Introduction

By reprogramming T cells to express chimeric antigen receptors (CARs) on their surface, CAR-T cells can harness the power of the self-immune system to fight malignant tumors in a non-major histocompatibility complex (MHC)-restricted manner, which has heralded a paradigm in cancer immunotherapy. Current research has primarily focused on CAR-T cells for the treatment of B-cell hematologic malignancies such as acute B-cell leukemia, B-cell lymphoma, and multiple myeloma (MM), demonstrating remarkable efficacy, sustained persistence, and the potential of drug-free remission. Clinical trials have reported that anti-cluster of differentiation (CD) 19 CAR-T cells achieved complete remission in up to 87.5% of patients with refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma, with durable responses extending to 16 months.[1] Similarly, anti-B cell maturation antigen (BCMA) CAR-T cells achieved a median progression-free survival (PFS) of 11.8 months in patients with R/R MM.[2] Additionally, based upon clinical trials and historical data, CAR-T therapy has been recommended as a second-line treatment within one year of the initial therapy for large B-cell lymphoma, alternative therapeutic approach to autologous stem cell transplantation.[3] This strategy is also exhibiting potential in solid tumors.[4]

The triumph of CAR-T cell therapy in eradicating pathological B cells and achieving sustained remissions has propelled researchers to explore its potential application in autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), pemphigus vulgaris (PV), etc., which are characterized by autoreactive B cells and diverse autoantibodies [Figure 1]. Conventional therapeutic modalities for autoimmune diseases include glucocorticoids, immunosuppressants, and monoclonal antibodies (mAbs). Glucocorticoids and immunosuppressants broadly suppress the immune system, leading to increased susceptibility to opportunistic infections, while mAbs provide targeted interventions. For example, the CD20-targeted mAb rituximab can selectively eliminate CD20+ B cells and alleviate SLE Disease Activity Index (SLEDAI) score by at least 2 units.[5] The tumor necrosis factor α-targeted mAb infliximab can achieve nearly twofold remission proportions of patients with Crohn’s disease compared to placebo.[6] Tocilizumab, an interleukin 6-targeted mAb, has been found to induce remission in 27% of rheumatoid arthritis (RA) patients based on the disease activity score using 28 joint counts, compared to a mere 0.8% in the placebo group.[7] Despite these advantages, a proportion of patients respond poorly,[8] the need for repeated administrations compromises compliance, human anti-chimeric antibody that is produced against mAb has been proven to decrease clinical response or result in possible infusion reactions,[9] and mAbs representing foreign antigenic materials may elicit host immune responses.[10]

Figure 1:

Pathogenesis of autoimmune diseases. Autoimmune disease is caused by a self-immune response against the own components, resulting in systemic or organ damage. Ach: Acetylcholine; AchR: Acetylcholine receptor; ACPA: Anticitrullinated protein antibody; AQP-4: Aquaporin 4; ASS: Antisynthetase syndrome; BBB: Blood–brain barrier; cCOII: Citrullinated type 2 collagen; dsDNA: Double-stranded deoxyribonucleic acid; Dsg: Desmoglein; IBD: Inflammatory bowel disease; IgG: Immunoglobulin G; LRP4: Low density lipoprotein receptor 4; MG: Myasthenia gravis; MMN: Multifocal motor neuropathy; MS: Multiple sclerosis; MuSK: Muscle tyrosine kinase; NMOSD: Neuromyelitis optica spectrum disorder; PV: Pemphigus vulgaris; RA: Rheumatoid arthritis; RNP: Ribonucleoprotein; SLE: Systemic lupus erythematosus; Sm: Smith; SS: Sjőgren’s syndrome; SSA: SS A antigen; SSB: SS B antigen; T1DM: Type 1 diabetes mellitus; tRNA: Transfer ribonucleic acid.

To date, a therapeutic strategy that achieves drug-free remission in autoimmune diseases remains elusive, making CAR therapy an enticing avenue. Compared to existing treatments, CAR-T cells hold promise in treating precisely due to their treat-to-target strategy, persistently due to their ability to self-expand in vivo [Supplementary Figure 1, https://links.lww.com/CM9/B986]. This paper reviewed preclinical and clinical studies of CAR-T and CAR-related therapies for autoimmune diseases, assessing their therapeutic efficacy, safety profiles, persistence, and the feasibility of clinical application. It also presents approaches to advance CAR-T therapy, with the aim of optimizing its application in autoimmune diseases.

Bibliometric Analysis of CAR-Related Therapy

VosViewer (version 1.6.19, Leiden University, Leiden, Netherlands) and CiteSpace (version 6.1.R6, Drexel University, Philadelphia, USA) were used to conduct the visualized bibliometric analysis of the academic publications in the field of CAR-related therapy retrieved from the Web of Science Core Collection (WOSCC) on September 25, 2023. Totally, 22,468 papers were retrieved and analyzed. Figure 2A portrays the annual progression of publications and growth rate from 1996 to 2023. It illustrates a steady escalation over these years, gaining momentum since 2017. This upsurge can be attributed to the initial clinical approval by the U.S. Food and Drug Administration for anti-CD19 CAR-T therapy in treating R/R B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma, marking a turning point in the field. Keyword co-occurrence was also analyzed to identify research hotspots and trends. By consolidating related terms such as “chimeric antigen receptor” and “chimeric antigen receptors”, as well as “immunotherapy” and “adoptive immunotherapy”, a top 15 keywords ranking list was generated [Table 1]. The overlay visualization of keyword co-occurrence showed the color shift from purple to yellow over time, illustrating the transition of CAR-related therapy from bench to bedside [Figure 2B]. Additionally, “adoptive immunotherapy” held the highest frequency, underlining its significance in the landscape. Since CAR-T is used as an immunotherapy for specific elimination of pathogenic B cells or plasma cells in B-cell hematological malignancies, which also involves the mechanisms of autoimmune disease pathogenesis, we extended exploration to the intersection between CAR-related therapies and autoimmune diseases, searching the WOSCC database and obtaining a total of 210 records. Among these documentations, 40 countries and 372 institutions have participated in promoting this technology. University of Pennsylvania was the most productive institution. Gerhard Krönke, Dimitrios Mougiakakos, and Georg Schett, who are from the same institution, were the most productive authors. Frontiers in Immunology was the most productive journal, while Journal of Immunology was the most cited journal. Figure 2C illustrates that despite limited publications, the overall trend indicates an increase by years, particularly robust in the period of 2019–2020. This surge can be attributed to an impactful animal experiment in 2019 that successfully employed anti-CD19 CAR-T cells to mitigate SLE, laying the groundwork for accelerated development.[11] Then, through keyword co-occurrence analysis, we summarized top five keywords about autoimmune disease types [Supplementary Table 1 and Figure 2D, https://links.lww.com/CM9/B986]. Aside from “autoimmune diseases”, the most frequent keywords included MS, SLE, RA, and experimental autoimmune encephalitis (EAE), which points to the broad application of CAR-related therapy. Furthermore, through reference co-citation analysis, we identified top eight references with the strongest citation bursts [Supplementary Figure 2, https://links.lww.com/CM9/B986]. The article (Strength: 6.78) with the strongest citation burst was Ellebrecht et al’s[12] animal experiment published in Science in 2016, demonstrating promising efficacy of chimeric autoantibody receptor (CAAR)-T cells targeting desmoglein-3 (Dsg3) for treating PV. Among these references, four papers (50%) are still in a state of citation burst, including Kansal et al’s[11] animal experiment on anti-CD19 CAR-T cells treating murine with lupus, Noyan et al’s[13] research on anti-human leukocyte antigen (HLA) CAR-regulatory T (Treg) cells for treating organ transplantation rejection, a case report of anti-CD19 CAR-T cells treating refractory SLE conducted by Mougiakakos et al[14] and a review article by June and Sadelain[15] discussing CAR therapy. As citation bursts refer to the sudden increase of citations of the paper, these top eight references are about emerging topics in the field of CAR-related therapy for treating autoimmune diseases, with the aforementioned four papers representing the latest research directions. To conclude, we conducted an extensive bibliometric analysis highlighting the expected growth in attention toward CAR-related therapies and their application in autoimmune diseases. In the ensuing section, we provide a comprehensive overview of preclinical and clinical research on CAR-related therapies for different autoimmune diseases [Supplementary Tables 2 and 3, https://links.lww.com/CM9/B986].

Figure 2:

Bibliometric analysis of CAR-related therapy and its application in autoimmune diseases. (A) The publications about CAR-related therapy are escalating; (B) Keywords co-occurrence overlay of CAR related therapy; (C) The publications about CAR-related therapy treating autoimmune diseases show an increase; (D) Keywords co-occurrence overlay of CAR-related therapy treating autoimmune diseases. CAR: Chimeric antigen receptor.

Table 1 - The top 15 keywords of CAR-related therapy. Rank Keywords Count Centrality 1 Adoptive immunotherapy* 5123 0.28 2 Chimeric antigen receptor† 2909 0.12 3 Therapy 2418 0.09 4 Expression 2085 0.06 5 T cells 1934 0.06 6 Cancer 1402 0.06 7 Lymphocytes 1310 0.03 8 Antitumor activity 1147 0.05 9 Activation 1090 0.03 10 Dendritic cells 1055 0.06 11 Natural killer cells 946 0.04 12 In vivo 911 0.02 13 Acute lymphoblastic leukemia 877 0.05 14 B cell 792 0.02 15 CAR T cells 763 0.01

*“Immunotherapy” is merged with “Adoptive immunotherapy”. †“Chimeric antigen receptors” is merged with “Chimeric antigen receptor”. CAR: Chimeric antigen receptor.

CAR-T Therapy in Autoimmune Diseases SLE

SLE is a systemic autoimmune disorder characterized by the presence of various autoantibodies that form immune complexes, which flow in the bloodstream and deposit in tissues to activate the complement system and recruit cytokines, ultimately inducing systemic damage.[16] Current treatments include glucocorticoids, immunosuppressants, and belimumab, but they often fall short in achieving drug-free remission. To address this, anti-CD19 CAR-T cell therapy has been proposed as a potential treatment. In animal studies, anti-CD19 CAR-T therapy showed promising results in alleviating lupus manifestations. Mice treated with anti-CD19 CAR-T cells exhibited reductions in plasma antibodies and improvements in longevity, proteinuria, splenomegaly, and skin damage. The CAR-T cells demonstrated sustained viability and functionality over time.[11] Another study compared anti-CD19 CAR-T cells with a mAb and found that CAR-T cells cleared more CD19+ B cells and prolonged the lifespan of mice.[17] CAR-natural killer (NK) cells, another type of cellular therapy, also showed potential in treating SLE. Anti-programmed cell death-ligand 1 (PD-L1) CAR-NK92 cells can recognize and kill follicular helper T cells characterized by elevated PD-1 expression on the surface, consequently reducing memory B cells proliferation and differentiation, immunoglobulin secretion, as well as ameliorating splenomegaly.[18] In summary, both CAR-T and CAR-NK cell therapies demonstrated efficacy in alleviating SLE manifestations in animal models, priming the ground for promising clinical trials.

In a pioneering clinical trial, autologous anti-CD19 CAR-T cells were administered to a patient with severe/refractory SLE who had failed to respond to other treatments. The therapy resulted in the depletion of circulating B cells, decreased antibody levels, and improvements in proteinuria and SLEDAI scores.[14] The same team then extended their investigation to five patients with refractory SLE, infusing 1 × 106/kg anti-CD19 CAR-T cells. The results indicated that anti-CD19 CAR-T therapy was well tolerated and could induce rapid remission in severe refractory SLE.[19] Besides, infusion of anti-CD19/BCMA CAR-T cells exhibited double benefits in a female with SLE and diffuse large B-cell lymphoma.[20] To date, 20 clinical trials of CAR-T therapy treating R/R SLE are underway, employing anti-CD19/BCMA CAR-T cells or anti-CD19 CAR-T cells [Supplementary Table 3, https://links.lww.com/CM9/B986]. In conclusion, both animal and clinical trials highlight the potential of CAR-T therapy for R/R SLE, but long-term, large-scale clinical trials are imperative to firmly establish its efficacy and safety.

RA

RA is an autoimmune disorder that affects joints and connective tissues (e.g., blood vessel, lung), significantly diminishes patients’ quality of life, with an approximately 4-fold increase in the incidence in woman vs. man.[21] In order to develop precise and radical remedies for RA, researchers are focused on targeting the anticitrullinated protein antibody, which is responsible for causing damage to multiple organs by binding to citrullinated residues within self-proteins (e.g., vimentin, α-enolase, fibronectin, fibrinogen, type II collagen, etc.).[22] One study by Zhang et al[23] involved the development of CAR-T cells that specifically targeted overreactive B cells, guided by citrullinated type II collagen (COII) and fluorescein isothiocyanate. In the presence of antigenic peptides, these CAR-T cells demonstrated proficiency in eliminating hybridoma cells generated through antigenic peptide immunization, alongside B cells from mice with COII-induced arthritis and RA patients. Notably, the CAR-T cells showed minimal off-target effects in killing macrophages, monocytes, and dendritic cells that express FcγR. Another approach involved the use of HLA-DR1-based CAR-T incorporating COII into its molecular architecture to target pathogenic CD4+ T cells that recognize RA-related autoantigens presented by HLA-DR alleles. In vitro, anti-DR1-COII CAR-T cells recognized and depleted CD4+ T cells; in COII-induced mice, these CAR-T cells significantly reduced the incidence, delayed the onset, and mitigated the severity of arthritis. Additionally, serologic markers such as autoantibodies and T cell proliferative responses were markedly reduced.[24] In summary, preclinical studies have demonstrated the efficacy and safety of CAR-T therapy for RA. However, the translation to clinical trials is essential to validate the feasibility of CAR-T therapy in human settings, encompassing considerations of safety, efficacy, durability, and cost-effectiveness.[25]

Type 1 diabetes mellitus (T1DM)

T1DM, also known as insulin-dependent diabetes mellitus, usually begins in childhood or adolescence. Due to autoantibodies such as glutamic acid decarboxylase antibodies and islet cell antibodies attacking pancreatic β cells, there is an absolute insulin deficiency, rendering blood glucose levels more volatile than in type II diabetes mellitus. Long-term insulin therapy is necessary for T1DM management, but patient adherence can be challenging. CAR-T therapy has emerged as a potential cure for T1DM by addressing this issue. In one study conducted by Zhang et al[26], they utilized the specific targeting ability of mAb287, which binds to the I-Ag7-B:9-23(R3) complex, to delay or prevent T1DM onset in non-obese diabetes (NOD) mice. They designed anti-mAb287 CAR-T cells, which could both kill antigen-presenting cells expressing this complex in vitro, and significantly delay the onset of hyperglycemia in mouse models of T1DM. However, over time CAR-T cells became progressively exhausted, there was no discernible difference in T1DM incidence among groups by week 30. On the other hand, another study explored the use of 5MCAR-T cells with five structure modules, which demonstrated lasting effects for up to 1 year in vivo. These CAR-T cells prevented T1DM onset, attenuated islet inflammatory response, and alleviated symptoms by specifically recognizing and eliminating CD4+ T cells expressing the BDC 2.5 T cell receptor.[27] In addition to CAR-T cells, researchers have investigated CAR-Tregs for T1DM. For instance, anti-HPi2 (clone HIC1-2B4.2B) CAR-Tregs demonstrated functional activity, however, their rapid exhaustion due to the multiple expression of HPi2 on all CD4+ T cells created a constant activation signal that hindered sustained in vivo function.[28] Similarly, insulin-specific CAR-Tregs lasted up to 4 months in vivo but failed to prevent T1DM development.[29] Additionally, tetraspanin 7, a membrane protein highly expressed on the surface of pancreatic β cells, was found to be inadequate recognized by CARs.[30] These setbacks may stem from inappropriate target antigens. Continued research endeavors are indispensable to refine and optimize these approaches, ensuring a tailored and effective therapeutic strategy for T1DM.

MS

MS is an autoimmune-mediated inflammatory demyelinating disease of the central nervous system (CNS). The primary targets of the autoimmune attack are myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP).[31] Currently, studies exploring CAR-T therapy for MS largely rely on preclinical investigations using EAE mouse models.[32] Fransson et al[33] initially designed anti-MOG CAR-Tregs for EAE, demonstrating significant in vitro immunosuppressive effects. In vivo, these cells successfully reversed the disease state and prevented relapse. Moreover, the overall astrocyte proliferation and myelin production were more vigorous in the anti-MOG CAR-Treg treatment group, suggesting a broader influence. Similarly, another preclinical study showed that anti-MOG/MBP CAR-Tregs alleviated EAE disease scores and delayed disease progression.[34] In addition to the immune-regulatory effects of CAR-Tregs, anti-CD19 CAR-T cells have also promise in ameliorating EAE by targeting B cells, which contribute to autoantibody production. Gupta et al[35] reported that anti-CD19 CAR-T cells significantly reduced EAE scores, delayed disease onset, and maintained the absence of CD19+ B cells for over 25 weeks, surpassing the efficacy of CD20 antibodies. However, contrasting findings were observed in another experiment where injection of anti-CD19 CAR-T cells resulted in a worsened form of EAE after 2 weeks, with a broader range of pathological demyelination and axonal loss, despite helping clear meningeal B-cell deposits implicated in the immunopathology of MS.[36] This may be attributed to the diverse autoimmune mechanisms involved in EAE. As for the CNS autoimmune diseases such as EAE, what makes CAR-related therapy outperform mAbs is its ability to migrate to the CNS to exert therapeutic effects. For example, B cells were thoroughly depleted in the periphery and within the CNS by anti-CD19 CAR-T cells, indirectly proving their penetration into the CNS.[35] And anti-MOG CAR-Treg cells were also shown to localize in the soma of several brain structures such as whiter matter of cerebellum and relieve EAE score.[33] This characteristic of CAR-T cells makes them favorable candidates for the treatment of CNS autoimmune diseases, while the differing experimental outcomes necessitate comprehensive animal studies to underscore CAR therapy’s efficacy and safety profile in MS.

Neuromyelitis optica spectrum disorder (NMOSD)

NMOSD is a group of autoimmune-mediated CNS primary inflammatory demyelinating diseases that mainly involve the optic nerves and the spinal cord, with autoantibodies targeting aquaporin (AQP)-4. Binding of AQP4-IgG produced by plasma cells to AQP4 on the surface of astrocytes recruits granulocytes and activates the complement system,[37] resulting in optic nerve and spinal cord injury. Qin et al[38] used anti-BCMA CAR-T cells in treating R/R AQP4-IgG-positive NMOSD. The primary outcome was safety, which was mainly reflected in hematologic toxicity, including leukopenia (100%), neutropenia (100%), anemia (50%), and thrombocytopenia (25%), and cytokine release syndrome (CRS) (grades 1–2). Notably, grade 3 and higher infections occurred mainly in patients over 60 years old with long-standing autoimmune dysfunction and use of immunosuppressants for more than 20 years. In terms of clinical manifestations, 11 (92%) patients achieved drug-free remission during a median follow-up period of 5.5 months, and showed varying degrees of improvement in scales, vision, ambulation, and voluntary urination and defecation; and serologic markers such as AQP4-IgG was also reduced, affirming anti-BCMA CAR-T cells’ efficacy and safety for AQP4-IgG-positive NMOSD patients. Moreover, the role of AQP4-IgG suggests the feasibility of constructing anti-AQP4 CAAR-T cells, specifically eliminating autoantibody-producing plasma cells, which aligns with the precise treat-to-target goal.

Myasthenia gravis (MG)

MG is an autoimmune disease caused by neuromuscular junction synaptic lesions.[39] It mainly manifests as morbid fatigue of the affected muscles, with severe cases impinging on respiratory muscles, leading to dyspnea. Current treatments for MG include cholinesterase inhibitors, immunosuppressants, and glucocorticoids. However, there are still a subset of patients showing resistance to these modalities. As a result, precise immunotherapy is emerging as a promising approach for MG treatment. For example, anti-muscle tyrosine kinase (MuSK) CAAR-T cells have been designed and have shown specific cytotoxicity against anti-MuSK B cell receptor (BCR)-expressing B cell in preclinical studies,[40] laying the groundwork for the clinical application of CAR therapy for MG. Apart from targeting autoantibodies like MuSK, anti-BCMA CAR-T cells also hold the potential for MG treatment. Recently, CAR-T cells engineered with RNA (rCAR-T) targeting BCMA were used to treat 14 patients with generalized MG. Remarkably, these rCAR-T cells displayed significant reductions in MG severity scales for up to 9 months of follow-up, with no observed adverse reactions such as dose-limiting toxicity, CRS or neurotoxicity. The use of temporary and non-replicable mRNA in these CAR-T cells reduces signal amplification, leading to decreased side effects and enabling outpatient infusions.[41] Currently, there are four ongoing clinical trials of CAR-T cell therapy targeting BCMA and CD19, as well as CAAR-T cell therapy targeting MuSK for MG treatment [Supplementary Table 3, https://links.lww.com/CM9/B986].

PV

PV is an autoimmune skin disorder, characterized by IgG that attacks desmoglein-1 (Dsg1) and Dsg3 depositing at the surface of keratinocytes.[42] Treating PV with glucocorticoids presents challenges, including increased infection risk and relapse after drug withdrawal.[43] To address these challenges, Ellebrecht et al[12] engineered anti-Dsg3 CAAR-T cells to specifically eliminate self-reactive B cells. This experiment verified that these cells can recognize and kill anti-Dsg B cells in vitro, as well as significantly improve gross and serologic performance in vivo. Notably, anti-Dsg3 CAAR-Ts demonstrated efficacy akin to anti-CD19 CAR-T cells in eliminating CD19+ Nalm-6 B cells expressing anti-Dsg3 BCRs from PV patients. Furthermore, the presence of anti-Dsg antibody in the blood of patients was simulated, proving that the antibody does not neutralize, but rather bolsters the efficacy and persistence of CAAR-T. Another experiment demonstrated that anti-Dsg3 CAAR-T cells can decrease serum and tissue-bound autoantibodies and target cell burden.[44] Overall, the preclinical findings strongly support the efficacy of CAAR-T cell therapy for PV. Accordingly, a phase I clinical trial of anti-Dsg3 CAAR-T cell therapy for mucosa-dominated PV is currently underway [Supplementary Table 3, https://links.lww.com/CM9/B986].

Other autoimmune diseases

In addition to these well-studied autoimmune diseases, CAR-T therapy is being expanded to diverse conditions.

Inflammatory bowel disease (IBD)

IBD includes Crohn’s disease and ulcerative colitis, which are both autoimmune disorders occurring in genetically predisposed populations in the presence of environmental triggers such as smoking and unhealthy diet.[45] Elinav et al[46] engineered anti-TNP CAR-Tregs using 2,4,6-trinitrophenol (TNP) as the target antigen in a mouse model of ulcerative colitis. Administering CAR-Tregs before or after the induction of ulcerative colitis could both improve the survival of mice. Another experiment improved the lentiviral transduction technique and reached a similar conclusion.[47] Apart from TNP, flagellin derived from Escherichia coli H18 (FliC) can also be utilized as target antigen. Accordingly, Boardman et al[48] devised anti-FliC CAR Tregs and demonstrated promising suppressive capability, suggesting the initial success of CAR-Treg therapy for IBD.

Sjögren’s syndrome (SS)

Characterized by dry mouth and eyes, severe SS can affect multiple systems without a current cure. Since anti-La/Sjögren’s syndrome B antigen (SSB) autoantibodies have been shown to be one of the serological hallmarks of SS, Meng et al[49] engineered anti-LaA CAAR-NK92MI cells, in which LaA is one of the key epitopes of autoantigens La/SSB. Promisingly, anti-LaA CAAR-NK92MI cells demonstrated specific cytotoxicity against anti-LaA antibody-positive SS patient blood samples.

Antisynthetase syndrome (ASS)

ASS is a severe subtype of idiopathic inflammatory myopathy mediated by anti-synthetase antibodies attacking cytoplasmic aminoacyl-tRNA synthetases involved in protein synthesis.[50] B cell depletion has shown promise in controlling disease progression and achieving radically cure ASS, which is initially verified by three case reports utilizing anti-CD19 CAR-T cells to treat patients with severe/refractory ASS. After CAR-T infusion, clinical manifestations and serologic markers of the three patients were all improved.[51–53]

Multifocal motor neuropathy (MMN)

MMN is considered to be mediated by autoimmunity and characterized by progressive asymmetric weakness.[54] A case report demonstrated symptomatic and serologic improvement of MMN in a 53-year-old patient with diffuse large B-cell lymphoma and coexisting refractory MMN after CAR-T treatment. Although the patient experienced severe adverse reactions, including grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS) and grade 2 CRS, the report still raised great potentials of CAR-T cells in depleting autoreactive B cells.[55]

Necrotizing crescentic glomerulonephritis (NCGN)

NCGN induced by anti-neutrophil cytoplasmic autoantibody (ANCA) is an autoimmune disease that lacks efficient treatment regimens. Recently, anti-CD19 CAR-T cells have been applied and exhibited considerable efficacy, protecting mice from kidney injury by infiltrating into lymphoid organs and kidneys, and depleting B cells, plasmablasts, and intermediate plasma cells, while with plasma cells spared. Although efficient, whether residual plasma cells could lead to disease relapse needs to be further verified due to the limited follow-up time currently.[56]

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis

CAR-T cell therapy was also utilized to treat NMDAR encephalitis, an autoimmune disorder characterized by autoantibodies against NMDAR subunit. The ex and in vivo experiments demonstrated that anti-NMDAR CAAR-T cells well combined the ability of activation, cytotoxicity, proliferation with high specificity and without off-target toxicity, holding promise in providing curative options for autoimmune encephalitis. Anti-NMDAR CAAR-T cells were also found in the meninges, suggesting their possible route into brain through the leptomeninges.[57]

Remaining Challenges for CAR-T Cell Therapy in Autoimmune Diseases

Through preclinical and clinical studies investigating CAR-related therapy for various autoimmune diseases, promising efficacy in serology and gross manifestations for CAR-T, CAAR-T, and CAR-Treg were observed. In addition to these findings, it is crucial to delve into other pivotal dimensions of CAR-T therapy, including the occurrence of adverse events, the persistence of therapeutic effects, and the potential resistance observed in patients [Supplementary Figure 1, https://links.lww.com/CM9/B986]. We also compared the incidence of side effects and persistence of CAR-related therapy between autoimmune diseases and hematological malignancies, with the aim of further optimizing CAR-T therapy for diverse autoimmune diseases.

Adverse effects CRS

The main adverse effect of CAR-T therapy is CRS, which involves the excessive release of cytokines by immune cells,[58] provoking a systemic inflammatory response. In clinical trials targeting hematological tumors, the incidence of CRS commonly surpasses 70%, sometimes escalating to severe grades,[2,59–65] even evolving into fulminant hemophagocytic lymphohistiocytosis.[66] However, no cases of grade 3 or higher CRS have been reported in clinical trials of CAR-T for autoimmune diseases.[14,19,38,67] This divergence may attribute to the higher target burden in hematologic tumors compared to autoimmune diseases.

ICANS

ICANS is characterized by symptoms such as headache, tremor, speech disturbance, delirium, and impaired consciousness, and in severe cases, cerebral edema. CAR-T cells are significantly increased in the cerebrospinal fluid of patients with ICANS, leading to direct toxic effects on brain cells.[68] Additionally, the destruction of blood–brain barrier results in enormous cytokines leakage into the brain, exacerbating neurotoxicity.[69] Clinical trial data reveal that neurotoxicity often accompanies higher-grade CRS.[2,60,61,63,64] To date, ICANS has not been reported in clinical trials of CAR-T for autoimmune diseases.[14,19,38,67]

Hematotoxicity

Hematotoxicity refers to conditions such as anemia, leukopenia, thrombocytopenia, or combinations thereof. Early onset of hematotoxicity may result from lymphocyte depletion prior to CAR-T treatment, while later onset may be associated with hematopoietic stem cell transplantation prior to CAR-T treatment and the severity of CRS during treatment.[70] In a clinical trial of anti-BCMA CAR-T cells for relapsed/refractory NMOSD, the most common grade 3 and higher adverse event was hematotoxicity,[38] while no prolonged or delayed cytopenias have been reported to date in the treatment of autoimmune diseases during the longest follow-up of 17 months.[19,38,52]

Off-target toxicity and on-target off-tumor toxicity

Off-target toxicity and on-target off-tum