are emerging in AID care. Preliminary economic analyses suggest that successful CAR-T therapy can markedly reduce downstream medical costs due to decreased need for chronic drug therapy, fewer complications necessitating inpatient care, and reduced rehabilitative and organ-support measures, which may offset upfront therapy costs in patients achieving long-term remission.
Emerging technologies aim to improve scalability and reduce manufacturing burdens. Allogeneic, off-the-shelf CAR products—often derived from inducible pluripotent stem cells (iPSCs) differentiated into T cells or natural killer (NK) cells—are gene-edited to remove antigenic surfaces that would prompt rejection and to lower graft-versus-host disease risk. These products could be deployed broadly without individualized manufacturing.
An alternative is in vivo CAR generation, in which targeted lipid nanoparticles carrying CAR-encoding RNA are infused to transfect host cells (typically T cells) and induce CAR expression directly in the patient. Both approaches have demonstrated principal feasibility in AID, but it remains unclear whether they can achieve the degree and durability of B cell depletion required to trigger sustained immune reset.
mRNA-based, transient CAR expression offers genomic-safety advantages by avoiding DNA integration and enabling reversibility. Ex vivo mRNA CAR-T cells have shown clinical effect in conditions such as myasthenia gravis. However, because mRNA-induced CAR expression dilutes with cell division, achieving sufficient initial CAR magnitude and/or repeated dosing may be necessary to reach complete B cell depletion in vivo. Vector-based in vivo approaches under development must consider the safety implications of DNA integration.
CAR-T cell therapies targeting B cell lineages have shown transformative potential for AID by inducing deep B cell depletion and an immune reset associated with prolonged, drug-free remission in some patients. Early safety data are encouraging, but larger and longer-term studies are required to define durability, optimal patient selection, lymphodepletion strategies, vaccination management, and long-term risks. Allogeneic off-the-shelf products, in vivo CAR generation, and mRNA-based strategies promise greater scalability but require rigorous evaluation of efficacy and safety, particularly their capacity to induce sustained immune reset. Identification of patients most likely to benefit—typically those with severe, refractory disease and at risk of irreversible damage—will be critical as pivotal trials progress and clinical placement of these therapies evolves.