In contrast to the chronic immune suppression associated with targeted biologic therapies, stem cell treatments, including both mesenchymal stem cell therapy (MSCT) and hematopoietic stem cell therapy (HSCT)—present a promising approach for potentially curing IMIDs by reinducing self-tolerance. This is supported by evidence from HSCT in MS, SSc, and Crohn’s disease (6), as well as significant symptom improvement in patients with SLE and IBD following MSCT (35). These therapies target the long-term and extensive depletion of immune cells, particularly within the B and T cell populations (6, 36, 37). HSCT offers the advantage of complete eradication of autoreactive cells and broad immune system regeneration, promoting tolerance to autoantigens and potential long-term remission in MS, SSc, and SLE (6). However, its major drawbacks include high toxicity from conditioning regimens, increased infection risk, potential relapses, GVHD risk in allo-HSCT, and relatively high treatment-related mortality (38, 39). MSCT provides potent immunomodulatory and anti-inflammatory effects with no need for chemotherapy, no GVHD risk, and fewer severe side effects than HSCT. However, its variable efficacy and uncertain long-term durability remain key drawbacks (37, 40). While HSCT and MSCT have been valuable in immune modulation, their limitations—toxicity, incomplete immune reset, and variability in efficacy—have paved the way for targeted cell therapy as a more precise, effective, and durable treatment for IMIDs. Unlike stem cell therapy, targeted cell therapy leverages immunoengineering to program immune cells to eliminate pathogenic cells directly within diseased tissues, precisely where they drive systemic autoimmunity (41). The application of immunoengineering has enabled T cells to express a chimeric antigen receptor (CAR) specifically targeting B cell surface antigens, revolutionizing the treatment of hematological malignancies and IMIDs (41, 42). CAR-T cells and T cell engineering to express a chimeric autoantibody receptor (CAAR) have emerged as a potentially curative strategy for autoimmunity, with the goal of achieving profound, short-term depletion of the B-cell compartment (43). CAR-T therapy offers selective depletion of pathogenic cells, deep and sustained B-cell depletion in tissues, high personalization, and the potential for long-term remission, but its main drawback is moderate toxicity, including risks of cytokine release syndrome (CRS) and neurotoxicity. Differences between stem cell therapy and CAR-T cell therapy have been identified in terms of composition, structure, mechanisms, preparation, pretreatment, and post-infusion monitoring ( Figure 1 ).

The evolution of CAR-T cell generations has focused on enhancing signal transduction and immune response. First-generation CAR-T cells contain a CD3ζ domain for activation, while second-generation CAR-T cells add a costimulatory domain (e.g., CD28, ICOS, or 4-1BB) to improve efficacy. Third-generation CAR-T cells further enhance activation by incorporating two costimulatory domains alongside CD3ζ. Fourth-generation CAR-T cells, known as TRUCK CARs, build on second-generation designs by introducing inducible cytokine expression, such as IL-12, to enhance the immune response. Fifth-generation CAR-T cells refine previous designs by integrating the IL-2R beta-chain, which activates the JAK/STAT pathway to optimize antigen-dependent T cell responses (44, 45).

In addition, multiple types of CAR-T cells have been engineered to address the complex immunopathology of hematologic malignancy and IMID. CAR-T cells target specific antigens on pathological cells, while CAAR-T cells recognize the B cell receptor (BCR) on self-reactive B cells to eliminate those involved in autoimmune diseases without requiring HLA or TCR recognition. In contrast, CAR-Treg therapy utilizes regulatory T cells to restore immune balance by suppressing excessive immune responses. CAR-NK cell therapies, with favorable safety and diverse sourcing of NK cells, may offer a cost-effective, “off-the-shelf” alternative that improves accessibility (46).

A key consideration in using CAR-T cells for IMID is determining how long they must persist for therapeutic effects. Unlike hematological malignancy, which may require long-term engraftment, a short burst of CAR-T cells might be enough to trigger an “immune reset” (47). Although the CD28 or 4-1BB co-stimulatory domains in CARs enhance the function T cells activation and anti-cancer activity, the ideal co-stimulatory domain for IMID remains unclear. However, minimizing toxicity will likely be a key consideration in the design of CAR therapies specifically for IMID (48).

T-cell-mediated autoimmunity in IMIDs leads to B-cell activation and autoantibody formation. Complete B-cell depletion may not be effective for refractory IMIDs, as residual autoreactive T cells and tissue-resident T cells could still sustain the disease (49). Engineered CAR-T cells can selectively target autoantigens such as CD19, CD7, and BCMA, eliminating autoreactive B cells, T cells, and plasma cells, to modulate the immune microenvironment and alleviate IMID symptoms (50, 51). In consistent with evidence from tumor studies showing that CAR-T cell residency in the bone marrow is more effective than peripheral persistence for tumor control (52, 53), CAR-T therapies not only deplete circulating B cells but also tissue-resident B cells, particularly in secondary lymphoid tissues, although memory B cells in these tissues may be resistant to depletion (49). However, whether CAR-T cell infiltration into tissues is insufficient or limited to certain subsets of CAR-T cells remains unclear. Furthermore, CAR-T cells derived from SLE patients can induce CD19-dependent activity against autologous primary B cells, accompanied by reduced inflammatory cytokine production (54).

Single-cell profiling and in-depth immunophenotyping in hematologic malignancy have demonstrated that long-lasting CD19-redirected CAR-T cells exhibit cytotoxic characteristics, along with sustained functional activation and proliferation, lasting for more than a decade (55, 56). Dynamic tracking of CAR-T cells in patients with anti-SRP necrotizing myopathy or myasthenia gravis suggests that anti-BCMA CAR-T cells may normalize the immune microenvironment, including the reconstitution of B-cell lineages with sustained reductions in pathogenic autoantibodies, inhibition of proliferative activity in CD8+ CAR-T cells, replacement of T cell subpopulations, and suppression of overactivated immune cells (57, 58). In vivo dynamic changes of CAR-T cells post-infusion revealed that the infused CAR-T cells were in a highly metabolically active state, with elevated glycolysis and biosynthetic gene expression. They gradually transitioned from a highly proliferative state to a highly cytotoxic state along a developmental trajectory, reaching a late remission phase characterized by a loss of proliferative activity but sustained cytotoxicity. Eventually, both proliferative and cytotoxic signatures in hematologic malignancy declined during the remission phase (59, 60). Longitudinal tracking of clones in blood and cerebrospinal fluid from five neuromyelitis optica spectrum disorder (NMOSD) patients treated with anti-BCMA CAR-T cell therapy suggests that CD8+ cycling CAR-T cells play a predominant role in autoimmunity, primarily derived from CD8+ effector T cells at baseline prior to manufacturing (61). Longitudinal analysis of peripheral blood mononuclear cells from an Scl70+ SSc patient suggested that CD19-CAR-T cell therapy reverses adaptive autoimmunity and restores Fcγ-receptor IIIA-expressing innate immune cells by reducing immune complex activity (62).

In two lupus mouse models (NZB/W and MRL-lpr strains), CD19 CAR-T cell transfer induced efficient and stable B cell depletion, elimination of circulating anti-DNA antibodies, and improvements in kidney function, spleen size, lymphocyte subset ratios, and skin inflammation, as well as a significant increase in lifespan (63). Furthermore, in the MRL-lpr lupus model, transfer of syngeneic anti-CD19 CAR-T cells resulted in a more sustained B-cell depletion effect than antibody treatment, prevented disease pathogenesis before the onset of symptoms, and exhibited therapeutic benefits at later stages of disease progression (64). Moreover, multiple preclinical models show that B cell activating factor (BAFF) CAR-T cell therapy effectively depletes autoreactive B cells, offering potential benefits such as avoiding B cell aplasia and preventing long-lived plasma cell escape, though it may also deplete normal mature B cells (65).

In a preclinical model of myeloperoxidase-anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis (AAV), CD19-targeted CAR T cells effectively depleted B cells and plasmablasts, promoted a decline in MPO-ANCA levels, and, crucially, provided protection against necrotizing crescentic glomerulonephritis (66).

The CD4+ T cells were genetically engineered to express a CAR targeting myelin oligodendrocyte glycoprotein (MOG) in combination with the murine FoxP3 gene, resulting in a reduction of disease symptoms and a decrease in IL-12 and IFN-γ mRNA levels in brain tissue from a murine model of MS (67). In a mouse model of MS, treatment with anti-CD19 CAR-T cells resulted in the elimination of meningeal B cell aggregates and exacerbated clinical disease; however, in another B-cell-dependent MS model, anti-CD19 CAR-T cells effectively depleted B cells in both peripheral tissues and the central nervous system (CNS), leading to a reduction in clinical scores and lymphocyte infiltration (68, 69). These contrasting findings in two MS models highlight the diverse autoimmune mechanisms that drive tissue pathology, emphasizing the importance of careful model selection aligned with the primary objectives of the study when evaluating CAR-T therapies (70).

Anti-N-methyl-d-aspartate receptor chimeric autoantibody receptor (NMDAR-CAAR) T cells, which consist of an extracellular multi-subunit NMDAR autoantigen and intracellular 4-1BB/CD3ζ signaling domains, effectively depleted engineered B cells expressing an NMDAR-reactive antibody, resulting in a reduction of serum and brain autoantibodies, with no evidence of off-target toxicity or adverse events (71). X-C motif chemokine receptor 1-specific chimeric antigen receptor T cells (XCR1-CAR-T) and CAR-Tregs led to the depletion of DC1, modestly suppressing the onset of Th1-driven experimental autoimmune encephalomyelitis (72).

Primary biliary cholangitis is characterized by an autoreactive T cell response targeting intrahepatic small bile ducts. CD8+ tissue-resident memory T cells induce apoptosis of bile duct epithelial cells and upregulate PD-1 expression. Treatment of DKO mice with PD-1 CAR-T cells selectively depleted liver CD8+ tissue-resident memory T cells and alleviated autoimmune cholangitis (73).

Graves’ disease (GD) is caused by stimulating antibodies that target the thyroid-stimulating hormone receptor (TSHR), referred to as TSH receptor antibodies (TRAb). TSHR-CAR-T was constructed by incorporating the first extracellular domain (21-413aa) of TSHR, fused with the CD8 transmembrane and intracellular signaling domain (4-1BB), which can recognize and effectively eliminate TRAb-producing B lymphocytes both in vitro and in vivo ( 74).

First-generation CD3-ζ-CAR T cells, expressing the β2-microglobulin component of MHC I and targeting the anti-InsB15-23-H-2Kd TCR, significantly reduced insulitis and protected non-obese diabetic (NOD) mice from T1DM (75). Another first-generation CAR cytotoxic T lymphocytes, equipped with five modules targeting clonotypic TCRs expressed by CD4+ T cells, could eliminate pathogenic CD4+ T cells, neutralize their impact on T1DM, and reduce insulitis in the pancreas of treated NOD mice (76). Two types of CD28-CAR Tregs targeting the human pancreatic endocrine marker Hpi2 demonstrated no immunologic function against the Hpi2 antigen in vitro, due to the broad expression of the Hpi2 antigen across multiple cell types. This underscores the importance of careful selection of the CAR recognition target (77). None of the 287 NOD mice treated with second-generation CD28-CAR and 4-1BB-CAR CD8+ T cells targeting the I-Ag7-B:9-23(R3) complex developed T1DM before 18 weeks of age; however, protection declined over time, indicating that these CAR-T cells can only delay, but not prevent, the development of T1D (78). The second-generation CD28-CAR Tregs targeting soluble insulin were unable to prevent T1DM development in NOD mice but remained present even after four months (79). Another second-generation CD28-CAR Tregs targeting the insulin B-chain 10-23 peptide MHC complex were constructed and co-transferred, preventing adoptive transfer diabetes induced by BDC2.5 T cells in immunodeficient NOD mice. Additionally, these Tregs prevented spontaneous diabetes in WT NOD mice (80). The use of InsB-g7 CAR Tregs for the reversal of autoimmune diabetes following islet transplantation may be more amenable to clinical translation than disease prevention.

As 20% to 30% of patients receiving factor VIII (FVIII) gene therapy (F8) produce neutralizing anti-FVIII antibodies, an engineered B-cell antibody receptor (BAR) targeting the immunodominant FVIII domains (A2 and C2) was developed. This receptor could effectively eliminate FVIII-reactive B-cell hybridomas both in vitro and In vivo, significantly reducing anti-FVIII antibody formation in hemophilic mice (81).

Allergic airway inflammation is characterized by airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergens. Carcinoembryonic antigen (CEA), which is expressed on the surface of adenoepitheliomas in the lung and gastrointestinal tract, was targeted by the development of an anti-CEA chimeric antigen receptor (CAR). Subsequently, CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25− effector T cells (Teffs) expressing the anti-CEA CAR were isolated from the spleens of anti-CEA CAR-transgenic (CARtg) mice (82). The targeted CD4+CD25+ regulatory T cells (Tregs) significantly reduced airway hyper-reactivity, airway eosinophilia, mucus hypersecretion, Th2 cytokine production, and allergen-specific IgE after sensitization with a model allergen. Furthermore, they efficiently suppressed the proliferation of CAR-expressing effector T cells (Teffs) in vitro, either upon stimulation through their T cell receptor (TCR) or via CAR binding to the cognate antigen (82). Given that IgE is a key mediator of allergic responses, IgE-expressing cells can be targeted by T cells through the recognition of the transmembrane form of IgE (mIgE), via the extracellular domain of the high-affinity IgE receptor, FϵRIα. Low-affinity FcϵRIα-based CARs are capable of mediating potent and specific T cell responses against mIgE-expressing target cells, even in the presence of secreted IgE (83). Type 2-high asthma, characterized by IL-5-driven eosinophilia, prompted the development of long-lived CAR T cells engineered with IL-5 as the targeting domain. These cells deplete BCOR and ZC3H12A, leading to sustained repression of lung inflammation and alleviation of asthmatic symptoms in asthma models (84).

Excessive cardiac fibrosis is associated with various forms of cardiac disease and heart failure; however, limited clinical interventions are available to address cardiac fibrosis. Adoptive transfer of T cells expressing CARs targeting fibroblast activation protein (FAP), an endogenous marker of cardiac fibroblasts, results in a significant reduction in cardiac fibrosis and the restoration of function after injury in mice (85). Transient antifibrotic CAR-T cells were generated In vivo by delivering modified messenger RNA (mRNA) encapsulated in T cell–targeted lipid nanoparticles (LNPs). Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury, highlighting the promising potential of In vivo generation of CAR T cells as a therapeutic platform for treating various diseases (86).

T cells were genetically engineered to express a MuSK chimeric autoantibody receptor (MuSK-CAART) containing CD137-CD3ζ signaling domains, which demonstrated comparable efficacy to anti-CD19 chimeric antigen receptor T cells in depleting anti-MuSK B cells and retained cytolytic activity even in the presence of soluble anti-MuSK antibodies (87).

A chimeric autoantigen-toxin molecule, consisting of the immunoreactive portion of the extracellular domain of desmoglein 3 and Pseudomonas exotoxin, was constructed to specifically recognize and eliminate autoimmune B cells in pemphigus vulgaris (PV). The chimeric molecules have been shown to bind and partially kill B cell hybridomas producing anti-desmoglein 3 monoclonal antibodies. They can also partially eliminate antigen-specific B cells from the spleens of mice immunized with desmoglein 3 (88). A CAAR, consisting of the PV autoantigen desmoglein (Dsg) 3 fused to CD137-CD3z signaling domains, exhibited specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro. It also expanded, persisted, and specifically eliminated Dsg3-specific B cells In vivo (89). DSG3 CAAR-T cells selectively kill DSG3-reactive B cells while sparing non-affected B cells, and they do not affect keratinocytes either in vitro or in vivo.

In the Fra-2 transgenic (Tg) mouse model, depleting circulating B cells with anti-CD20 mAb infusion three days before CAR-T cell injection resulted in deeper B-cell depletion in both peripheral blood and lesional lungs compared to anti-CD20 mAb alone. However, CAR-T cell infusion significantly increased lung collagen content, histological fibrosis scores, and right ventricular systolic pressure, while also worsening clinical outcomes and increasing mortality in Fra-2 Tg mice (90). While anti-CD20 mAb pre-treatment may enhance CAR-T cell engraftment and persistence (91), it could also lead to unpredictable adverse effects. The persistence and accumulation of CD19-targeted CAR-T cells in lesional lung tissue may be exacerbated by severe lung inflammation. Given the extensive lung involvement in the Fra-2 model compared to murine lupus (92), these findings suggest that CD19-targeted CAR-T cells may not be suitable for initial use in SSc patients with a high lung inflammatory burden.

Dysregulated B-cell activation drives IgG4-related disease (IgG4-RD). In a LatY136F knock-in mouse model, CD19-targeted CAR-T cell infusion depleted B-cells and reduced CD138+ plasma cells, with CD28 co-stimulatory domain CAR-T cells showing greater efficacy than 4-1BB CAR-T cells. Importantly, CAR-T cells derived from IgG4-RD patients demonstrated effective in vitro functionality, highlighting their potential for clinical application (93).

Given that carcinoembryonic antigen (CEA) is overexpressed in both human colitis and colorectal cancer, CEA-specific CAR regulatory T cells (Tregs) were developed. These cells suppress the severity of colitis in the T-cell-transfer colitis model and reduce the subsequent colorectal tumor burden in the azoxymethane–dextran sodium sulfate model for colitis-associated colorectal cancer (94).

CAR-T therapy for lymphoma has shown dual benefits, improving both lymphoma and concurrent SLE or anti-phospholipid syndrome (95, 96). Two studies have demonstrated the therapeutic potential of CD19 CAR-T cell therapy in patients with concurrent SLE and lymphoma. A 41-year-old female with a 20-year history of SLE, recently diagnosed with stage IV diffuse large B-cell lymphoma, who received BCMA-CD19 compound CAR-T cells, exhibited reductions in nuclear, cytoplasmic, and granular ANA and total immunoglobulin levels, achieving remission of both SLE and lymphoma (97). Furthermore, fifty-eight patients with concurrent B-cell non-Hodgkin lymphoma and IMIDs who received CD19 CAR-T cell therapy showed significant reductions in inflammatory markers, seronegative conversion of autoantibodies, and a decrease in the use of steroids and disease-modifying anti-rheumatic drugs (98).

A case series with follow-up of eight SLE patients has raised cautious optimism for anti-CD19 CAR-T cell therapy in SLE, particularly regarding deep B-cell depletion, disease remission, seroconversion, cytokine modulation, refractory immune thrombocytopenia, reactivity profiles, GMP-grade preparation, and safety (9, 10, 99–104). In contrast to adult SLE, anti-CD19 CAR-T cell therapy also rescued pediatric SLE patients with/without lupus nephritis (LN) (105–107). More importantly, a Phase 1 study of BCMA and CD19-directed compound CAR-T therapy demonstrated the ability to simultaneously reset the humoral and B-cell immune systems and deplete disease-causing autoantibodies derived from B cells and long-lived plasma cells in patients with SLE/LN (108). CNS involvement, including encephalitis and transverse myelitis, is a severe manifestation of SLE. Notably, a 21-year-old man with SLE and progressive transverse myelitis showed improved neurological function, muscular strength, and regression of MRI lesions after treatment with a second-generation CAR T-cell therapy (CD19 binder and 4-1BB co-stimulation), along with decreased CSF protein (109). Increasing evidence indicates that plasmacytoid dendritic cells (pDCs) play a significant role in the development of IMIDs, primarily through the overproduction of proinflammatory cytokines (110). Two Phase 2 trials have suggested that the elimination of pDCs is beneficial in improving both systemic and cutaneous lupus erythematosus (111, 112). A preliminary study demonstrated the feasibility of producing CD123-targeted CAR-T cells from the T cells of patients with IMIDs, as well as their in vitro cytotoxicity against circulating autologous pDCs (113).

The current treatment for antiphospholipid syndrome (APS) involves indefinite anticoagulation with vitamin K antagonists to prevent thrombotic recurrence, with no curative option to permanently eradicate antiphospholipid antibodies (aPL). However, a patient with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and a nearly 30-year history of APS achieved DLBCL remission, as assessed by PET-CT, and normalization of anticardiolipin antibodies at 1-year follow-up after CAR T-cell treatment (96). Another 65-year-old woman with SLE, APS (triple aPL positivity), and DLBCL achieved ongoing complete remission of DLBCL after anti-CD19 CAR T-cell treatment, along with seroconversion of lupus anticoagulant, anti-cardiolipin, and anti-beta2 glycoprotein I antibodies (114). Both cases suggest a promising role for targeted cell therapy in treating pro-thrombotic autoimmune disorders.

Several adult cases of CD19 CAR-T cell therapy in Anti-synthetase syndrome have demonstrated resolution of muscle, lung, and skin inflammation, despite prior failure of two B-cell-depleting antibodies, suggesting that the depth of B-cell depletion is significantly greater with CAR-T cell-based therapy than with antibody-based B-cell depletion (10, 115–117). A satisfactory response to anti-CD19 CAR-T cell therapy has recently been reported in a 12-year-old caucasian boy with refractory juvenile dermatomyositis, which was resistant to multiple lines of immunosuppressive treatment, including B-cell depletion with rituximab (118).

There are no FDA-approved therapies for the immune-mediated necrotizing myopathy (IMNM) subtype of idiopathic inflammatory myopathy. The first IMNM patient in the RESET-Myositis™ phase I/II trial (NCT06154252) treated with fully human 4-1BBz anti-CD19 CAR T-cell therapy (CABA-201) showed decreased CK levels, improved muscular strength, depleted peripheral B-cells, and a reduction in autoantibodies to baseline (119). Additionally, a patient with anti-signal recognition particle IMNM, refractory to multiple available therapies, who was treated with BCMA-CAR-T cells, demonstrated a favorable safety profile, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 months (57). Encouragingly, treatment with genetically engineered, healthy donor-derived CD19-targeted CAR-T cells (TyU19) alleviated severe skeletal muscle damage in a patient with refractory IMNM and reversed extensive fibrotic damage to critical organs in two patients with diffuse cutaneous systemic sclerosis (120).

The first promising experience with CD19-targeted CAR-T cells in diffuse cutaneous systemic sclerosis (SSc) was reported in a 60-year-old man, who exhibited rapid improvement in heart function, as assessed by 68Ga-FAPI-04 PET-CT, joint health from MRI, and skin fibrosis, alongside seroconversion of antinuclear antibody (ANA) and anti-RNA polymerase III autoantibodies, as well as stable lung function parameters (121). A 38-year-old woman with Scl70+ systemic sclerosis (SSc) and rapidly progressive non-specific interstitial pneumonia, treated with third-generation CD19 CAR-T cells, showed sustained amelioration of lung function and dramatic regression of imaging findings, including the disappearance of Fcγ-receptor-activating immune complexes (122). Four additional patients with SSc, treated with CD19 CAR-T therapy, did not exhibit disappearance of anti-Scl70 antibodies, and their EUSTAR activity index did not regress to negative levels (10). The absence of anti-Scl70 antibody seroconversion, along with reduced EUSTAR activity in all affected organs, suggests that prolonged CAR-T cell persistence may promote seroconversion, potentially leading to extended B-cell depletion, impaired vaccination responses, and an immunocompromised state (123). Therefore, the benefit-risk balance of pretreatment, CAR-T cell persistence and the duration of B-cell depletion must be carefully evaluated. Encouragingly, the same research group recently confirmed that CD19-targeting CAR T-cell therapy may prevent the progression of fibrotic and vascular organ manifestations in SSc patients (124).

Universal anti-fluorescein isothiocyanate (FITC) CAR-T cells, in combination with FITC-labelled citrullinated peptides, have been shown to specifically redirect and eliminate hybridoma cells and autoreactive B cell subsets from RA patients by specifically recognizing FITC-labelled citrullinated peptide epitopes. The cytotoxicity of these CAR-T cells was strictly dependent on the presence of the peptides in a dose-dependent manner (125). Several cases of RA with coexisting myasthenia gravis, SSc, Sjogren’s syndrome, and DLBCL demonstrated that CD19-directed CAR T-cell therapy not only achieved stable clinical remission but also led to seroconversion of anticitrullinated protein antibody (ACPA), indicating the eradication of ACPA-specific plasma cells (126–129). Notably, in three patients with difficult-to-treat RA, fourth-generation CD19-targeted CAR T-cells (CD19/aIL-6/aTNFα) improved symptoms, reduced effusion, synovitis, osteitis, and tendinitis (via ultrasound and MRI), and induced seroconversion of rheumatoid factor and anti-CCP antibodies (130). This study presents a novel therapeutic approach that combines TNF and IL-6 inhibition with B-cell depletion in a single CAR T-cell platform, enhancing RA treatment efficacy while also mitigating CRS.

A first-in-human trial provided preliminary evidence of the efficacy of DSG3-CAART in patients with active anti-DSG3 mucosal PV. This therapy specifically lyses human anti-DSG3 B cells, decreases target cell burden, reduces serum and tissue-bound autoantibodies, and enhances DSG3-CAART engraftment (131).

Two patients with progressive MS who received CD19 CAR-T cell therapy (KYV-101) showed CAR-T cell presence and expansion in the cerebrospinal fluid, without neurotoxicity, alongside a reduction in intrathecal antibodies in one patient (132). The FDA has granted Fast Track Designation to the autologous, fully human CD19 CAR-T cell product candidate, KYV-101, for the treatment of patients with refractory progressive MS (133).

A first-in-human clinical study of CT103A indicated that BCMA CAR T-cell therapy resulted in improvements in disability and quality of life outcomes, a reduction in AQP-4 antibodies, and a manageable safety profile in patients with relapsed or refractory AQP4-IgG seropositive neuromyelitis NMOSD (134).

In contrast to the conventional DNA-based approach, autologous BCMA RNA chimeric antigen receptor T cells (BCMA rCAR-T), as exemplified in the Descartes-08 trial, resulted in clinically meaningful reductions in all measures of myasthenia gravis severity, including the induction of minimal symptom expression and the elimination of dependence on intravenous immunoglobulin infusions in adults with generalized myasthenia gravis (NCT04146051) (135). A 33-year-old woman with anti-acetylcholine receptor (anti-AChR)-positive generalized myasthenia gravis received a second-generation anti-CD19 CAR T construct (KYV-101), resulting in a 70% reduction in pathogenic anti-AChR antibodies and the maintenance of protective vaccination IgG titers, which paralleled an improvement in the patient’s muscle strength and reduction in fatigue (136).

Two patients with highly relapsed and refractory myasthenia gravis—one with AChR-IgG and the other with MuSK-IgG—treated with BCMA CAR-T, resulting in B cell lineage reconstitution, exhibited favorable safety profiles and sustained clinical improvements (58). The safe administration of anti-CD19 CAR T cells in two women with concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome resulted in profound B cell depletion and normalization of acetylcholine receptor and voltage-gated calcium channel N-type autoantibody levels, which paralleled significant neurological responses (137).

A 69-year-old female with a 9-year history of treatment-refractory stiff-person syndrome, characterized by deteriorating episodes of stiffness, received an infusion of autologous anti-CD19 CAR T cells (KYV-101), resulting in a reduction of GABAergic medication, as well as improvements in leg stiffness, gait, walking speed, and daily walking distance (138).

In a 52-year-old male patient with severe, therapy-refractory proteinase-3 (PR3)- AAV, anti-CD19 CAR T-cell therapy induced both clinical remission and seroconversion of PR3-ANCA (139). Initial bone marrow biopsies, taken post-rituximab and before anti-CD19 CAR T-cell therapy, showed CD19⁺/CD20^- B cells, including plasma cells in bone marrow. However, a second biopsy after CAR T-cell therapy revealed CAR T cells and the absence of CD19+ B cells or CD19^low plasma cells in bone marrow, while CD138⁺/CD19^- plasma cells persisted. These findings confirm limited ability of rituximab to eliminate tissue-resident B cells in primary and secondary lymphoid organs and highlight effective B-cell depletion in the bone marrow following anti-CD19 CAR T-cell therapy.

There are two cases of IBD-like colitis following CAR T cell therapy for lymphoma have been reported, highlighting the need for close monitoring of lower gastrointestinal symptoms in patients undergoing CAR T-cell therapy (140, 141). More importantly, additional data is required to validate the effectiveness and safety of CAR-T therapy in patients with IBD.

As cytopenia and hypogammaglobulinemia are potential side effects of CAR T-cell therapy, infection has become an increasingly recognized complication, arising from both host-related factors and CAR T-associated factors (142). Like hematological malignancies, patients with IMIDs undergoing CAR T-cell therapy typically have relapsed/refractory disease with a history of multiple treatments, can lead to immune exhaustion, decreased bone marrow reserve with preexisting cytopenia, and delays in post-treatment immune recovery (143). Compared to patients undergoing stem cell therapy, post-CAR T-cell immune reconstitution is less well understood. Research on infection and immune recovery after CAR T-cell therapy is essential for developing effective prophylactic and treatment strategies for these patients (144). Hypogammaglobulinemia occurs in most patients after CAR T-cell therapy, requiring enhanced immunologic monitoring to identify those at high risk for severe infections and mortality who may benefit from immunoglobulin replacement (145).

Two toxic effects of CAR T-cell therapy are of particular concern: cytokine release syndrome, which is mediated by CAR T-cell activation upon target cell engagement and the release of proinflammatory mediators such as IL-6, and neurotoxicity syndrome, which involves endothelial activation and disruption of the blood–brain barrier (146). Cytokine release syndrome rates in cancer range from 42% to 93% across all therapeutic cell products (146), however, in IMIDs, the occurrence was minimal, with no high-grade or prolonged bone marrow toxicity observed (10). More importantly, the key risk factor for both toxic effects in tumors is a high target cell burden, which is not present in IMIDs.

Although FDA adds boxed warning of secondary cancer to CAR T-cell therapies in hematologic malignancy, there is no solid evidence to support a higher risk of secondary cancer among IMID patients treated with CAR T than those treated with other therapies. A retrospective comparative cohort study showed a comparable safety profile of CAR T-cell therapy for cancer patients with and without pre-existing autoimmune or inflammatory disease (147). Notably, the DESCAR-T registry indicates a very low risk of T cell malignancy in patients with hematologic malignancies following CAR T-cell therapy, and integration site analysis suggests that the therapy may have contributed to the development of secondary T cell malignancy (148). Alternative factors, including prior multiple lines of treatment, immune dysfunction and clonal hematopoiesis of underlying disease, likely play a greater role than insertional mutagenesis in predisposing CAR-T-treated patients to secondary hematologic malignancies (148). Although the benefits of CAR T-cell therapy for IMID outweigh the risks, vigilant monitoring for secondary cancer remains essential.