CAR-T cell therapy: A new dawn in the treatment of autoimmune disease

Abstract

Autoimmune diseases (AIDs) are a class of diseases caused by autoimmune intolerance, which can be divided into systemic and organ-specific diseases. AIDs affect approximately 10% of the global population and rank among the leading causes of disability and mortality. At present, immunosuppressive agents are the first choice for the treatment of AIDs. B-cell-targeted therapies—particularly CD20 monoclonal antibodies—have brought new hope for systemic AIDs, yet a subset of patients still respond poorly. As a rapidly developing cellular immunotherapy technology, Chimeric antigen receptor T cell (CAR-T) plays an important role in the treatment of hematological malignancies. CAR-T targeting B-cell-specific antigens can rapidly deplete circulating B cells, thereby reducing the formation of autoantibodies, which has become the basis for research on CAR-T in the treatment of autoimmune diseases. Currently, many studies are underway, and CAR-T and its derivative therapies bring new hope for the treatment of autoimmune diseases.

Introduction

Autoimmune diseases (AIDs), including systemic lupus erythematosus (SLE), anti-synthetase syndrome (ASS), systemic sclerosis (SSc), and multiple sclerosis (MS), are triggered by abnormal adaptive immunity and have various clinical manifestations. In these patients, immune intolerance to antigens leads to the formation of autoreactive T and B cells, which attack their own organs^1,2 (Fig. 1). Additionally, AIDs are associated with inadequate negative regulation of abnormal immune responses by regulatory T cells (Tregs) ³ . AIDs affect approximately 10% of the global population and rank among the leading causes of disability and mortality. A substantial proportion of patients present with severe, complex, and rapidly progressive disease for which curative therapies are lacking, representing a long-standing clinical challenge ⁴ . AID can be classified into systemic and organ-specific according to their cumulative range. Examples of systemic AIDs include SLE, SSc, Sjögren Syndrome (SS), and rheumatoid arthritis (RA). Common organ-specific AIDs include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalomyelitis (AE), and autoimmune cholangitis ⁵ .

Figure 1.

The key role of B cells in the pathogenesis of AIDs. Overactivated B cells produce a variety of autoantibodies by differentiating into plasma cells, while also activating other immune cells to attack own normal tissues.

Immunosuppressants, including corticosteroids and disease-modifying anti-rheumatic drugs, are commonly used to treat AIDs. They suppress the immune system by inhibiting the inflammatory cascade, reducing disease severity, and slowing its progression; however, they do not cure the disease ⁶ . Given the critical role of B cells in the development of AIDs, B cell depletion may be a potential cure. Monoclonal antibodies and antibody-drug conjugates targeting B cell surface antigens are also currently used in AID therapy but have shown limited efficacy ⁷ .

Conventional autologous hematopoietic stem cell transplantation (ASCT) relies on high-dose chemotherapy ± total-body irradiation to eradicate aberrantly activated autoreactive T and B lymphocytes and force an immune-system “reset.” The reconstructed immune system may restore tolerance to autoantigens, thereby reducing or terminating autoimmune responses. ASCT may induce long-term remission or even functional cure in various refractory diseases. However, its substantial treatment-related toxicity—encompassing transplant-related mortality, severe infections, and disease relapse—coupled with rigorous patient-selection criteria, confines ASCT to a narrow, carefully chosen population ⁸ . Chimeric antigen receptor T cells (CAR-T) were first used for the treatment of hematological malignancies. In vitro gene editing technology enables CAR-T cells to express chimeric antigen receptors (CAR). After in vivo infusion, these CAR-T cells specifically recognize target antigens and rapidly proliferate to exert antitumor effects (Fig. 2), making them an important treatment option for B cell malignancies at this stage ⁹ . To date, several CAR-T cell therapies have been approved for marketing, including Tisagenlecleucel, Axicabtagene ciloleucel, Brexucabtagene autoleucel, Obecabtagene autoleucel, and Lisocabtagene maraleucel for B-cell acute lymphoblastic leukemia and lymphomas, as well as Idecabtagene vicleucel and Ciltacabtagene autoleucel for multiple myeloma. Previous studies have shown that CAR-T targeting B cell-specific surface antigens such as CD19 and CD20 can induce rapid and sustained depletion of circulating B cells to relieve AIDs, showing unique advantages in the treatment of AIDs ² , and even offers the possibility of a cure for these diseases ¹⁰ . At the same time, given the burden of chronic infectious diseases, the mortality and morbidity of infections in immunocompromised individuals, and the emergence of multidrug-resistant pathogens, CAR-T cell therapy has also begun to show therapeutic promise in chronic infectious diseases, particularly acquired immunodeficiency syndrome (AIDS) ¹¹ . However, CAR-T cell therapy inevitably faces adverse treatment effects such as immunosuppression, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and organ function damage. Therefore, it is necessary to fully assess the risks and benefits of treatment before initiation. In summary, this review focuses on the application of CAR-T and its derived therapies as cellular immunotherapy technologies for AIDs and summarizes the existing research progress.

Figure 2.

Procession of CAR-T therapy. The first step of CAR-T therapy is to collect patient’s T cells through leukapheresis, and then modify the T cells to convert to CAR-T in vitro. Prior to reinfusion of CAR-T, patient needs to undergo preconditioning, namely chemotherapy, to remove lymphocytes.

Abbreviations: CAR, chimeric antigen receptor; CAR-T cells, chimeric antigen receptor T cells; Flu/Cy, fludarabine/cyclophosphamide.

Application of CAR-T in systematic AID

SLE

SLE is a chronic AID common in women of childbearing age. It often involves multiple organs and systems, leading to symptoms such as fatigue, joint pain, light sensitivity, and rash. Lupus nephritis is also one of its most common manifestations. Corticosteroids, immunosuppressants, and biological agents are commonly used therapeutic drugs; however, many patients remain refractory to these therapies ¹² . SLE was one of the earliest AIDs used in CAR-T research.

Kretschmann et al. successfully isolated a sufficient number of T cells for CAR-T production from patients with SLE and prepared CD19-targeted CAR-T cells using a lentivirus. In in vitro experiments, these CAR-T cells showed a high amplification rate and activity, specifically lysing the target CD19-positive cells, but had no lytic effect on CD19-negative cells ¹³ . In a study by Dingfelder et al. ¹⁴ , CAR-T cells prepared from T cells isolated from the lymphocytes of patients with SLE showed CAR-mediated CD19-dependent killing effects on autologous primary B cells and, at the same time, led to a decrease in inflammatory cytokine production. Wilson et al. ¹⁵ found that the depletion of activated B cells expressing B cell mature antigen (BCMA) by CAR-T cells based on TNFSF13 could significantly prolong the lifespan of mice with severe SLE. Jin et al. found that anti-CD19 CAR-T cell therapy showed a more persistent B cell depletion effect in MRL-lpr mice (a spontaneous mouse SLE model with severe lupus nephritis) compared to antibody therapy. The transfusion of homologous anti-CD19 CAR-T cells not only prevents the onset of disease before the onset of symptoms but also shows therapeutic effects in the later stages of disease progression ¹⁶ . The success of these preclinical experiments confirmed the feasibility of using anti-CD19 CAR-T cells to treat SLE and provided experimental support for the application of CD19-targeted CAR-T therapy in SLE.

Mackensen et al. conducted a study in which five patients with refractory active SLE received CD19-targeted CAR-T cell therapy. With the expansion of CAR-T cells in vivo, the patients experienced relief of clinical symptoms and normalization of laboratory indicators, with a median lupus activity index of 0 and seroconversion of anti-double-stranded DNA (anti-dsDNA) antibodies. All patients achieved remission after 3 months (including glucocorticoids and immunosuppressants), and the CAR-T therapy was well-tolerated. Only 3 patients developed grade 1 CRS, and no ICANS occurred Long-term follow-up showed that the B cells reconstructed after CAR-T treatment were naïve B cells, indicating a non-cell-transformed B cell receptor ¹⁷ . The results of this study confirm the feasibility and safety of CD19-targeted CAR-T in SLE, warranting studies with longer follow-up and larger sample sizes. In the recent data published by Müller et al., eight patients with SLE achieved a symptom-free disease state within 6 months after receiving CD19-targeted CAR-T therapy. A 29-month follow-up showed sustained remission. Additionally, the anti-dsDNA antibody disappeared and remained negative; complement factor C3 levels normalized, proteinuria disappeared, and all patients stopped immunosuppressants ¹⁸ . This study provides data supporting the CAR-T cell-based treatment of SLE. Nunez et al. performed a serological analysis of patients with SLE after CD19-targeted CAR-T cell infusion. The results showed that serum levels of inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, and IL-10, were decreased in six patients at 3 months after infusion. As B cells secrete these cytokines, this finding may be related to CAR-T-mediated B cell depletion. Five patients showed a significant decrease in SLE-related antibodies ¹⁹ . As CAR-T cells consume B cells expressing CD19 during treatment, the humoral immunity of the patients was suppressed, and the production of autoantibodies was reduced or even completely stopped to achieve disease control and finally drug-free remission.

Taubmann et al. described a 32-year-old woman diagnosed with SLE at 33 weeks’ gestation. Despite treatment with glucocorticoids and hydroxychloroquine, she developed lupus nephritis after delivery. After failing to respond to multiple drug treatments, the patient received CD19-targeted CAR-T therapy based on her refractory disease status. Subsequently, SLE activity rapidly improved, and the symptoms disappeared within the first week of treatment. Disease remission was achieved after 3 months with anti-dsDNA antibodies testing negative. At the 9-month follow-up post-CAR-T cell infusion, the patient remained in drug-free remission ²⁰ . The case report by Krickau et al. described a patient with severe and rapidly progressing SLE. The patient developed grade 4 lupus nephritis after a dramatic deterioration in renal function 6 months after disease onset. The patient eventually received CD19-targeted CAR-T cell therapy. Subsequently, the patient experienced a rapid decline in SLE activity, resolution of arthritis symptoms, normalization of complement C3 and C4 levels, and disappearance of all autoantibodies. The patient’s renal function also improved, and despite residual protein loss, serum albumin levels returned to normal. There were no clinical signs of edema, and urine analysis showed no nephritis ²¹ . Mougiakakos et al. also used CD19-targeted CAR-T cells to treat a patient with severe refractory active SLE who presented with lupus nephritis. After infusion, the patient achieved serological and clinical remission, a decreased SLE activity index, and control of lupus nephritis ²² . The treatment results in these cases show that anti-CD19 CAR-T therapy can control disease activity in patients with SLE presenting with lupus nephritis, achieve clinical and serological remission of the disease, and ultimately free these patients from hemodialysis and long-term dependence on drugs.

BCMA is another commonly used target in CAR-T cell therapy for hematologic malignancies, particularly multiple myeloma, and current research is also confirming its feasibility as a target for CAR-T cell therapy in AIDs. Hu et al. treated seven patients with lupus nephritis using BCMA CAR-T cells. Except for one patient, peripheral B cells were efficiently depleted within the first month and rebounded by 3 months. The clinical symptoms and laboratory indicators of all patients improved significantly, with five patients achieving complete drug-free remission. However, the urinary protein levels in two patients did not drop below the normal upper limit. No patients experienced ICANS or severe infection, and only one patient developed grade 1 CRS. Additionally, the patients’ immunoglobulin levels and autoantibody titers decreased significantly, while complement levels increased, suggesting that the treatment primarily affected short-lived CD19+ plasma cells or antibody-secreting cells. Post-treatment, the patients’ 24-hour urinary protein and protein-to-creatinine ratios significantly decreased, but changes in glomerular filtration rate were limited. Repeated kidney biopsies showed a significant reduction in immune complex deposition in the renal tissue, with improved disease status, further confirming the effectiveness of BCMA-targeted CAR-T cell therapy in alleviating renal pathological damage ²³ . These findings provide strong evidence for the application of BCMA-targeted CAR-T cell therapy in the treatment of lupus nephritis and offer important references for future research and clinical practice.

Dual-targeted CAR-T cells also exhibit advantages in the treatment of SLE. Wang et al. developed a BCMA-CD19 compound, CAR T cells (cCAR), which targets both CD19 and BCMA on the surface of B cells. In subsequent clinical trials of cCAR for SLE or lupus nephritis (NCT04162353 and NCT05474885), all 13 patients achieved peripheral blood B cell depletion within 1–10 days after cCAR infusion, and 3–6 months later, 12 out of the 13 patients met the Lupus Low Disease Activity State (LLDAS) criteria and were negative for autoantibodies. Symptoms disappeared in patients with simple SLE, and drug-free remission was achieved. In patients with lupus nephritis, renal function improved after cCAR treatment, disease progression stopped, and partial renal damage was reversed ²⁴ . Feng et al. reported that CD19 and BCMA targeted CAR-T cells induced rapid and deep remission. Twelve patients with active and severe SLE were treated with CD19and BCMA CAR-T cells. After a median follow-up of 118.5 (45-524) days, all patients had decreased disease activity scores and successfully discontinued SLE-related drugs, whereas peripheral B cells recovered approximately 3 months after CAR-T infusion and no patient relapsed during the follow-up period. All patients developed Grade 1 CRS, with no occurrence of ICANS ²⁵ . The safety and efficacy of the dual-targeted CAR-T cells in severe and refractory SLE represent an important future direction for SLE treatment. Currently, several clinical trials for dual target CAR-T cells are in progress, including NCT05858684, NCT05474885, and NCT06350110. Further improvement of SLE treatment is expected in the future.

SLE was one of the first AIDs to be associated with CAR-T therapy, and current preclinical experiments and clinical trials have achieved great success, bringing hope for patients with SLE and lupus nephritis (Table 1). However, currently published data involve small sample sizes and short follow-up periods, indicating that there is still a long way to go to understand the potential of CAR-T cells in SLE treatment.

Table 1.

Preclinical and clinical progress of CAR-T therapy in SLE.

Phase	Study/trial	Target	Model/subjects	Outcomes
Preclinical study	Kretschmann et al.	CD19	T cells from SLE patients	Successfully generated CD19 CAR-T with high expansion and specific lysis of CD19⁺ cells; no off-target effect.
	Dingfelder et al.	CD19	Autologous primary B cells from SLE patients	CAR-T mediated CD19 dependent B cell killing and reduced inflammatory cytokine secretion.
	Wilson et al.	BCMA	Severe SLE mouse model	BCMA CAR-T depleted activated B cells and significantly prolonged survival.
	Jin et al.	CD19	MRL-lpr mice (spontaneous lupus nephritis model)	Anti-CD19 CAR-T achieved more persistent B-cell depletion than antibody therapy; prevented disease onset and reversed established disease.
Clinical trail	Mackensen et al.	CD19	5 refractory active SLE patients	All achieved drug-free remission within 3 months. B cells reconstituted with a naïve phenotype, and only three cases of grade 1 CRS occurred.
	Müller et al.	CD19	8 SLE patients	Symptoms disappear within 6 months, anti dsDNA remained negative, C3 normalized, proteinuria disappears, and sustained drug-free remission
	Hu et al.	BCMA	7 lupus-nephritis patients	5 patients achieved complete drug free remission, reduced renal tissue immune complexes, decreased proteinuria, and no ICANS/severe infection.
	Wang et al.	CD19+BCMA	13 SLE/ lupus nephritis patients	12/13 achieved LLDAS criteria with negative autoantibodies, partial renal function reversal in nephritis patients, and no ICANS
	Feng et al.	CD19+BCMA	12 severe active SLE	All patients achieved drug-free remission, with B-cell reconstitution within 3 months, no relapse, and only grade 1 CRS.

Abbreviations: BCMA, B cell mature antigen; CAR-T, chimeric antigen receptor T cell; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; LLDAS, lupus low disease activity state; SLE, systemic lupus erythematosus.

AIDS

AIDS is a systemic immune system failure disease caused by human immunodeficiency virus (HIV) infection. Even though antiretroviral therapy (ART) can improve clinical outcomes in patients, it cannot eradicate the viral reservoir and patients need to take medication for life ²⁶ . Current research indicates that CAR-T cell therapy can achieve disease control by enhancing HIV specific immune responses.

CAR-T cells based on broad-spectrum neutralizing antibodies (bNAb) target HIV-1 Env protein, which is only expressed on the surface of virus producing cells. In the preliminary clinical trial, 14 patients received bNAb based CAR-T cell therapy. The results indicate that the CAR-T cell is safe and well tolerated, capable of significantly reducing viral reservoirs and delaying virus rebound after antiretroviral therapy interruption. Although the virus eventually rebounds, the rebound time is significantly prolonged compared to historical controls ²⁷ . Mi et al. developed a CAR-T cell strategy that can specifically recognize and kill HIV-1 infected cells by combining fluorescein isothiocyanate (FITC) labeled broad-spectrum neutralizing antibodies. FITC.CAR-T cells showed significantly enhanced cytotoxicity against HIV-1 infected cells after binding to FITC labeled bNAbs (including VRC01, 10E8, and N6), up to about 70%, and were able to effectively clear latent HIV-1 pools. In mouse models, the CAR-T cells significantly inhibited HIV-1 rebound after ART treatment interruption, reducing viral load by about 90% while maintaining the stability of CD4+T cells ²⁸ . This modular design not only provides a new strategy for the functional cure of HIV-1, but also provides a broad application prospect for the treatment of other infectious diseases and cancers.

M10 CAR-T cells are a type of tri-functional CAR-T cell with a bispecific CAR molecule, a single chain variable fragment Fc fusion antibody derived from 10E8, and a CXC chemokine receptor (CXCR) 5 receptor that promotes cell migration to the germinal center. In vitro experiments have shown that M10 CAR-T cells can simultaneously exert cytotoxic effects on HIV infected cells, neutralize free viruses, and CXCR5 mediated B cell follicular homing ability. In the subsequent phase I clinical trial, 18 HIV-1 infected patients received M10 CAR-T cell infusion. 74.3% of patients showed significant inhibition of viral rebound after treatment, with an average viral load decrease of 67.1%. Additionally, 10 patients experienced a sustained decrease in cell-related HIV-1 RNA levels during the 150 day observation period, indicating that M10 cells can significantly reduce the viral reservoir ²⁹ . This study suggests that M10 cell therapy may achieve long-term control of the virus by selectively clearing activated HIV-1 reservoirs, providing new possibilities for functional cure of HIV-1.

Maldini’s research focuses on a novel dual chimeric antigen receptor (Dual CAR) T-cell therapy aimed at reducing HIV infection by specifically targeting the HIV envelope. The research team designed dual CAR-T cells that simultaneously express both 4-1BB/CD3- Zeta and CD28/CD3- Zeta endogenous domains. This dual CAR-T cell combines the advantages of two co stimulatory signals, significantly enhancing the in vivo expansion and effector function of the cells. In bone marrow, liver, thymus humanized mouse models, dual CAR-T cells significantly reduced HIV induced CD4+T cell loss and accelerated HIV suppression in the presence of ART, reducing viral burden in tissues. In addition, by co expressing C34-CXCR4 fusion inhibitors, CAR-T cells gained HIV resistance, thereby improving cell survival and effector function ³⁰ . This study provides important insights into the development of CAR-T cell therapy for HIV infection and demonstrates a novel dual CAR-T cell product that not only alleviates HIV pathology but also has broad antiviral activity. In the future, further optimization of CAR-T cell design is needed to improve its efficacy and persistence in HIV infection, explore other methods to enhance the HIV resistance of CAR-T cells, and validate the effectiveness of Dual CAR-T cell therapy in more preclinical models and final clinical trials.

The depletion of T cells caused by chronic immune activation is an important factor affecting the persistence of CAR-T cells. Rapamycin is mainly used to inhibit transplant rejection reactions. Mu et al. found that during chronic HIV infection, low-dose and intermittent rapamycin reduced the markers of T cell depletion by improving the metabolism and transcriptome modification of CAR-T cells, and promoted the expression of stem cell related genes, thus restoring and improving the function of anti-HIV CAR-T cells, providing new insights for CAR-T cells to treat AIDS ³¹ . CAR-T cell therapy exerts selective pressure on rebounding viruses, leading to the emergence of virus escape mutations, indicating that CAR-T cells can effectively function in vivo and limit virus replication. The emergence of virus escape mutations suggests that multiple CAR-T cell combination therapies may be needed in the future to further control the disease. In addition, Carrillo et al.’s study showed that CAR-T cells prepared from peripheral blood have limited expansion and persistence, thus limiting their ability to control the virus ³² . Compared with peripheral blood, CAR-T cells derived from hematopoietic stem/progenitor cells exhibit better expansion, tissue distribution, and viral load suppression in animal models of HIV infection, making them a potential new therapeutic strategy for providing long-term immune monitoring and viral control for HIV infected patients.

Although CAR-T cell therapy has made certain progress in the treatment of AIDS, it has not yet achieved a cure for the disease and still faces issues such as viral escape and long-term viral rebound. Therefore, further in-depth research is still needed in the future.

SSc

SSc is an autoimmune connective tissue disease characterized by multiple organ involvement and skin fibrosis. Early manifestations include Raynaud’s phenomenon and occult swelling of the extremities and face, with skin thickening and hardening being the most prominent clinical feautres ³³ . In addition to producing autoantibodies, B cells can also produce a variety of profibrotic and proinflammatory factors, and interact with fibroblasts or other immune cells, thus playing a key role in the occurrence and development of SSc ³⁴ .

Bergmann et al. first reported the use of CD19-targeted CAR-T therapy to treat patients with severe refractory SSc. After CAR-T infusion, the patient achieved seroconversion and rapid improvement in heart, skin, and joint symptoms. This included improvement of signs of right ventricular strain, reduced skin fibrosis, decreased frequency of Raynaud’s phenomenon, improved wrist arthritis, and reduction of tender joints. Only grade 1 CRS was observed, with no occurrence of ICANS ³⁵ . This supports the central role of B cell-mediated autoimmunity in SSc and offers infinite possibilities for the application of CAR-T cells in SSc. Müller et al. reported their findings concerning four patients with SSc. After receiving CD19-targeted CAR-T cells, the SSc activity index scores of the four patients decreased, and all immunosuppressants were stopped ¹⁸ . Merkt et al. reported a case of SSc complicated by progressive pulmonary fibrosis. After receiving CD19-targeted CAR-T therapy, the patient’s skin fibrosis subsided; dyspnea gradually subsided; lung lesions significantly improved on imaging; and autoantibodies and C-reactive protein levels gradually normalized ³⁶ . The results of several case reports have shown the safety and feasibility of CD19-targeted CAR-T therapy in SSc, providing a precedent for subsequent large-scale clinical trials.

For the first time, Wang et al. successfully used CAR-T cells targeting CD19 (TyU19) from healthy donors to treat two patients with severe and refractory SSc. Within 2 weeks of CAR-T infusion, both patients achieved B cell depletion. During the 6-month follow-up, both patients experienced deep remission, and the clinical response index of the disease significantly improved. Simultaneously, inflammation and fibrosis reversals (including lung and skin) were observed in the patients. No adverse reactions associated with the treatment, including CRS and graft-versus-host disease (GVHD), were observed in both patients ³⁷ . TyU19, as a type of CAR-T cells with allogenic origin, utilizes CRISPR-Cas 9 technology to knock out the T cell receptor in the preparation process to treat GVHD, showcasing the great potential of universal CAR-T to treat AIDs. A clinical trial (NCT05859997) of TyU19 for AID treatment is ongoing, indicating a possibility for the wider application of TyU19. There are many related clinical trials in progress, such as NCT06328777 and NCT06414135 targeting CD19 and NCT06503224 and NCT06350110 targeting CD19/BCMA, to enhance treatment approaches for SSc.

Idiopathic inflammatory myopathies (IIMs)

IIMs are a group of autoimmune connective tissue diseases mainly affecting skeletal muscles and manifest as muscle weakness. Corticosteroids and immunosuppressants are the first-line treatments ³⁸ . Müller et al. included three patients with IIMs in their study. After receiving CD19-targeted CAR-T therapy, their muscle function normalized; extramuscular disease activity ceased; and immunosuppressants were successfully discontinued ¹⁸ . These results support the application of CD19-targeted CAR-T therapy in IIMs; however, the sample size of this study was small, warranting further exploration on a larger scale.

Immune-mediated necrotizing myositis (IMNM) is a unique and common form of IIMs, characterized by symmetrical muscle weakness, abnormally increased creatine kinase levels, muscle necrosis, and regeneration ³⁹ . Qin et al. reported a patient with IMNM who received BCMA-targeted CAR-T therapy. The patient showed good safety after receiving CAR-T cell infusion, with continuous clinical improvement for over 18 months, including decreased pathogenic autoantibodies. The results of the single-cell analysis showed that the pathways related to immune and inflammatory responses were downregulated after CAR-T infusion, normalizing the immune microenvironment in vivo, reconstructing B cell lineage, replacing T cell subsets, and inhibiting overactive immune cells ⁴⁰ . Wang et al. ³⁷ also studied a patient with refractory IMNM. After TyU19 treatment, the patient’s disease, clinical symptoms showed improvement, and imaging examinations indicated a significant improvement in edema and muscle atrophy of the thighs. Therefore, off-the-shelf allogeneic CAR-T cells may also be a future treatment option for IIMs, requiring further study for its clinical translation.

ASS is a special IIM. Müller et al. reported a case of ASS in a patient who received CD19-targeted CAR-T therapy. After CAR-T cell infusion, the patient experienced pseudo-aggravation of myalgia and increased creatine kinase levels. Researchers believe that this short-term deterioration was a result of a pseudoinflammatory state in the muscles mediated by B cell killing and CAR-T activation in vivo. Subsequently, the patient’s physical function, extramuscular disease activity, and ASS symptoms all showed significant improvement ⁴¹ . Pecher et al. also reported a case of refractory ASS, treated with rituximab and azathioprine, accompanied by progressive myositis and interstitial lung disease. After CD19-targeted CAR-T cell infusion, the patient’s clinical symptoms were quickly relieved. With the first week following CAR-T cell therapy, the patient experienced CRS. By the seventh day, the patient exhibited clinical and serological deterioration, including increased muscle pain, elevated serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. The authors hypothesize that the CAR-T-induced CRS may have activated pre-existing autoreactive T cells. Over time, the patient’s muscle and pulmonary function improved, disease-related serological markers and anti-Jo-1 antibody levels persistently decreased, and muscle magnetic resonance imaging indicated an improvement in the disease’s imaging features ⁴² . The treatment results of these two patients showed the feasibility, tolerance, and safety of CAR-T cells in the treatment of ASS. However, longer follow-ups and larger sample sizes are required to verify these findings. Currently, the results of clinical trials on IIMs, such as NCT06462144, NCT06462144, and NCT06154252, are eagerly awaited.

RA

CAR-T cells may also be an effective treatment option for RA. Haghikia et al. reported the case of a patient with RA and MG. The patient was diagnosed with systemic AchR antibody-positive MG in the early stages and developed anti-citrulline protein antibody (ACPA)-positive RA several years later. After various treatment methods failed to effectively control disease activity, the patient was treated with KYV-101. Subsequently, MG activity decreased rapidly; the patient went into complete remission; muscle strength recovered; arthritis symptoms disappeared; and the serum ACPA titer decreased. The patient tolerated the CAR-T therapy well and only developed grade 1 CRS ⁴³ . Although, in this case, the patient achieved seroconversion of ACPA after CAR-T treatment, the patient was not refractory to RA, and there is a lack of large-scale studies to verify it. Therefore, related experiments are still needed to explore CAR-T treatment for refractory RA.

Brand et al. developed CD8+CAR-T (DR1CART) in preclinical experiments that target HLA-DR and selectively kill CD4+T cells. In vitro experiments have shown that CAR-T cells can specifically kill CD4+T cells. In a mouse model, the CD4+T cell response significantly decreased after DR1CART infusion, and the severity of autoimmune arthritis was also reduced ⁴⁴ . Therefore, HLA-DR CAR-T cells have certain developmental prospects for AIDs. However, Zhang et al. ⁴⁵ developed another anti- FITC-resistant CAR-T therapy that can eliminate autoreactive B cell subsets in RA by binding to FITC-labeled antigenic peptide epitopes. While the feasibility of CAR-T cells has been demonstrated in in vitro experiments, further research is required to explore its efficacy and safety in treating RA in clinical settings.

SS

SS is a systemic AID characterized by the invasion of exocrine glands, such as the lacrimal and salivary glands, and abnormal B cell proliferation. Existing treatment methods are mostly symptomatic, and their inhibitory effects on gland injury and systemic disease activity are limited ⁴⁶ .

Sheng et al. reported a case of SS with diffuse large B cell lymphoma (DLBCL) treated with CD19-targeted CAR-T cells. The patient had a 10-year history of active SS complicated with DLBCL. After CAR-T treatment, the patient went into complete remission of lymphoma, and antinuclear antibody and anti-Ro-52 were negative for the first time on the 90th day. Six months after CAR-T cell infusion, the serum cytokine levels returned to normal, and symptoms of dry mouth improved, indicating partial remission of SS. In the early stages of treatment, the patient developed grade 2 CRS and grade 1 ICANS, which were completely controlled after the intervention ⁴⁷ . However, the patient also received tocilizumab and methylprednisolone treatment after CAR-T infusion, and these immunosuppressive agents may have an impact on the treatment of SS. These findings suggest the feasibility of CAR-T therapy in treating SS, warranting further clinical trials with larger sample sizes.

Others

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a life-threatening systemic AID that often involves the kidneys and shows necrotizing crescentic nephritis (NCGN). The main autoantibodies in these patients were myeloperoxidase (MPO) and protease 3 ⁴⁸ . A preclinical experiment by Lodka et al. confirmed the protective effect of CD19-targeted CAR-T cells against ANCA-induced acute renal injury. In vivo experimental results show that CD19-targeted CAR-T cells can deplete B cells and reduce the production of plasma cells in mice with anti-MPO-induced glomerulonephritis, preventing ANCA-induced acute kidney injury by reducing B and plasma cells ⁴⁹ . Therefore, CD19-targeted CAR-T therapy may be a potential strategy for preventing ANCA-induced vasculitis and NCGN. Currently, several clinical trials targeting AID-related acute kidney injury, such as lupus nephritis, NCGN, and immunoglobulin G 4 (IgG4)-related diseases (NCT06497387 targeting BCMA and NCT06285279 and NCT06497361 targeting CD19 and BCMA at the same time), are underway, and their results are expected to be announced.

CAR-T can simultaneously treat both diseases without compromising efficacy and safety for patients with B cell non-Hodgkin lymphoma (B-NHL) and AIDs. In a matched study by Wang et al., 58 (4.3%) of 1,363 patients with B-NHL who received CD19-targeted CAR-T therapy had AIDs at the same time, and the patients were divided into two groups based on the presence of AIDs. The analysis of the two groups showed that the incidence, severity, and treatment of CRS and ICANS were similar, with comparable overall survival rates. However, after CAR-T cell infusion, the serum inflammatory markers of patients with AIDs decreased (P = 0.03); autoantibodies were negatively transformed; and the use of corticosteroids and anti-rheumatic drugs decreased (P < 0.01) ⁵⁰ . Therefore, for patients with both B-NHL and AIDs, CD19-targeted CAR-T therapy can impact both diseases simultaneously, making them a feasible choice for such patients. However, this was a retrospective analysis, and further prospective experiments are required to verify this conclusion.

Peng et al. developed a candidate product, CABA-201, a kind of anti-CD19 CAR-T, in preclinical experiments. In vitro experiments proved that CABA-20 had specific cytotoxicity for CD19-positive Nalm6 cells but had no off-target effects on primary human cells. CABA-201, derived from primary T cells of several patients with AIDs (including SLE, MS, and RA), stably expresses anti-CD19 CAR and effectively eliminates autologous CD19-positive B cells in vitro ⁵¹ . Therefore, CABA-201 is a potential treatment option for AIDs and is worthy of further experimentation and clinical translation

In short, CAR-T cell therapy has exhibited promising therapeutic efficacy in the treatment of a variety of systemic autoimmune diseases (Table 2). Additionally, ongoing research endeavors are exploring its potential application in treating type 1 diabetes, rheumatoid arthritis, and other conditions, thereby offering new hope to a vast patient population.

Table 2.

Analysis of studies for CAR-T in systemic autoimmune diseases.

Diseases	Pathogenic autoantibody	Targets	Effects	Research phase
SLE	Represented by antinuclear antibodies	CD19 and BCMA	Disease activity is controlled and disease remission is achieved	Clinical Studies
MG	Anti-acetylcholine receptor antibody	CD19 and BCMA	Clinical symptoms improve and Pathogenic autoantibody titers decrease	Clinical Studies
SSc	Multiple antibodies	CD19	Symptoms improve and fibrosis is reversed	Clinical Studies
IIMs	Represented by anti-Jo-1 antibodies	CD19 and BCMA	Muscle function normalizes and extramuscular disease activity ceases	Clinical Studies
RA	Represented by rheumatoid factor antibodies	CD19 and HLA-DR	Arthritis symptoms improve, and antibody titers decrease	Preclinical and Clinical Studies
SS	Represented by antinuclear antibodies	CD19	Disease achieves partial remission	Clinical Studies
NCGN	Myeloperoxidase and protease 3	CD19	Occurrence of ANCA-induced acute kidney injury is prevented	Preclinical Studies

Abbreviations: BCMA, B cell mature antigen; IIMs, idiopathic inflammatory myopathies; MG, Myastheni agravis; NCGN, necrotizing crescentic nephritis; RA, rheumatoid arthritis; SLE, Systemic lupus erythematosus; SS, Sjögren Syndrome; SSc, systemic sclerosis.

The application of CAR-T in organ-specific AID

In organ-specific autoimmune diseases, CAR-T cells have also demonstrated their unique advantages (Table 3).

Table 3.

Analysis of studies for CAR-T in organ-specific autoimmune diseases.

Diseases	Pathogenic autoantibody	Targets	Effects	Research phase
MS	/	CD19	Cerebrospinal fluid antibody levels decrease	Clinical Studies
NMOSD	Anti-AQP4 antibody	CD19	Nervous system inflammation is controlled and serum APQ4 antibody level decreases	Clinical Studies
AE	/	CD19 and XCR1	Immunosuppression is achieved to suppress AE	Preclinical Studies
SPS	/	CD19	Symptoms improve and the need for gamma-aminobutyric acid-targeting medication is decreased	Clinical Studies
PBC	/	PD-1	Tissue-resident memory CD8+T cells are cleared and the PBC is controlled	Preclinical Studies
GD	TRAb	TRAb	B cells that produce TRAb are cleared	Preclinical Studies

Abbreviations: AE, autoimmune encephalitis; GD, Graves’ disease; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder; PBC, primary biliary cholangitis; SPS, Stiff-person syndrome.

MG

MG is a B-cell-driven disorder characterized by neuromuscular conduction dysfunction, leading to fatigue and muscle weakness. It is usually caused by antibodies against the acetylcholine receptor (AchR); in a small number of patients, muscle-specific tyrosine kinase (MuSK) autoantibodies can be detected in the serum ⁵² .

Haghikia et al. reported the treatment of patients with MG using whole-human autologous CD19-targeted CAR-T cells for the first time. After diagnosis, the patient received various treatments, including thymectomy, acetylcholinesterase inhibitors, B cell depleting antibodies (such as rituximab), and immunosuppressants, but still showed disease progression. After lymphodepletion and CAR-T cell infusion, myasthenia eventually improved (including the improvement of muscle strength and fatigue), circulating anti-AchR antibody titers decreased, and no CAR-T treatment-related adverse events were recorded ⁵³ . Tian et al. reported two cases of MG in patients treated with BCMA-targeted CAR-T cells. Both patients had highly relapsed and refractory MG, with the former being AChR-IgG positive and the latter MuSK-IgG positive. They demonstrated a good safety profile and sustained clinical improvement 18 months after BCMA-targeted CAR-T cell infusion. No case of CRS or ICANS was observed, while only varying degrees of cytopenia were noted, which resolved completely within 1 month. No delayed adverse reactions were observed ⁵⁴ .

Dual-targeted CAR-T therapy is an option for MG. In a case report by Zhang et al., a patient with refractory anti-AchR-positive MG showed improvement and achieved clinical remission after bispecific BCMA/CD19 targeted CAR-T cell infusion. Oral medications, including prednisone, tacrolimus, and pyridostigmine, were subsequently tapered to discontinuation without disease relapse or progression. Additionally, the patient’s pathogenic antibody anti-AchR levels gradually decreased to negative ⁵⁵ . This dual-specificity strategy enabled deeper depletion of the B-cell lineage: CD19+ B cells were rapidly cleared, while BCMA+ long-lived plasma cells—traditionally resistant to conventional therapies—were also eliminated. These findings suggest that simultaneous targeting of CD19 and BCMA can produce more complete and durable suppression of autoantibody production than either antigen alone, providing a rationale for further exploration of dual CAR-T therapy in MG.

MG and Lambert-Eaton myasthenia syndrome (LEMS) are AIDs affecting neuromuscular conduction and can also occur simultaneously ⁵⁶ . In a study by Motte et al., two patients with MG and LEMS received various immunotherapies but were still in a state of severe disease activity. However, after CD19 CAR-T (KYV-101) infusion, all patients experienced rapid clinical and serological remission and recovered full mobility. Two months later, they resumed their daily lives and transitioned from wheelchair dependence to cycling and mountain climbing ⁵⁷ .

Currently, most CAR-T cells transfer DNA into T cells using gene-editing technology, allowing them to express the CAR. Descartes-08, a mRNA-based BCMA-targeting CAR-T (rCAR-T), has shown unique advantages in treating MG. Clinical trial MG-001 (NCT04146051) explored the safety, tolerance, and feasibility of Descartes-08 in patients with MG. All 14 patients received Descartes-08 infusion, and their disease severity decreased. Among them, two patients’ dependence on immunoglobulin decreased, and three patients reached a stage of minimal symptoms. No dose-limiting toxicity, CRS, or ICANS with immune effects occurred during treatment ⁵⁸ . Additionally, patients did not undergo lymphocyte depletion conditioning, yet successfully achieved a reduction in serum levels of B-cell activating factor (P < 0.05) and a proliferation-inducing ligand (P < 0.05), B-cell survival factors, and soluble BCMA, which have previously been shown to be correlated with the severity of MG ⁵⁹ . This first study on rCAR-T on AIDs shows that Descartes-08 may be a safe and effective method to treat MG. Therefore, the potential value of rCAR-T in AIDs, including MG, deserves further exploration.

Tian et al. ⁵⁴ believed that after CAR-T cell infusion, the reconstruction of the B cell lineage in patients, that is, B cell-specific immune reset, reduction of pathogenic autoantibodies, and normalization of the B cell-related immune microenvironment, is the basis of BCMA-targeted CAR-T therapy. Therefore, CAR-T cells play an important role in treating AIDs caused by B cell immune abnormalities. Currently, numerous clinical trials targeting CD19, such as NCT05828225, NCT06371040, and NCT06359041, are underway, with the publication of these results awaited.

MS

MS is an immune-mediated disease characterized by demyelinating inflammatory lesions in the central nervous system. Glucocorticoids are its first-line therapy ⁶⁰ . B cells play an important role in the inflammatory central nervous system environment of MS ⁶¹ .

Fischbach et al. published the first case report of progressive MS treatment with KYV-101. In their report, both patients treated with KYV-101 achieved clinical symptom improvement, namely, an increase in walking distance, and demonstrated acceptable safety, which included grade 1 CRS. The following were observed in the cerebrospinal fluid: a significant decrease in antibody levels and the existence and amplification of CAR-T cells. No signs of ICANS, a common neurological complication of CAR-T treatment, were observed ⁶² . Although CAR-T cells targeting CD19 have shown effectiveness and safety in MS, existing data are from case reports. Therefore, larger sample sizes and longer follow-up periods are needed to provide data support for the application of CAR-T in MS. Ongoing clinical trials, including Trial KYSA-7 (NCT06138132) and NCT04561557, indicate its potential in the treatment of MS.

NMOSD

NMOSD is an autoimmune inflammatory disease of the central nervous system, with aquaporin 4 (AQP4) playing an important role in its occurrence and development. Therefore, eliminating plasma cells that produce IgG, which can bind to AQP4 in the optic nerve and spinal cord, is an important means of treating NMOSD ⁶³ . CT103A, a CAR-T cell therapy agent targeting BCMA, has shown a strong clinical effect in treating multiple myeloma (MM) and may be a feasible choice for NMOSD. In an ongoing clinical trial in China (NCT04561557), 17 patients with NMOSD were included, with 12 receiving CT103A infusion. All patients developed CRS, with grades ranging from 1 to 2. After a median follow-up of 5.5 months, the quality of life for all patients improved, and Expanded Disability Status Scale (EDSS) scores decreased. Among them, 11 patients achieved drug-free remission and did not relapse after discontinuing corticosteroids and immunosuppressants, with a decreasing trend in serum AQP4 antibody levels. In addition, two patients with SS achieved serological remission and clinical improvement, and one patient with RA exhibited an improvement in RA disease activity 12 weeks post-infusion, which included a reduction in disease activity scores and a decrease in erythrocyte sedimentation rate ⁶⁴ . CAR-T therapy has shown controllable safety and good therapeutic effects in patients with recurrent and refractory AQP4-IgG seropositive NMOSD. Currently, the trial has entered the expansion stage, and we look forward to the publication of the latest test data. Qin et al. performed a single-cell analysis of the cerebrospinal fluid of patients with NMOSD after BCMA-targeted CAR-T cell therapy. The results highlighted the role of CD8-positive CAR-T cells in treatment, showing that anti-BCMA CAR-T cells can effectively enter the cerebrospinal fluid, specifically kill plasmablasts and plasma cells, and inhibit nervous system inflammation ⁶⁵ . Additionally, multiple clinical trials targeting NMOSD with CAR-T cells, including NCT05828212 (targeting CD19) and NCT03605238 (targeting CD19 and CD20), provide new therapeutic options for NMOSD.

AE

CAR-T therapy is also useful in AE treatment. In a preclinical experiment by Gupta et al. ⁶⁶ , after injecting CD19-targeted CAR-T into an experimental AE (EAE) mouse model, the researchers found deep and persistent B cell depletion in the peripheral lymphoid tissue and central nervous system. However, the depletion was independent to amelioration of EAE symptoms. Since type 1 dendritic cells (DC1) can promote the development of type 1 helper T cells by producing cytokines, depletion of DC1 can inhibit autoimmune responses. Tregs also play an important role in negatively regulating the immune response in vivo ⁶⁷ . Moorman et al. developed X-C motif chemokine receptor 1 (XCR1)-specific CAR-T cells and DC1-specific CAR-Tregs. The experimental results showed that DC1 depletion caused by XCR1CAR-T cells or immunosuppression caused by XCR1CAR-Tregs could moderately inhibit Th1-driven EAE ⁶⁸ . Therefore, clearing CAR-T or CAR-Treg cells of dendritic cells in the body is also a possible important means of treating AIDs, necessitating further exploration.

Others

Stiff-person syndrome (SPS) is a rare autoimmune disease of the nervous system that mainly manifests as progressive stiffness and muscle spasms. In most patients, antibodies against amphiphysin or glutamic acid decarboxylase (GAD) can be detected ⁶⁹ . Faissner et al. described a patient with a 9-year history of refractory SPS who was successfully treated with CD19-targeted CAR-T cells. Following the infusion of KYV-19, the patient demonstrated a favorable tolerability profile to CAR-T cells, manifesting only grade 2 CRS, which was effectively managed with dexamethasone, tocilizumab, and symptomatic supportive therapy. There was a marked improvement in the patient’s clinical symptoms, including a reduction in leg stiffness, a significant increase in the number of steps taken, and an enhancement in walking speed by over 100%. Additionally, the patient’s usage of GABAergic medications, which are typically employed for the treatment of this condition, decreased by 40%. No further immunotherapy was administered subsequent to the CAR-T cell therapy ⁷⁰ . While CD19-targeted CAR-T cells may also be a potential treatment for SPS, the low incidence of the disease and the limited number of patients who receive CAR-T treatment indicate the need for further research to establish the efficacy of CAR-T in the treatment of SPS.

Primary biliary cholangitis (PBC) is a chronic progressive autoimmune cholestasis disease with the liver as the main target organ. It is characterized by an autoreactive T cell response to small bile ducts in the liver. Tissue-resident memory CD8+T cells (Trm) are an important component of the intrahepatic immune microenvironment ⁷¹ . Zhu et al. discovered the cytotoxicity against bile duct epithelial cells in PBC mediated by CD8+Trm with high expression of programmed cell death protein 1 (PD-1) and the potential therapeutic effect of PD-1-targeted CAR-T on PBC through preclinical experiments. Researchers observed CD8+Trm cells in a mouse model of PBC. These cells highly express markers related to activation and cytotoxicity and induce apoptosis of bile duct epithelial cells. At the same time, the expression of various immune checkpoint molecules, including PD-1, is upregulated in these cells. CAR-T cells targeting PD-1 can selectively clear CD8+Trm cells from the liver and relieve PBC ⁷² . This experiment demonstrates the pathogenic effect of CD8+Trm cells on PBC and highlights the therapeutic potential of PD-1-targeting CAR-T cells for treating PBC.

Graves’ disease (GD) is also a typical organ-specific AID, characterized by an abnormal increase in thyroid-stimulating antibodies (TRAb) targeting the thyroid-stimulating hormone receptor (TSHR). Duan et al. proposed that targeting and eliminating B cells that produce TRAb is a possible method to treat GD, and based on this, preclinical research was carried out. They designed TSHR-CAR-T cells, capable of targeting the antigenic fragment of pathogenic TRAb. TSHR-CAR-T has demonstrated the ability to effectively identify and eliminate B cells that produce TRAb, both in vitro and in vivo; therefore, TSHR-CAR-T is a promising method to treat GD, worthing further exploration in clinical translation ⁷³ .

Challenges faced by CAR-T therapy in treating AIDs

Despite the potential of CAR-T therapy in treating AIDs, many problems remain to be solved (Table 4), including immunosuppression, recurrence, CRS, and ICANS.

Table 4.

Challenges faced in the process of CAR-T therapy in AIDs.

Challenges	Strategies	Efficacy	Research phases
Immunosuppression	CAAR-T; avoid to use drugs inhibit T cell function 70	By specifically targeting B cells that produce autoantibodies and alleviating the suppression of T cells, the risk of general immune suppression is reduced.	Preclinical and clinical studies
Permanent organ damage	Determine the best time for CAR-T treatment and carry out treatment as soon as possible 2	Intervention at the prodromal stage of the disease can avert irreversible damage to systemic organs, thereby enhancing the quality of life for affected individuals	Clinical studies
CRS, ICANS,	Symptomatic and immunosuppressive therapy71,74	The majority of patients may achieve complete recovery following glucocorticoid and symptomatic supportive treatment. However, those who experience severe CRS and ICANS may exhibit poorer therapeutic outcomes.	Clinical studies
Relapse	Long-term monitoring of patients 2 ; second infusion of CAR-T 75	No patients have been observed to relapse with AIDs after receiving CAR-T, hence the efficacy remains unclear.	Clinical studies
Expensive and time consuming	Off-the-sheft CAR-T34,76	Further research is still needed.	Clinical studies
Others: infection, hematological toxicity, hypogammaglobulinemia, etc.	Symptomatic and immunosuppressive therapy	Patients receiving CAR-T therapy typically experience a transient bone marrow phase, and supportive treatment can generally help patients get through it smoothly.	Clinical studies

Abbreviations: AID, autoimmune disease; CAAR-T, chimeric autoantigen receptor T cell; CAR-T, chimeric antigen receptor T cell; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.

Immunosuppression

Generally, CAR-T cells target all B cells expressing the target antigen, which can lead to immunosuppression after CAR-T cell infusion. Chimeric autoantigen receptor T cells (CAAR-T) recognize and attach to their targets through extracellular antibody fragments, directing the cytotoxic effects of T cells to B cells that produce autoantibodies, thus reducing the risk of general immunosuppression (Fig. 3) ⁷⁷ .

Figure 3.

Mechanism of CAR-T and CAAR-T. (a) After specifically recognizing the surface antigens of B cells, such as CD19 or B cell mature antigen (BCMA), chimeric antigen receptor T cell (CAR-T) can directly induce apoptosis of B cells by secreting perforin and granase and can also secrete cytokines to recruit immune cells and kill B cells. (b) CAAR-T, chimeric autoantigen receptor T cell (CAAR-T) is similar to CAR-T in that it targets B cell receptors on the surface of B cells by modifying T cells to express autoantigens, thereby specifically eliminating B cells that cause autoreactions without affecting the function of normal B cells.

Abbreviations: BCMA, B cell mature antigen; BCR, B cell receptor. CAAR, chimeric autoantigen receptor; CAAR-T, chimeric autoantigen receptor T cell; CAR, chimeric antigen receptor; CAR-T, chimeric antigen receptor T cell.

Pemphigus vulgaris (PV) is a group of autoimmune chronic skin diseases caused by epidermal cell lysis, mediated by autoantibodies against desmoglein 3 (DSG3) ⁷⁵ . Mucosal-dominant PV (MPV) is a type of PV. Chang et al. developed DSG3-CAART, which expresses DSG3 autoantibodies and targets only anti-DSG3B cells. Previous data showed that DSG3-CAART from all participants showed a specific lytic effect against DSG3-expressing cells in vitro, with no restrictive toxicity or serious adverse reaction after infusion ⁷⁴ . Therefore, CAAR-T cells represent a potential method for treating pemphigus. Related clinical trials (such as NCT04422912) are underway, showing potential for treating pemphigus.

Oh et al. developed MuSK-CAART with CD137-CD3ζ with T cells, which can accurately target B cells expressing anti-MuSK autoantibodies. MuSK-CAART can consume anti-MuSK B cells in vitro. In in vivo experiments, MuSK-CAART reduced anti-MuSK IgG levels in an MG mouse model without reducing the level of B cells or total IgG, indicating selective depletion of MuSK-specific B cells ⁷⁶ . The success of this preclinical experiment laid the foundation for the application of new research drugs and the development of a phase I clinical study (NCT05451212) of MuSK-CAART for the treatment of MuSK autoantibody-positive MG.

There are also studies that use CAAR-T to treat AE. Anti-N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis is one of the common AE. It is caused by pathogenic autoantibodies secreted by plasmablasts against NMDAR and can manifest as psychosis, seizures, and cognitive impairment ⁷⁸ . Based on its pathogenesis, eliminating NMDAR-specific memory B cells is a possible method to treat this disease. Reincke et al. developed an NMDAR-specific CAAR-T (NMDAR-CAART). The CAAR of CAAR-T specifically binds to the anti-NMDAR B cell receptor using its antigen, and the cytotoxicity of T cells expressing the CAAR is only directed at B cells that produce NMDAR autoantibodies, while the other protective B cells are not affected. In in vitro and in vivo experiments, NMDAR-CAART showed cytotoxicity by specifically killing target cells, which led to a decrease in autoantibodies in the serum and cerebrospinal fluid, and there were no signs of adverse events ⁷⁹ . Therefore, CAAR-T cells, a new therapeutic method targeting autoantibody-producing cells, have shown broad prospects in many diseases, and further preclinical experiments and clinical translation are required.

In addition, as patients need to stop immunosuppressants and undergo chemotherapy to clear lymphocytes before CAR-T infusion, the body undergoes deep depletion of B cells after CAR-T infusion; therefore, the adaptive immunity of the body depends only on T cells at that stage. Drugs that inhibit T cell function include mycophenolate mofetil, calcineurin inhibitors, and Janus Kinase inhibitors ⁸⁰ .

CRS and ICANS

CRS and ICANS are the two most common adverse reactions with CAR-T cell therapy in treating hematological malignancies. CRS is a systemic inflammatory response syndrome triggered by the activation of immune cells and the release of a large number of cytokines during CAR-T treatment, characterized by fever, fatigue, and myalgia ⁸¹ . Its core mechanism involves cytokine-storm–induced endothelial activation and injury, leading to increased vascular permeability, microthrombosis, and multi-organ dysfunction ⁸² . ICANS is a disease characterized by a pathological process involving the central nervous system after immunotherapy, which leads to the activation or participation of endogenous or infused T cells and/or other immune effector cells, manifesting as aphasia, changes in consciousness levels, cognitive dysfunction, epilepsy, and brain edema ⁸³ . Studies show that endothelial injury is likewise a pivotal step in ICANS: blood–brain-barrier disruption, vasogenic edema, and up-regulated endothelial adhesion molecules facilitate immune-cell infiltration and amplify neurotoxicity ⁸⁴ (Table 5). However, to date, no cases of high-grade CRS or ICANS have been reported in studies of CAR-T-cell therapy for autoimmune diseases. This may be attributed to the higher disease burden in patients with hematologic malignancies, but the standard treatment protocols for CRS and ICANS in AIDs must be carefully evaluated ⁸⁵ .

Table 5.

Classification of CRS and ICANS.

Grade	Cytokine release syndrome			Immune effector cell-associated neurotoxicity syndrome
	Fever	Hypotension	Anoxia	Consciousness	Immune effector cell score	Other Manifest
1	≥38.0°C	/	/	Normal consciousness	7–9	/
2	≥38.0°C	No pressors needed	Low -flow nasal catheter or by blow-by method	Mild somnolence awaking to voice	3–6	/
3	≥38.0°C	Pressors, such as norepinephrine	High flow oxygen intake	Awakening only to tactile stimulus	0–2	Any clinical seizure or non-convulsive seizures on electrocardiograph that resolve with intervention, and/or focal edema on neuroimaging
4	≥38.0°C	Multiple pressor medications are required	Positive pressure ventilation	Stupor or coma	0	Prolonged seizure (>5 minutes) or repetitive clinical or electrical seizures without return to baseline, and/or diffuse cerebral edema, and/or elevated intracranial pressure

Abbreviations: CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.

Symptomatic supportive therapy, with glucocorticoids as the first line of treatment, is typically used to treat CRS and ICANS. Studies on its treatment with tocilizumab and anakinra (an interleukin-1 receptor blocker) are ongoing^86,87.

Others

The occurrence and development of AIDs often lead to permanent organ damage, such as lupus nephritis secondary to SLE, pulmonary fibrosis secondary to SSc, and endocrine gland atrophy in SS. Therefore, the early diagnosis and treatment of AIDs are important. Previous studies have shown that CAR-T therapy can reverse the development of permanent organ damage in AIDs^21,22. Currently, CAR-T therapy is not the first choice of treatment for AIDs, and the best treatment modality for severe AIDs remains inconclusive. However, earlier intervention is more favorable for reversing permanent organ damage. Therefore, further research is required to determine the optimal time to use CAR-T therapy in AIDs.

Relapse is a significant challenge in CAR-T therapy for hematological malignancies, with a second infusion of CAR-T cells considered a feasible option to treat patients after relapse ⁸⁸ . Regarding the application of CAR-T therapy in AIDs, there are no reported cases of relapse, possibly due to the small sample size of patients in existing studies. This may also be due to the short duration of research on CAR-T cells for AID treatment and the short follow-up periods. Therefore, extending the follow-up period is essential to explore the recurrence of AIDs in patients after CAR-T therapy.

The exploration of CAR-T derived therapy in AID

CAR-NK

CAR-NK can kill target cells through CAR-dependent and NK cell receptor dependent pathways to achieve disease control. CAR-NK does not cause CRS, ICANS, or GVHD during treatment ⁸⁹ , and “off-the-sheft” allogenetic-derived CAR-NK reduces money and time costs compared to CAR-T. Based on the advantages shown by CAR-NK, its application in AIDs is also being explored.

T Follicular helper cells (TFH) interact with B cells and induce B cell differentiation, which plays an important role in humoral immunity. The dysregulated TFH is related to AID ⁹⁰ . PD-1 was highly expressed on TFH surface. Reighard et al. designed a PD-L1 CAR NK that specifically targets cells with high PD-1 expression. During in vitro co-culture, PD-L1 CAR NK was able to selectively eliminate TFH without clearing B cells or naive T cells. After TFH clearance, the proliferation, differentiation and immunoglobulin secretion of memory B cells decreased in vitro. After infusion of PD-L1 CAR NK into SLE mouse model, the number of CD4 + T cells with high expression of PD-1 decreased, and the splenomegaly was improved ⁹¹ . Preclinical experiments are the basis for the development of CAR-NK therapy AID targeting PD-1, which brings hope for subsequent CAR-NK therapy AID. Currently, there are a number of clinical trials of CAR-NK treatment of AID in progress, and their targets are all CD19, and CAR-NK still has a long way to go in the treatment of AID.

CAR-Treg

Studies have shown that Tregs play a non-specific immunosuppressive role in the immune system, and in AID, the accumulation and dysfunction of Tregs at the inflammatory site is one of the important links in the occurrence of AID ⁹² . Treg cell therapy shows great potential in AID, and CAR transduction for Treg can improve the targeting of Treg and enable it to more accurately target diseased tissues.

Fransson et al. constructed MOG-CAR Tregs that target myelin oligodendrocyte glycoprotein (MOG). In vitro, MOG-CAR Treg effectively inhibited the proliferation of effector T cells. In vivo, MOG-CAR Treg reduced symptoms in mice with EAE and reduced pro-inflammatory cytokine mRNA levels in brain tissue ⁹³ . In Elinav et al.’s study, CAR-Treg targeting 2,4,6-Trinitrophenol (TNP) inhibited the proliferation of effector T cells in vitro, and infusion of CAR-Treg into mice with colitis reduced their symptoms and improved survival ⁹⁴ .

Dall’era et al. treated one SLE patient with adoptive Treg (NCT02428309). The results show that Treg cell therapy can alter the balance of Th1 and Th17 subsets in the local inflammation, manifested by a decrease in interferon-gamma producing CD4+T cells and an increase in IL-17a producing CD4 and CD8+T cells, and ultimately manifested in tissue inflammation resolution and disease control ⁹⁵ .

CAR-Treg may also be a CAR-based cell therapy for AIDs treatment. By targeting inflammatory local tissues and producing immunosuppressant effects, CAR-Treg reduces local inflammatory response, alleviates patients’ symptoms and achieves disease control. Currently ongoing clinical trials of CAR-Treg therapy AIDs include NCT06361836, etc., which brings infinite possibilities for the treatment of AIDs.

Conclusion

CAR-T-cell therapy offers a transformative treatment strategy for AIDs and has demonstrated remarkable efficacy across multiple AIDs, yet it remains in its infancy. Immunosuppression, organ damage, and hematologic toxicity remain unavoidable adverse events. Unlike hematological malignancies, AIDs generally carry a lower antigen burden, allowing reduced CAR-T dosing and a lower likelihood of adverse events. Consequently, B-cell reconstitution occurs earlier and more rapidly than in the oncologic setting, is dominated by naïve B-cell phenotypes, and signals a resetting of the immune system ⁹⁶ . Future efforts must focus on optimizing CAR design, enhancing safety, minimizing long-term toxicities, and refining patient selection, while high-quality clinical trials are urgently needed to confirm efficacy and define suitable indications ⁹⁷ . As research advances, CAR-T and its next-generation derivatives may become powerful tools capable of curing AIDs.