CAR-T AND autoimmune diseases in nervous system

CAR-T AND autoimmune diseases in nervous system | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 24 February 2025 V1 Latest version Share on CAR-T AND autoimmune diseases in nervous system Authors : Shun-yu Yao , Miao-qiao Du , Huan Yang , Qiu-ming Zeng , Hao Zhou , Xiuli Zhang , Sugimoto Kazuo , Jia Liu , Lan-xin Lin , Xu-hui Kang , Dai-yi Jiang , and Yong Peng 0000-0001-8390-7668 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174037565.55680073/v1 274 views 218 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract not-yet-known not-yet-known not-yet-known unknown Chimeric Antigen Receptor T-cell (CAR-T) therapy, an innovative method in cancer immunotherapy, has shown remarkable effectiveness in addressing several hematological malignancies. Recent developments in immunology indicate that CAR-T therapy could potentially be applicable to treating autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. This review aims to explore the mechanisms underlying CAR-T therapy in both cancer and autoimmune diseases, highlighting the similarities and differences in its therapeutic targets and immune modulation strategies.The therapy mainly operates by genetically altering T cells to recognize and target specific antigens present on cancer cells or dysfunctional immune cells associated with autoimmune reactions. In autoimmune diseases, CAR-T can be designed to target pathogenic B cells, T cells, or other immune cell populations responsible for tissue damage. While the application of CAR-T in autoimmune diseases remains largely experimental, early clinical studies show promising results, though challenges such as immune tolerance, cytokine release syndrome, and neurotoxicity remain.Furthermore, this review examines the latest advancements and clinical implementations of CAR-T therapy in treating autoimmune disorders of the nervous system, such as Myasthenia Gravis, Neuromyelitis Optica Spectrum Disorder, Guillain-Barré Syndrome, Idiopathic Inflammatory Myopathy, Multiple Sclerosis, Autoimmune Encephalitis, and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. Despite being in its early stages, CAR-T therapy presents a novel and highly promising strategy for modulating the immune system in autoimmune diseases, with the potential to reshape therapeutic paradigms in the future. CAR-T AND autoimmune diseases in nervous system Shun-yu Yao 1,2 , Miao-qiao Du 1,2 , Huan Yang 3 , Qiu-ming Zeng 3 , Hao Zhou 3 , Xiuli Zhang 4 , Sugimoto Kazuo 5,6 , Jia Liu 5,6 , Lan-xin Lin 1,2 , Xu-hui Kang 1,2 , Dai-yi Jiang 1,2 , Yong Peng 1,2* 1 Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China. 2 Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan 412000, China. 3 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 4 Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, China 5 Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. 6 Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, China. * Correspondence: Yong Peng Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Renmin Road 571, Zhuzhou, Hunan, 412000, People’s Republic of China Tel: +86-731-28290233 Cellular: +86-13973398998 Fax: +86-731-28290077 E-mail: [email protected] , [email protected] Researcher ID: G-9270-2018 ORCID identifier: 0000-0001-8390-7668 Abstract: Chimeric Antigen Receptor T-cell (CAR-T) therapy, an innovative method in cancer immunotherapy, has shown remarkable effectiveness in addressing several hematological malignancies. Recent developments in immunology indicate that CAR-T therapy could potentially be applicable to treating autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. This review aims to explore the mechanisms underlying CAR-T therapy in both cancer and autoimmune diseases, highlighting the similarities and differences in its therapeutic targets and immune modulation strategies.The therapy mainly operates by genetically altering T cells to recognize and target specific antigens present on cancer cells or dysfunctional immune cells associated with autoimmune reactions. In autoimmune diseases, CAR-T can be designed to target pathogenic B cells, T cells, or other immune cell populations responsible for tissue damage. While the application of CAR-T in autoimmune diseases remains largely experimental, early clinical studies show promising results, though challenges such as immune tolerance, cytokine release syndrome, and neurotoxicity remain.Furthermore, this review examines the latest advancements and clinical implementations of CAR-T therapy in treating autoimmune disorders of the nervous system, such as Myasthenia Gravis, Neuromyelitis Optica Spectrum Disorder, Guillain-Barré Syndrome, Idiopathic Inflammatory Myopathy, Multiple Sclerosis, Autoimmune Encephalitis, and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. Despite being in its early stages, CAR-T therapy presents a novel and highly promising strategy for modulating the immune system in autoimmune diseases, with the potential to reshape therapeutic paradigms in the future. Graphical abstract Keywords: CAR-T therapy, autoimmune diseases, immunotherapy, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, immune modulation, cytokine release syndrome，Myasthenia Gravis，Neuromyelitis Optica Spectrum Disorder，Idiopathic Inflammatory Myopathy，Multiple Sclerosis，Autoimmune Encephalitis，Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease，Guillain-Barré Syndrome Highlights: 1. Success of CAR-T Therapy in Cancer Immunotherapy : CAR-T cell therapy has demonstrated significant efficacy in the treatment of various hematological malignancies, marking a revolutionary advancement in cancer immunotherapy. 2. Potential of CAR-T in Autoimmune Diseases : This section discusses the fundamental principles of immune diseases and the similarities between immune system disorders and tumors in terms of CAR-T therapy. Recent immunological research indicates that CAR-T therapy also holds potential for application in autoimmune diseases. 3. Application of CAR-T in Neuroimmunological Diseases : The development of CAR-T therapy for neuroimmunological disorders is progressively advancing and encompasses seven treatment-resistant conditions. This section delves into the therapeutic mechanisms, available animal models, and clinical findings. Studies indicate that CAR-T therapy shows promising results, especially in treating refractory cases. 4. Immune Modulation Mechanism: CAR-T cells are engineered to target cancer or dysfunctional immune cells, thereby regulating immune responses. In autoimmune diseases, CAR-T can be designed to target pathogenic B cells, T cells, and other immune cell populations, thereby suppressing excessive immune reactions. 5. Challenges and Future Development: Although CAR-T therapy holds significant promise for treating autoimmune diseases, issues like immune tolerance, cytokine release syndrome (CRS), and neurotoxicity persist. Future research, including combination therapies and optimization of CAR-T safety profiles, may enhance its therapeutic efficacy. Introduction Chimeric Antigen Receptor T-cell (CAR-T) therapy, an innovative form of immunotherapy, has transformed the approach to treating hematologic malignancies. By genetically modifying a patient’s T cells to express chimeric receptors targeting specific cancer antigens, CAR-T therapy has shown remarkable success in treating B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (Mitra et al 2023). This innovative approach has not only transformed cancer therapy but also raised interest in its potential application for treating autoimmune diseases(Fesnak et al 2016). Autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes, are distinguished by an excessive immune reaction that targets the body’s own tissues.These disorders affect millions globally and present significant treatment challenges. Current therapies often involve broad-spectrum immunosuppressive drugs, which can alleviate symptoms but fail to provide long-term disease control and are associated with severe side effects(Bao et al 2022). Therefore, more targeted therapeutic strategies are urgently needed(Mitra et al 2023). While CAR-T therapy has demonstrated significant efficacy in treating cancer, its use in autoimmune diseases remains experimental (Blache et al 2023). Unlike in cancer, where CAR-T cells target malignant cells, in autoimmune conditions, CAR-T can be designed to target particular immune cells—such as pathogenic B cells, autoreactive T cells, or other immune components driving the autoimmune reaction (Schett et al 2023). This precision-based approach may offer a more effective treatment, potentially providing long-term benefits with fewer side effects than conventional therapies(Bao et al 2022). This review seeks to examine the mechanisms and potential applications of CAR-T therapy in autoimmune diseases, with a focus on neuroimmunological disorders. It contrasts the therapeutic approaches employed in cancer and autoimmune conditions, outlines ongoing clinical trials, addresses the challenges specific to autoimmune contexts, and suggests directions for future research. By examining CAR-T’s role in both cancer and autoimmune diseases of the nervous system, we seek to highlight its broader potential for immune system modulation and its transformative implications for the treatment of autoimmune disorders 2. Overview of CAR-T Therapy 2.1 Definition of CAR-T Therapy Chimeric Antigen Receptor T-cell (CAR-T) therapy signifies a transformative advancement in immunotherapy, demonstrating remarkable effectiveness in addressing hematologic malignancies (Melenhorst et al 2022). This individualized treatment method entails genetically modifying a patient’s T cells to produce a synthetic receptor, termed a chimeric antigen receptor (CAR), which enables the recognition and targeting of specific antigens on cancer cells (Miao et al 2022) .In contrast to natural T cells, which depend on antigen presentation through the major histocompatibility complex (MHC), CAR-T cells are designed to directly identify tumor-associated antigens. This bypasses MHC restrictions, allowing for a robust and targeted immune response (Kalos et al 2011, Melenhorst et al 2022). The CAR structure epitomizes synthetic biology’s potential, combining domains from distinct biological origins into a functional therapeutic receptor.A CAR usually comprises an extracellular domain for antigen recognition, sourced from monoclonal antibodies, a transmembrane segment that secures the receptor to the T cell membrane, and an intracellular domain responsible for signaling and activating the T cell following antigen binding(Locke et al 2022). Recent advancements have integrated co-stimulatory signaling domains (e.g., CD28, 4-1BB) to enhance CAR-T cell proliferation, persistence, and anti-tumor activity in vivo(Mazinani & Rahbarizadeh 2022). This innovative design underpins the transformative potential of CAR-T therapy, which has already demonstrated durable remission in patients with otherwise refractory malignancies(Kaljanac & Abken 2023). 2.2 The Process of Manufacturing CAR-T Cells The generation of CAR-T cells involves a series of complex, highly controlled steps, each critical to ensuring the final product’s safety, specificity, and efficacy. This process leverages advances in cell engineering, molecular biology, and clinical-grade cell manufacturing to produce a living drug tailored to individual patients(Jayaraman et al 2020). 2.2.1 Collection of T Cells via Leukapheresis The procedure commences with leukapheresis, during which T cells are harvested from the patient’s peripheral blood. This procedure isolates T cells while reinfusing other blood components back into the patient, minimizing discomfort and risk. The collected T cells serve as the foundation for CAR-T cell therapy(Jayaraman et al 2020). 2.2.2 Genetic Engineering of T Cells After isolation, T cells undergo genetic modification to express the CAR, usually accomplished through viral transduction with lentiviral or retroviral vectors. These vectors deliver the CAR-encoding genes into the T cells, ensuring stable integration and expression (Arjomandnejad et al 2022, Pan et al 2022). The CAR is designed to recognize tumor-specific antigens, such as CD19 in B-cell malignancies, bypassing the need for antigen presentation via MHC. Additionally, the inclusion of intracellular co-stimulatory domains (e.g., CD28, 4-1BB) augments T cell activation, expansion, and persistence, significantly improving clinical efficacy(Melenhorst et al 2022). 2.2.3 Expansion and Quality Control After transduction, the engineered T cells are expanded ex vivo under carefully controlled conditions.In this stage, cytokines like interleukin-2 (IL-2) are employed to promote proliferation, resulting in the production of millions of CAR-T cells. Rigorous quality control testing ensures that the cells meet predefined safety, potency, and purity criteria(Glienke et al 2022). These tests include sterility assays, transduction efficiency assessments, and functionality tests to confirm that the CAR-T cells can recognize and kill target cells(Rodriguez-Otero et al 2023). 2.2.4 Patient Conditioning and Cell Infusion Before CAR-T cell infusion, patients typically undergo lymphodepleting chemotherapy. This preparatory step reduces the patient’s native immune cells, creating a favorable environment for the infused CAR-T cells to expand and function effectively(Miao et al 2022). The CAR-T cells are then thawed and reinfused into the patient intravenously. Post-infusion, the cells actively seek out and eliminate cancer cells, often exhibiting memory-like properties that enable long-term surveillance and protection against disease recurrence (Melenhorst et al 2022). 2.2.5 Current Challenges and Future Directions Despite its success, CAR-T therapy faces significant challenges.The potential for serious adverse reactions, including cytokine release syndrome (CRS) and neurotoxicity, underscores the need for meticulous patient surveillance(Zhang et al 2020) . Moreover, the high production costs and long manufacturing timelines limit accessibility.Investigators are examining universally applicable CAR-T cells sourced from healthy individuals, which may lower expenses and enhance accessibility (Lin et al 2021) . Furthermore, initiatives to apply CAR-T therapy to solid tumors and autoimmune conditions are in progress, with early findings suggesting possible effectiveness across a wider range of clinical scenarios (Kaljanac & Abken 2023). By addressing these challenges through technological and procedural refinements, CAR-T therapy is poised to expand beyond hematologic malignancies, paving the way for a new era of precision medicine (Bao et al 2022). 2.3 The precise mechanism of CAR-T therapy on cancer The exact methodology of Chimeric Antigen Receptor (CAR) T cell therapy has transformed cancer treatment, especially for hematological cancers like B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). The fundamental concept of CAR-T therapy involves utilizing genetically modified T cells to accurately and effectively target tumor-specific antigens. These engineered T cells are designed to overcome the limitations of conventional T cell responses, making them a powerful weapon in the fight against cancer(Mitra et al 2023). The therapeutic process begins with the extraction of a patient’s T cells, which are genetically modified to express CARs capable of recognizing specific antigens on tumor cells, such as CD19 in B-cell malignancies.Chimeric antigen receptors (CARs) are engineered receptors that consist of an extracellular domain for antigen binding, usually sourced from a monoclonal antibody, connected to intracellular signaling components, including CD3ζ and costimulatory molecules such as CD28 or 4-1BB. Upon recognizing an antigen, these domains trigger downstream signaling cascades, which result in T cell activation, expansion, and the destruction of tumor cells (Zhang et al 2021). A notable characteristic of CAR-T therapy is the sustained presence of engineered T cells within the body. Clinical research has shown that CAR-T cells can be detected in patients’ peripheral blood for 3 to 6 months, preserving their anti-tumor efficacy over an extended duration(Finney et al 2019, Martinez & Moon 2019). This persistence is critical for achieving sustained remission, with approximately 30–40% of patients attaining long-term remission, potentially indicative of a functional cure (Kersten et al 2020). The effectiveness of CAR-T cells is inherently based on their capacity to circumvent the MHC-restricted antigen presentation necessary for native T cells. By directly identifying surface antigens on tumor cells, CARs facilitate potent immune responses regardless of MHC compatibility.Furthermore, the integration of costimulatory signaling domains augments T cell expansion, cytokine secretion, and resilience against exhaustion, all of which are crucial for eliminating cancer cells(Raje et al 2019). However, the robust activity of CAR-T cells is not without challenges.The treatment frequently results in significant adverse reactions, notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These side effects stem from the overactivation of CAR-T cells, which triggers the unrestrained release of pro-inflammatory cytokines like IL-6 and IFN-γ. The severity of these reactions correlates with the tumor burden at the time of treatment, as larger tumor loads result in heightened T cell activation and cytokine production (Kersten et al 2020). Strategies to mitigate these toxicities include the use of corticosteroids, anti-IL-6 receptor antibodies, and optimized dosing regimens (Bao et al 2022). Although CAR-T therapy has achieved remarkable success in hematological malignancies, it encounters substantial challenges in treating solid tumors. Such obstacles comprise an immunosuppressive tumor microenvironment, varied antigen expression, and physical barriers that hinder CAR-T cell penetration. To address these challenges, researchers are exploring novel approaches such as engineering CAR-T cells to secrete pro-inflammatory cytokines, incorporating suicide genes to enhance safety, and combining CAR-T therapy with immune checkpoint inhibitors(Kersten et al 2020). As of April 2023, six CAR-T therapies have been approved, reflecting the rapid evolution and clinical validation of this innovative approach.Present research efforts are centered on enhancing the understanding and optimization of the mechanisms governing CAR-T cell activation and longevity, reducing adverse effects, and expanding the utility of CAR-T therapy to a wider range of cancer types. This confluence of molecular engineering, immunology, and clinical innovation underscores the transformative potential of CAR-T therapy as a precise and powerful tool in the fight against cancer (Abramson 2020, D’Agostino & Raje 2020). 2.4 The possible mechanism of CAR-T therapy on autoimmune disease The potential mechanisms of CAR-T therapy, initially successful in cancer treatment, are now being investigated as a novel therapeutic approach for autoimmune diseases (Mougiakakos et al 2021). This therapy involves engineering T cells to specifically target and eliminate pathological antigens, offering a more precise alternative to conventional autoimmune disease treatments. CAR-T therapy is characterized by fewer side effects and longer-lasting therapeutic effects compared to traditional immunosuppressive therapies (Sun et al 2023) .These T cells, modified with CARs, secrete cytotoxic substances like perforin and granzymes to target autoreactive immune cells and also direct both effector and regulatory T cells (Tregs) into the autoimmune milieu, thereby enhancing immune regulation and promoting the restoration of self-tolerance (Labanieh & Mackall 2023). The multidimensional action of CAR-T therapy makes it a promising approach for treating autoimmune diseases(Blache et al 2023). The mechanisms by which CAR-T therapy affects autoimmune diseases can be primarily divided into three key approaches: 1.Cytotoxic Activity Against Target Cells: CAR-T cells achieve their cytotoxic function through the recognition and direct elimination of target cells expressing specific antigens. These target cells are often autoreactive immune cells, especially B cells producing pathogenic autoantibodies. For instance, in systemic lupus erythematosus (SLE), CD19-targeted CAR-T cells are used to reduce the number of CD19+ B cells, which are responsible for producing harmful autoantibodies. Upon infusion, these CAR-T cells expand in the patient’s body and specifically target and deplete B cells, thus reducing the inflammatory responses and immune dysregulation characteristic of SLE(Bao et al 2022, Blache et al 2023). This approach offers a more precise and targeted therapy compared to broad immunosuppressive agents typically used in autoimmune diseases(Mougiakakos et al 2021). 2.Chimeric Autoantibody Receptor T Cells (CAAR-T): CAAR-T cells represent an advanced form of CAR-T therapy, specifically designed to target B cells that secrete autoantibodies. For example, in the case of myasthenia gravis (MG), MuSK CAAR-T cells are engineered to target and eliminate B cells producing muscle-specific tyrosine kinase (MuSK) antibodies. The extracellular domain of the MuSK antigen is incorporated into the CAR, allowing these cells to specifically target and destroy pathogenic B cells responsible for the autoimmune damage in MG. By selectively depleting these B cells, CAAR-T cells can reduce disease progression and improve clinical outcomes in patients with MG(Oh et al 2023). 3.CAR-Regulatory T Cells (CAR-Tregs): CAR-Treg therapy entails modifying Tregs to direct and regulate the activity of autoreactive immune cells, thereby reestablishing immune balance.In autoimmune diseases such as type 1 diabetes (T1D), CAR-Treg therapy uses second-generation CAR constructs containing insulin-specific single-chain variable fragments (scFvs) and the Foxp3 sequence, a key marker for Tregs. These CAR-Tregs are derived from CD4+ T effector cells and are reprogrammed to become insulin-specific Tregs (CAR-cTregs). By targeting autoreactive T cells and other immune cells involved in autoimmune damage, CAR-Tregs help mitigate immune-mediated tissue destruction and restore self-tolerance. This approach holds significant potential for diseases driven by immune dysregulation and could provide a more targeted therapeutic option compared to conventional treatments(Terskikh et al 1997). In summary, CAR-T therapy for autoimmune diseases leverages the precision of genetically modified immune cells to specifically target and modulate the immune system(Bao et al 2022). This approach offers a more specific, effective, and long-lasting alternative to traditional treatments, which often rely on broad immunosuppressive strategies that fail to address the root causes of autoimmune diseases. By targeting autoreactive immune cells and enhancing immune regulation through engineered Tregs, CAR-T therapy could provide a more tailored and efficient therapeutic option for autoimmune diseases in the near future(Oh et al 2023). 2.5 The shared mechanism of CAR-T therapy on autoimmune disease and cancer Despite the seemingly contrasting nature of cancer and autoimmune diseases, both share several underlying immunological mechanisms (Rahat & Shakya 2016). These conditions are both characterized by dysregulation of the immune system—cancer typically involves immune evasion or suppression, whereas autoimmune diseases result from hyperactivation of immune responses(Sakowska et al 2022). This fundamental connection suggests that strategies targeting immune tolerance and immune cell regulation could be beneficial in the treatment of both diseases(Niccolai et al 2020, Sakowska et al 2022). Over the years, these fields were considered separate, with minimal overlap in therapeutic approaches.Recent advancements, such as the identification of immune checkpoints and the creation of inhibitors targeting PD-1 and CTLA-4(Rahat & Shakya 2016), have highlighted the importance of investigating autoimmune diseases for the advancement of cancer therapies (Masetti et al 2021) .The understanding that immune dysregulation is crucial in both cancer and autoimmunity has spurred the creation of common therapeutic approaches, such as those aimed at immune checkpoints (Niccolai et al 2020). Chronic inflammation is a common hallmark of both cancer and autoimmune diseases(Cappelli & Shah 2020). It contributes to immune system dysfunction, promotes tumorigenesis, and increases the risk of malignancies in patients with autoimmune disorders. Furthermore, the microenvironments in both cancerous and autoimmune tissues exhibit significant similarities, such as hypoxia and the infiltration of immune cells like macrophages, neutrophils, and T cells(Franks & Slansky 2012, Giat et al 2017). Significantly, recent research has demonstrated that dysbiosis, or an imbalance in the microbiota, can influence immune responses, thereby contributing to the development of both cancer and autoimmune diseases(Niccolai et al 2020). These findings highlight the importance of the microbiota as a potential link between these two conditions and suggest that improving microbiota health could provide therapeutic opportunities(Cappelli & Shah 2020, Franks & Slansky 2012). The connection between autoimmune diseases and cancer operates in both directions. Individuals with autoimmune rheumatic conditions exhibit an increased likelihood of certain cancers (Chen et al 2019), with the extent of this risk differing based on the specific autoimmune disease (Blache et al 2023) . The persistent inflammation and autoimmunity in these patients are intricately linked to the development of cancer (Masetti et al 2021). Conversely, some cancer therapies, particularly immune-based treatments, may induce autoimmune-like conditions. This intersection of cancer and autoimmunity has led to a renewed focus on CAR-T cell therapy, which was originally developed for cancer treatment but is now being investigated for autoimmune diseases such as systemic lupus erythematosus (SLE) and myasthenia gravis (MG) (Pavlasova & Mraz 2020). The potential of CAR-T therapy lies in its ability to modulate immune cell activity in both cancer and autoimmune diseases by targeting specific immune components(Gurrea-Rubio & Fox 2022). In cancer therapy, CAR-T cells are modified to recognize tumor-specific antigens, thereby facilitating the elimination of cancer cells (Gurrea-Rubio & Fox 2022) . For autoimmune conditions, CAR-T cells can be engineered to target autoreactive B or T cells, thereby restoring immune tolerance. A prime example is the use of CD20-targeting CAR-T therapies, which have demonstrated efficacy in treating B-cell lymphomas and autoimmune diseases such as rheumatoid arthritis (RA) (Steinmetz et al 2009). Another promising target is CXCR3, a chemokine receptor found on a range of immune cells such as T cells, dendritic cells, and natural killer (NK) cells, as well as on non-immune cells including fibroblasts and endothelial cells. CXCR3 ligands play a crucial role in immune cell recruitment, and research has shown that targeting this axis could effectively manage both autoimmune diseases and cancer(Barash et al 2014, Nagpal et al 2006). In rheumatoid arthritis, for instance, elevated CXCR3 expression correlates with increased levels of CXCL9 and CXCL10 in synovial fluid, indicating its involvement in disease pathogenesis(Kuo et al 2018, Ruschpler et al 2003). Furthermore, the CXCR3 pathway has been associated with the progression of lupus nephritis and inflammatory bowel disease (IBD) (Van Raemdonck et al 2015). In cancer, CXCR3 ligands contribute to immune cell recruitment into the tumor microenvironment, where they promote anti-tumor immunity. CXCR3+ lymphocytes, attracted by CXCL9 and CXCL10, infiltrate tumors and inhibit tumor growth in various cancer types. Additionally, CXCL4 and CXCL4L1, known for their antiangiogenic properties, prevent metastatic spread by inhibiting lymphangiogenesis, further enhancing anti-tumor immunity. These findings suggest that targeting CXCR3 ligands could represent a dual therapeutic strategy for treating both cancer and autoimmune diseases(Zheng et al 2014). Interleukin-6 (IL-6), a pivotal pro-inflammatory cytokine, is also essential in the pathogenesis of both autoimmune disorders and cancer. IL-6 contributes to the differentiation of Th17 cells and serves as a primary mediator of inflammatory responses in conditions such as rheumatoid arthritis (Gurrea-Rubio & Fox 2022) .A number of IL-6 inhibitors have been authorized for the treatment of RA, and current research is investigating IL-6 as a potential therapeutic target in cancer, especially prostate cancer, where the IL-6-STAT3 signaling pathway plays a role in tumor advancement.Furthermore, COX-2 inhibitors, including celecoxib and rofecoxib, which are employed to address osteoarthritis and inflammation associated with RA, have demonstrated potential in enhancing survival rates among patients with colon cancer and non-small cell lung cancer; however, their cardiovascular risks continue to be a matter of concern (Chen et al 2000, Liu et al 2015). In preclinical studies, the CD6-CD318 axis has emerged as a potential target for both cancer and autoimmune diseases(Gurrea-Rubio & Fox 2022) .The inhibition of CD6 has demonstrated the ability to impede the differentiation of Th1 and Th17 cells, while concurrently augmenting the cytotoxic functions of T cells and NK cells. These findings suggest that targeting CD6 and its ligand CD318 could reduce autoimmune disease activity by modulating effector T cell differentiation, while also stimulating anti-cancer immune responses. This dual-targeting approach could hold significant promise for treating both conditions concurrently(Gurrea-Rubio & Fox 2022). Although CAR-T therapy holds significant promise for treating both autoimmune diseases and cancer, it is not without certain challenges.Cancer treatments can sometimes induce autoimmune-like syndromes, underscoring the need for careful patient management (Gurrea-Rubio & Fox 2022) Current research efforts are directed toward enhancing the safety and effectiveness of CAR-T cells, with particular emphasis on developing regulatory CAR-T cells and chimeric autoantibody receptor T cells to more effectively tackle cancer and autoimmune diseases. These advancements may lead to improved and safer treatment options for patients affected by these conditions(Blache et al 2023). Please see figure 1 3. The Role of CAR-T in the Treatment of Autoimmune Diseases in Nervous system 3.1 Myasthenia Gravis (MG) Myasthenia gravis (MG) is an autoimmune condition marked by compromised neuromuscular signaling as a result of autoantibodies directed against acetylcholine receptors (AChRs) or muscle-specific kinase (MuSK) (Gilhus 2016) . Conventional therapies, including corticosteroids and wide-ranging immunosuppressants, frequently entail notable adverse effects and inconsistent effectiveness, highlighting the necessity for more precise treatment approaches.Recent progress in Chimeric Antigen Receptor T-cell (CAR-T) therapy has demonstrated significant promise in the treatment of MG (Gilhus 2016, Motte et al 2024). CD19-targeted CAR-T therapy has emerged as a promising strategy in both preclinical and clinical settings. In mouse models of MG, CD19-CAR-T cell treatment resulted in a substantial reduction in AChR-specific autoantibodies and improved muscle strength (Motte et al 2024). In clinical applications, anti-CD19 CAR-T cells have induced sustained remission in patients with refractory MG by depleting autoreactive B cells and reducing circulating autoantibodies (Tian et al 2024). Notably, single-cell RNA sequencing of immune cell populations from treated patients identified proliferating cytotoxic-like CD8+ T cell clones as key effectors in reversing autoimmunity (Tian et al 2024). In addition to CD19 targeting, CAR-T cells specific to BCMA have shown encouraging outcomes in the management of MG. In a clinical trial utilizing RNA-engineered CAR-T cells (rCAR-T) targeting BCMA, 14 patients experienced significant improvements in MG severity scores, with a follow-up period extending up to 9 months. In addition to CD19 targeting, CAR-T cells specific to BCMA have shown encouraging outcomes in the management of MG.The use of non-replicating mRNA to engineer these CAR-T cells minimizes signal amplification, facilitating outpatient administration and reducing the risk of severe adverse effects(Liu et al 2024). MuSK-specific CAR-T cells represent another innovative approach. Anti-MuSK chimeric autoantibody receptor T (CAAR-T) cells have been engineered to selectively target MuSK autoantibody-producing B cells, exhibiting high specificity and cytotoxicity in preclinical studies(Oh et al 2023) .These encouraging preclinical results have prompted the launch of clinical trials, including the Descartes-08 CAR-T cell trial (NCT04146051), aimed at assessing the safety and effectiveness of MuSK-targeted CAR-T cells in individuals with generalized MG. Emerging therapies, including B cell-specific monoclonal antibody-siRNA conjugates (Ibtehaj et al 2023) and mesenchymal stem cell therapy (Yu et al 2010), are complementing the growing repertoire of immunomodulatory treatments.These targeted therapies provide multiple benefits compared to conventional immunosuppressants, such as a more rapid onset of action, diminished side effects, and the possibility of sustained long-term disease remission (Menon et al 2020). To summarize, CAR-T cell therapy signifies a transformative approach in the management of MG (Sukockiené et al 2024) . Through its precise targeting of pathogenic B cells and modulation of immune responses, CAR-T therapies hold the potential to revolutionize treatment outcomes for MG. Ongoing clinical trials are essential for refining these approaches, optimizing efficacy, and expanding their applicability to other autoimmune neuromuscular disorders (Motte et al 2024, Tian et al 2024). 3.2 Neuromyelitis Optica Spectrum Disorder (NMOSD) Neuromyelitis optica spectrum disorder (NMOSD), a rare yet serious autoimmune condition affecting the central nervous system (CNS), is marked by repeated episodes of inflammation and demyelination, primarily targeting the optic nerves and spinal cord (Qin et al 2024b) . The disease is often associated with autoantibodies targeting aquaporin-4(AQP4-IgG), which lead to complement activation and astrocyte damage.Clinically, NMOSD may lead to substantial disability, such as blindness and paralysis, profoundly affecting patients’ quality of life (Uzawa et al 2024). Current treatment strategies primarily focus on immunosuppression using therapies such as corticosteroids, azathioprine, rituximab, and eculizumab. While these treatments can reduce relapse rates and disease progression, they are often associated with limited efficacy in refractory cases, long-term toxicity, and a heightened risk of infections due to broad immunosuppression(Shi et al 2022). Against this backdrop, recent advancements in chimeric antigen receptor (CAR) T-cell therapy have shown promising potential to address these challenges by offering a targeted and more precise immunotherapy approach.A phase 1 trial evaluating anti-BCMA CAR T-cells in patients with AQP4-IgG-positive NMOSD yielded remarkable outcomes: 92% (11 out of 12) of participants attained remission without medication, accompanied by notable clinical enhancements, such as restored vision, enhanced mobility, and improved management of bladder and bowel functions, over a median follow-up period of 5.5 months (Qin et al 2023). Blood and cerebrospinal fluid (CSF) analyses revealed significant reductions in AQP4-IgG levels and the depletion of pathogenic plasmablasts and plasma cells, highlighting the efficacy and safety of this approach. Single-cell analyses demonstrated that the primary effectors were proliferating cytotoxic-like CD8+ CAR T-cells, which successfully traversed the blood-brain and blood-CSF barriers to eradicate plasmablasts and plasma cells within the cerebrospinal fluid(Qin et al 2023) This unique capability suggests that CAR T-cells can target immune cells within the central nervous system (CNS) while minimizing off-target effects, differentiating them from conventional therapies.Moreover, preclinical models of experimental autoimmune encephalomyelitis (EAE) have shown that disease suppression can be achieved using anti-CD19 and myelin-specific CAR T-cells, underscoring their potential utility in a wider range of CNS autoimmune disorders (De Paula Pohl et al 2020, Gupta et al 2023). Notably, the therapeutic effect of anti-CD19 CAR T-cells in EAE was observed independently of complete B-cell depletion, suggesting alternative immunomodulatory mechanisms(Gupta et al 2023). These findings have opened new avenues for precision medicine approaches in NMOSD, including the development of anti-AQP4 chimeric autoantibody receptor (CAAR) T-cells that specifically eliminate autoantibody-producing plasma cells (Brittain et al 2024). This strategy aligns with treat-to-target principles and offers a tailored, long-term therapeutic option for patients with refractory NMOSD. Current ongoing clinical trials further validate this potential, such as studies investigating BAFFR CAR-T (NCT06561009) and universal CAR-T cells targeting BCMA (NCT06633042) These studies seek to assess the safety and effectiveness of CAR T-cell therapy in refractory AQP4-IgG-positive NMOSD, expanding upon prior findings that indicate a promising safety record and few adverse events, such as diminished risks of cytokine release syndrome and neurotoxicity(Liu et al 2024). By synthesizing these clinical and preclinical findings, CAR T-cell therapy is establishing itself as a pioneering immunotherapeutic strategy for NMOSD, providing notable clinical advantages and the prospect of sustained remission.As research progresses, CAR T-cells may establish a new paradigm for managing NMOSD and other autoimmune CNS diseases (Shahabifard et al 2023). 3.3 Multiple Sclerosis (MS) The nervous system (NS) constitutes a sophisticated network that governs and harmonizes bodily functions. It encompasses the central nervous system (CNS), which consists of the brain and spinal cord, and the peripheral nervous system (PNS), linking the CNS to the remainder of the body(Correale et al 2017) . Disorders of the NS, particularly autoimmune diseases like multiple sclerosis (MS), present significant therapeutic challenges.MS is a chronic, inflammatory condition marked by immune-mediated damage to the myelin sheath and axons, resulting in progressive neurological impairment. Although there have been advancements in comprehending its pathogenesis, MS remains without a cure, and current therapies predominantly aim to manage symptoms, decrease relapses, and retard disease progression (Marcus 2022). The clinical management of MS faces several challenges. Traditional disease-modifying therapies (DMTs), such as interferons, glatiramer acetate, and monoclonal antibodies targeting B cells (e.g., ocrelizumab and rituximab), can reduce disease activity but are associated with significant limitations, including incomplete efficacy, frequent relapses, and risks of adverse effects, such as infections and malignancies(Yamout et al 2024) Advanced treatments, including hematopoietic stem cell transplantation (HSCT), provide the potential for sustained remission but also entail significant risks, such as therapy-associated mortality and profound immunosuppression. These limitations highlight the urgent need for innovative approaches that can more effectively target the complex immune mechanisms underlying MS while minimizing off-target effects(Correale et al 2017). Recent developments in CAR-T cell therapy have shown its promise in addressing multiple sclerosis (MS), especially its progressive variants.A groundbreaking clinical study provided the first evidence of CD19-targeted CAR-T cell therapy’s safety and potential efficacy in two progressive MS patients (Fischbach et al 2024, Rankin & Shah 2024) The administration of CD19 CAR-T cells was well-tolerated, with no occurrences of immune effector cell-related neurotoxicity syndrome (ICANS), even though CAR-T cells were identified in the cerebrospinal fluid (CSF). Notably, a significant reduction in intrathecal antibody production was observed in one patient, sustained until day 64 post-infusion. This suggests that CAR-T cells, through expansion and targeted depletion of CD19+ B cells in the central nervous system (CNS), could modulate the pathogenic immune response in MS without inducing neurotoxicity. Preclinical research corroborates these results, demonstrating that anti-CD19 CAR-T cells can mitigate experimental autoimmune encephalomyelitis (EAE), a commonly utilized animal model of multiple sclerosis (MS), through the depletion of B cells in both peripheral tissues and the central nervous system (Gupta et al 2023) .Furthermore, engineered regulatory T cells (Tregs) that express myelin-specific chimeric antigen receptors (CARs) have shown effectiveness in inhibiting autoimmune reactions in EAE models, presenting another potential approach for cell-based therapies (De Paula Pohl et al 2020) .Nonetheless, translating preclinical findings into therapeutic approaches for humans presents a considerable challenge, largely because of the intricate interactions among immune cells in the pathogenesis of MS, including B cells, T cells, and elements of the innate immune system (Baker & Amor 2015) (Ma et al 2023). In comparison to traditional MS therapies, CAR-T cell therapy offers unique advantages, including precise immune modulation and durable responses. Current treatments, such as monoclonal antibodies targeting B cells, are effective but may require continuous administration and carry risks of immune-related adverse events. CAR-T cells, by contrast, can provide sustained depletion of pathogenic B cells, potentially reducing the need for repeated treatments and offering long-term disease control(Teoh & Chng 2021). Beyond CD19-targeted approaches, alternative strategies are under investigation to further enhance therapeutic efficacy. Liver-directed gene therapy has shown promise in inducing antigen-specific regulatory T cells, effectively reversing disease progression in EAE models (Keeler et al 2018). Other cell therapy strategies include myelin-forming oligodendrocyte replacement, hematopoietic stem cell transplantation, and mobilization of endogenous stem cells, which aim to restore CNS integrity and function (Ma et al 2023). Ongoing clinical trials, such as the evaluation of CC-97540 in relapsing or progressive MS (NCT06220201), are expected to provide valuable insights into the safety, tolerability, and efficacy of advanced cell-based therapies. As research progresses, CAR-T cell therapy holds promise not only as a transformative treatment for MS but also as a blueprint for addressing other autoimmune diseases of the nervous system. Larger clinical trials are essential to validate these findings, optimize protocols, and establish CAR-T therapy as a viable option in the management of MS and beyond (Brittain et al 2024). This growing body of evidence underscores CAR-T therapy’s potential to revolutionize the treatment of MS, offering hope for patients with limited therapeutic options and paving the way for novel interventions in neuroimmunology. 3.4 Autoimmune Encephalitis (AE) AE comprises a diverse array of inflammatory autoimmune disorders predominantly impacting the brain tissue, meninges, and spinal cord, with an annual incidence rate of roughly 1 in 100,000 (Brittain et al 2024, Shang et al 2024) . It represents 10-20% of encephalitis cases and is characterized by a subacute onset of seizures, cognitive impairment, and psychiatric disturbances, all of which substantially affect the quality of life for those impacted.Conventional therapies, such as steroids, intravenous immunoglobulin, and plasmapheresis, frequently prove insufficient, especially in cases that are resistant to treatment (Shin et al 2018). B cells are crucial in the pathogenesis of AE through the production of autoantibodies that target both neuronal cell surface and intracellular antigens. Depending on the antigen’s location, the autoantibodies associated with AE can be classified into those directed against neuronal cell surface antigens and those targeting intracellular antigens.Directing CAR-T cells against CD19 or B-cell maturation antigen (BCMA) has shown efficacy in reducing B cells within both peripheral and central nervous system (CNS) tissues, providing a more targeted and enduring method for treating AE (Gupta et al 2023, Qin et al 2024b). Case reports and initial clinical trials have indicated that CAR-T therapy possesses transformative potential for immune-mediated neurological disorders. Notably, CD19-CAR-T cells have exhibited effectiveness in reducing symptoms of antibody-mediated encephalitis, particularly in patients who are unresponsive to standard treatments. Notably, in conditions such as systemic lupus erythematosus, idiopathic inflammatory myositis, and systemic sclerosis, CD19-CAR-T therapy has helped patients achieve remission and discontinue long-term immunosuppressive treatments.Notably, substantial clinical improvements have also been documented in patients with neuromyelitis optica spectrum disorder and myasthenia gravis(Brittain et al 2024, Müller et al 2024). Experimental studies further confirm the therapeutic potential of CAR-T in AE.Anti-CD19 CAR-T cells have demonstrated substantial therapeutic advancement in experimental autoimmune encephalomyelitis (EAE), a frequently utilized animal model for AE, by reducing B cell populations in both peripheral lymphoid tissues and the central nervous system. One study revealed that transferring anti-CD19 CAR-T cells into C57BL/6 mice pretreated with cyclophosphamide and immunized with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) resulted in significantly reduced clinical scores and lymphocyte infiltration compared to cyclophosphamide treatment alone.Notably, in the absence of B cell depletion or antigen specificity, CAR-T cells appeared to enhance disease outcomes, indicating that alternative immune regulatory mechanisms might play a role in the observed therapeutic benefits(Gupta et al 2023). Although direct clinical trials targeting AE with CAR-T therapy are still limited, existing evidence underscores its potential as a groundbreaking treatment strategy. Unlike conventional therapies, CAR-T cells offer a more targeted and potentially curative approach to managing autoimmune-mediated inflammation.Moreover, no notable adverse events, including immune effector cell-related neurotoxicity syndrome (ICANS), have been observed, indicating a promising safety profile in AE patients undergoing CAR-T cell therapy(Blache et al 2023). However, challenges remain, such as optimizing CAR design, preventing relapse, and ensuring long-term safety (Sell et al 2021). 3.5 Idiopathic Inflammatory Myopathy (IIM) Chimeric antigen receptor T-cell (CAR-T) therapy demonstrates significant potential for treating idiopathic inflammatory myopathies (IIM), a category of rare autoimmune disorders marked by persistent muscle inflammation, weakness, and systemic complications. Existing treatments for IIM, such as glucocorticoids and immunosuppressive therapies, frequently result in considerable side effects and incomplete remission, underscoring the critical need for novel therapeutic approaches. Recent advances in CAR-T therapy offer hope for addressing these challenges, leveraging its ability to target specific immune components while minimizing off-target effects(Dourado et al 2023, Silva et al 2022). Preclinical research employing murine models has shown the effectiveness and safety of CAR-T therapy, featuring notable suppression of tumor growth and enhanced survival rates in both autoimmune and oncological settings(Jin et al 2019). Specifically, mouse models of IIM have provided valuable insights into disease pathogenesis and therapeutic mechanisms(Afzali et al 2017, Okiyama et al 2024). Enhanced CAR-T designs, such as those engineered to secrete IL-18 or IL-12, have shown superior in vivo expansion, persistence, and efficacy, even without preconditioning regimens (Avanzi et al 2018, Kueberuwa et al 2018). These findings underscore the adaptability and potential of CAR-T cells in treating immune-mediated diseases. Clinical evidence has further reinforced the therapeutic promise of CAR-T cells in IIM and related autoimmune disorders. CD19-targeted CAR-T cells have demonstrated remarkable success in treating refractory anti-SRP necrotizing myopathy, severe myositis, and systemic sclerosis, achieving sustained B-cell depletion and significant clinical remission (Qin et al 2024a). In a groundbreaking study, CRISPR-Cas9-engineered, CD19-directed CAR-T cells derived from healthy donors were used to treat a patient with refractory immune-mediated necrotizing myopathy. The infused cells persisted for over three months, achieved complete B-cell depletion within two weeks, and led to a profound remission with no serious adverse events during a six-month follow-up(Wang et al 2024). These findings highlight CAR-T’s potential to induce durable remission with a favorable safety profile compared to conventional therapies (Qin et al 2024a). Ongoing clinical trials further exemplify CAR-T’s expanding role in autoimmune diseases, including systemic lupus erythematosus, ANCA-associated vasculitis, and IIM (NCT06462144, NCT06548607, NCT06549296). CAR-T therapy offers distinct advantages, such as fewer side effects, longer-lasting effects, and improved accessibility through allogeneic CAR-T platforms (Mitra et al 2023). The integration of advances in myositis classification, diagnostics, and outcome measures into trial designs promises to optimize therapeutic outcomes and expand CAR-T applications(Wang et al 2024). Although challenges remain, such as mitigating risks like cytokine release syndrome and optimizing target selection, the progress in CAR-T research underscores its transformative potential for IIM (Connolly et al 2024). With continued clinical and preclinical advancements, CAR-T therapy is poised to redefine the treatment landscape for IIM and other autoimmune diseases, addressing current limitations and significantly improving patient outcomes(Kale et al 2024). 3.6 Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) Myelin oligodendrocyte glycoprotein antibody-related disorder (MOGAD) is an uncommon autoimmune condition marked by demyelination within the central nervous system, manifesting in diverse clinical presentations including optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis(Ambrosius et al 2020, Pedapati et al 2020). Diagnosis relies on detecting MOG-specific antibodies using cell-based assays and MRI imaging (Ambrosius et al 2020). Current treatment strategies focus on managing acute attacks with high-dose corticosteroids and plasma exchange, followed by long-term immunosuppressants like azathioprine, mycophenolate mofetil, and rituximab for relapse prevention. Intravenous immunoglobulins (IVIG) have also demonstrated efficacy in reducing relapse frequency and improving disability outcomes(Hacohen et al 2018). However, despite these interventions, some patients experience refractory disease, necessitating novel therapeutic approaches. Recent progress in cell-based immunotherapy, especially chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated potential in meeting the unmet needs of MOGAD. CAR-T therapy, which has transformed cancer treatment, is currently being investigated for its applicability to autoimmune diseases.In the experimental autoimmune encephalomyelitis (EAE) model, which is commonly employed to study demyelinating diseases, CD19-targeted CAR-T cells successfully eliminated B cells from both peripheral tissues and central nervous system areas, showcasing substantial therapeutic effectiveness (Gupta et al 2023). These findings suggest that targeting autoreactive B cells, which play a critical role in MOGAD pathogenesis, could mitigate disease activity. A groundbreaking case report highlighted the application of CD19-directed CAR-T therapy in an 18-year-old patient with refractory MOGAD who had suffered multiple relapses despite conventional immunotherapies. Following C(Cabrera-Maqueda et al 2024). This case underscores the safety and efficacy of CAR-T therapy in refractory MOGAD and highlights its potential to provide durable remission. Advancements in CAR-T cell engineering, including the incorporation of synthetic notch (synNotch) receptors and cytokine-releasing components, could improve specificity, durability, and treatment efficacy. SynNotch-CAR-T cells, initially developed for glioblastoma, hold promise for central nervous system autoimmune disorders due to their improved targeting and reduced off-target effects(Choe et al 2021). Additionally, liver-directed gene therapies inducing MOG-specific regulatory T cells have shown efficacy in reversing disease symptoms in mouse models, offering complementary approaches to CAR-T therapy (Keeler et al 2018). While the potential of CAR-T therapy in MOGAD is immense, challenges remain. The rarity of MOGAD complicates large-scale clinical trials, and the heterogeneity of patient responses necessitates personalized therapeutic strategies. Further research is needed to optimize CAR-T protocols, mitigate risks such as cytokine release syndrome (CRS), and establish long-term safety and efficacy(Hacohen et al 2018). Ongoing clinical trials and preclinical studies will be instrumental in advancing this innovative therapy, potentially transforming the management of MOGAD and other central nervous system autoimmune disorders(De Paula Pohl et al 2020, Derdelinckx et al 2021). not-yet-known not-yet-known not-yet-known unknown 3.7 Guillain-Barré Syndrome（GBS） Recent research has underscored the promise of chimeric antigen receptor (CAR) T-cell therapy for managing immune-mediated conditions, such as Guillain-Barré Syndrome (GBS), a peripheral neuropathy marked by swiftly advancing weakness and loss of reflexes.Although conventional therapies like plasma exchange and intravenous immunoglobulin continue to be central to GBS management, their limitations in facilitating complete recovery have spurred interest in innovative therapeutic approaches (Shahrizaila & Yuki 2011). CAR-T therapy, originally developed for hematologic malignancies, has demonstrated its ability to modulate immune responses by selectively targeting pathogenic immune cells. Although its application in GBS is still in its infancy, case reports suggest a complex interplay between CAR-T therapy and immune regulation in GBS, with rare instances of CAR-T-induced Guillain-Barré-like syndrome reported(Grant et al 2022). These results highlight the necessity for a deeper comprehension of CAR-T’s mechanisms and the refinement of its application to maximize its therapeutic benefits while minimizing adverse effects. The potential for CAR-T therapy in GBS lies in its capacity to target and eliminate autoreactive B cells, thereby reducing autoantibody production—a key driver of GBS pathogenesis.Notwithstanding these advances, considerable challenges persist, such as pinpointing ideal antigenic targets, mitigating risks like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and maintaining therapeutic efficacy without aggravating neurological symptoms(Brudno & Kochenderfer 2016, Neelapu et al 2018). Biomarkers such as ferritin levels and platelet counts may help predict neurotoxicity severity and guide safer clinical application(Karschnia et al 2019). Further research is crucial to define CAR-T therapy’s role in GBS, both as a novel treatment strategy and as a potential contributor to immune complications. By advancing our understanding of GBS immunopathology and optimizing CAR-T design to specifically target disease mechanisms, this innovative therapy holds promise to address the limitations of current treatments and improve outcomes for patients with GBS(Song et al 2023).Table 1 not-yet-known not-yet-known not-yet-known unknown 4. Innovations in CAR-T therapy The development of CAR-T cell therapy for neuroimmunological disorders is progressing swiftly, with a specific emphasis on enhancing both effectiveness and safety. One promising strategy is targeting specific antigens, as seen in myasthenia gravis (MG), where CAR-T therapy targeting B cells associated with anti-MuSK antibodies effectively reduces autoantibody production and inflammation, leading to significant clinical improvements(Haghikia et al 2024) .This method underscores the capability of CAR-T therapy to selectively target disease-specific immune cells without inducing widespread immune suppression. An additional novel approach entails the use of regulatory CAR-T cells (CAR-Tregs), engineered to re-establish immune tolerance and mitigate immune-driven damage in conditions like multiple sclerosis and autoimmune encephalitis.By introducing CAR-Tregs, researchers aim to suppress pathological immune responses that drive tissue damage, promoting long-term remission in these conditions. Clinical trials have shown promising results in the ability of CAR-Tregs to modulate immune responses without exacerbating systemic immunosuppression, thus potentially offering a safer alternative to conventional immunosuppressive treatments. In addition, multi-targeted CAR-T cells are being developed to overcome antigen escape, a phenomenon where tumor or immune cells evolve to evade targeted therapies. By targeting multiple antigens simultaneously, these CAR-T cells ensure continued therapeutic efficacy in complex diseases with heterogeneous antigens, such as relapsed or refractory cancers and neuroimmunological diseases(Sterner & Sterner 2021). For example, dual-target CAR-T cells targeting both CD19 and CD22 have shown efficacy in reducing antigen escape and improving outcomes in relapsed/refractory acute lymphoblastic leukemia(Hu et al 2021). Recent advancements also include the use of CRISPR/Cas9 gene editing and RNA engineering to enhance CAR-T cell therapy. CRISPR technology allows for precise genomic modifications, optimizing CAR-T cells to address challenges such as T cell exhaustion, toxicity, and manufacturing limitations (Kavousinia et al 2024) . For instance, CRISPR/Cas9 can be used to create CAR-T cells with enhanced persistence and reduced susceptibility to exhaustion, improving their long-term efficacy in neuroimmunological diseases.Furthermore, RNA-based methodologies are emerging as a means to regulate CAR-T cell activity in vivo, enabling more precise adjustment of their therapeutic impacts and reducing adverse effects like cytokine release syndrome (CRS) and neurotoxicity (Schaible et al 2023). For example, RNA-engineered CAR-T cells have shown promise in reducing CRS in clinical trials, offering a safer therapeutic alternative. Moreover, synthetic biology is being explored to develop genetic switches that provide spatiotemporal control over CAR-T cell activity, enhancing safety by preventing uncontrolled immune responses and minimizing off-target effects (Lu et al 2024). Despite these innovations, several challenges remain. For example, immune tolerance in neuroimmunological diseases presents a unique challenge, as the immune system must be carefully modulated without compromising the body’s ability to respond to infections.In multiple sclerosis (MS), cytokine release syndrome (CRS) may develop after CAR-T cell therapy, resulting in central nervous system (CNS) inflammation and potentially worsening disease manifestations. Mitigating these challenges might involve the use of combination treatments, such as integrating CAR-T therapy with immunomodulatory drugs or checkpoint inhibitors to enhance both safety and effectiveness.Moreover, customized CAR-T therapy, designed to address patient-specific antigens and immune responses, has the potential to surmount these challenges by providing more targeted treatment alternatives. This approach could be particularly beneficial in the context of neuroimmunological diseases, where the precise timing of immune modulation is critical to avoid damaging healthy CNS tissue (Li et al 2020, Tao et al 2024). In conclusion, while these innovations in CAR-T cell therapy are still in the early stages, they offer significant promise for treating neuroimmunological disorders. By overcoming current limitations, such as immune tolerance and CRS, and leveraging advanced technologies like CRISPR and RNA engineering, CAR-T therapies have the potential to revolutionize the treatment of diseases like MS, autoimmune encephalitis, and other CNS autoimmune diseases. As research continues, combination therapies and precision medicine approaches will be key to optimizing these therapies and expanding their applicability (Li et al 2020, Tao et al 2024). The future of CAR-T cell therapy lies in harnessing these innovations to offer more personalized, precise, and effective treatments for patients suffering from complex neuroimmunological diseases (Dimitri et al 2022). not-yet-known not-yet-known not-yet-known unknown 5. Conclusion To summarize, CAR-T cell therapy has shown considerable potential in addressing both hematologic malignancies and autoimmune disorders. In oncology, CAR-T cells have transformed the management of conditions like B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma by targeting particular tumor markers, resulting in notable clinical outcomes. In autoimmune diseases, particularly neuroimmunological conditions like MG, NMOSD and MS, CAR-T therapy has shown substantial potential in refractory or treatment-resistant cases, where conventional therapies often fail. CAR-T cells targeting B cells, such as CD19, BCMA, and MuSK, have proven effective in depleting pathogenic B cells, modulating immune responses, and improving clinical outcomes. These findings underscore the versatility of CAR-T cells in modulating the immune system across different disease contexts. Nonetheless, although the findings are encouraging, clinical data are still constrained in various autoimmune conditions, such as GBS and MOGAD, where CAR-T cell therapy is in its initial phases of investigation. The full therapeutic capacity in these disorders has yet to be thoroughly understood, and more extensive, multicenter trials are necessary to comprehensively assess the safety, efficacy, and long-term results of CAR-T therapy.Grasping the operational mechanisms, including the impact of B-cell depletion and T-cell modulation in these conditions, will be essential for refining CAR-T therapy and adapting it to particular autoimmune disorders. Looking forward, future research should focus on optimizing CAR-T cell design to improve their efficacy, targeting strategies, and safety profiles.Advancements like dual-targeted CAR-T cells and engineered CAR-T cells designed to target particular autoantibodies or immune cell populations offer promising new therapeutic pathways. Furthermore, combination treatments incorporating CAR-T cells, immune checkpoint inhibitors, or immunomodulatory drugs may augment overall therapeutic efficacy by synergistically addressing immune escape mechanisms and reducing adverse effects such as cytokine release syndrome (CRS) and neurotoxicity. Additionally, personalized CAR-T therapy, tailored to the specific immunopathology of individual patients, will likely become a critical strategy to address the complexity and heterogeneity of autoimmune diseases. Advances in synthetic biology, including genetic switches and spatiotemporal control, offer the potential to fine-tune CAR-T cell activity, ensuring that immune responses are both precise and safe, with minimal off-target effects. In conclusion, although CAR-T cell therapy demonstrates significant promise for treating autoimmune diseases, ongoing preclinical investigations, clinical trials, and studies into underlying mechanisms are crucial to enhance these treatments and broaden their utility to a wider array of neuroimmunological and systemic autoimmune conditions.As CAR-T technology continues to advance and is combined with complementary treatment methods, CAR-T therapy is set to emerge as a groundbreaking strategy in personalized medicine for autoimmune disorders, providing more effective and long-lasting therapeutic solutions for patients globally. not-yet-known not-yet-known not-yet-known unknown Abbreviations: AChR: Acetylcholine ReceptorAE: Autoimmune EncephalitisAIDs: Autoimmune DiseasesALL: Acute Lymphoblastic LeukemiaANCA: Anti-Neutrophil Cytoplasmic AntibodyAQP4: Aquaporin-4BCMA: B-Cell Maturation AntigenB-ALL: B-cell Acute Lymphoblastic LeukemiaCAR: Chimeric Antigen ReceptorCAR-T: Chimeric Antigen Receptor T-cellCAAR-T: Chimeric Autoantibody Receptor T-cellCNS: Central Nervous SystemCRS: Cytokine Release SyndromeCSF: Cerebrospinal FluidCTLA-4: Cytotoxic T-Lymphocyte-Associated Protein DLBCL: Diffuse Large B-Cell Lymphoma DMTs: Disease-Modifying Therapies EAE: Experimental Autoimmune Encephalomyelitis FL: Follicular Lymphoma GBS: Guillain-Barré Syndrome ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome IL-6: Interleukin-6 IIM: Idiopathic Inflammatory Myopathy IVIG: Intravenous Immunoglobulin MG: Myasthenia Gravis MM: Multiple Myeloma MOGAD: Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease MS: Multiple Sclerosis MuSK: Muscle-Specific Kinase MHC: Major Histocompatibility Complex NMOSD: Neuromyelitis Optica Spectrum Disorder NS: Nervous System RA: Rheumatoid Arthritis rCAR-T: RNA-Engineered Chimeric Antigen Receptor T-cell SLE: Systemic Lupus Erythematosus Tregs: Regulatory T Cells Figure Legend: Figure1 1) Chronic Inflammation: Both autoimmune diseases and cancer are characterized by persistent inflammation, which contributes to immune system dysfunction and tissue damage. 2) Immune Dysregulation: Autoimmune diseases result from immune hyperactivation, while cancer often involves immune evasion or suppression. CAR-T therapy targets dysregulated immune responses in both conditions. 3 )Microenvironmental Similarities: The hypoxic microenvironment and immune cell infiltration (e.g., macrophages, T cells) are common in both cancer and autoimmune tissues. 4) Microbiota Dysbiosis: Altered microbiota composition influences immune responses, linking autoimmune diseases and cancer. 5) Targeted Pathways: a. CXCR3 Axis: Regulates immune cell recruitment in both cancer and autoimmune diseases. b. IL-6 Pathway: A pro-inflammatory cytokine involved in Th17 differentiation, inflammation, and tumor progression. c. CD6-CD318 Axis: Modulates effector T cell differentiation and enhances anti-tumor immunity while reducing autoimmune activity. 6) Therapeutic Applications: CAR-T cells engineered for tumor-specific antigens (e.g., CD19, CD20) are being adapted to target autoreactive immune cells, restoring immune tolerance in autoimmune diseases. Table1 Disease CAR-T Target Efficacy Safety Clinical Trial Phase Clinical Trial ID Commercial Availability Trial Completion Status reference Myasthenia Gravis (MG) CD19, BCMA, MuSK Reduced AChR autoantibodies, sustained remission Favorable profile, no dose-limiting toxicities Phase 1/2 NCT04146051 No Phase1 （Gilhus, 2016; Motte et al., 2024; Tian et al., 2024） Neuromyelitis Optica Spectrum Disorder (NMOSD) BCMA, CD19, AQP4-IgG Significant clinical improvement; reduced AQP4-IgG levels Minimal CRS and neurotoxicity Phase 1 NCT06561009, NCT06633042 No Phase1 （Qin et al., 2023; Qin et al., 2024b; Brittain et al., 2024） Multiple Sclerosis (MS) CD19, Myelin-specific CARs Reduction in antibody production, modulation of immune response No ICANS observed; CNS safety demonstrated Phase 1 NCT06220201 No Phase1 （Fischbach et al., 2024; Rankin & Shah, 2024; Gupta et al., 2023） Autoimmune Encephalitis (AE) CD19, BCMA Effective in refractory cases, symptom alleviation Favorable with no significant ICANS Phase 1/2 NCT04146051 No Phase1 （Shang et al., 2024; Gupta et al., 2023; Brittain et al., 2024） Idiopathic Inflammatory Myopathy (IIM) CD19, Enhanced CAR-T designs Significant remission in refractory cases Favorable with reduced CRS risk Phase 1 NCT06462144 No Phase1 （Dourado et al., 2023; Wang et al., 2024; Qin et al., 2024a） Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) CD19 Clinical improvement in refractory cases Safety demonstrated in case studies Case study Case Report No Completed (Case Study) （Cabrera-Maqueda et al., 2024; Ambrosius et al., 2020; Hacohen et al., 2018） Guillain-Barr Syndrome (GBS) Autoreactive B cells Potential reduction in autoantibody production Safety data limited; potential adverse events Exploratory N/A No N/A （Brudno & Kochenderfer, 2016; Grant et al., 2022; Song et al., 2023） Ethics approval and consent to participate Not Applicable. This is a review. Consent for publication Not Applicable. Availability of data and materials Not Applicable Conflict of Interest The authors declare that the research was conducted without any commercial or financial relationships that could be construed as potential conflicts of interest. Credit authorship contribution statement Y.P. received funding support and developed the research hypothesis. YP, XHK, SYY, XLZ, SK, JL, MQD, LXL, DYJ, QC, HJ. wrote the main manuscript. The final manuscript is the end product of the joint writing efforts of all authors. Funding This work was supported by the Scientific Research Project of Hunan Provincial Health Commission, PR China (No. C202303076574 to YP), Key Plans of Hunan Administration Traditional Chinese Medicine, PR China (No. A2023039 to YP), University-Hospital Joint-Fund of Hunan University of Chinese Medicine, PR China (No. 2022XYLH198 to YP), Fund for Creative Research Group of Affiliated First Hospital of Hunan Traditional Chinese Medical College, PR China (No. 2021B-003 to YP), and Technology Plan Project of Zhuzhou City, Hunan Province, PR China (No. 2021-009 to YP). Acknowledgements not-yet-known not-yet-known not-yet-known unknown Thanks for the critical comments from Prof. Jian Yin, Department of Neurology, Beijing Hospital, Beijing, China. Reference： Abramson JS. 2020. Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. Transfusion medicine reviews 34: 29-33Afzali AM, Ruck T, Wiendl H, Meuth SG. 2017. 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Keyword autoimmunity Authors Affiliations Shun-yu Yao Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Miao-qiao Du Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Huan Yang Xiangya Hospital Central South University View all articles by this author Qiu-ming Zeng Xiangya Hospital Central South University View all articles by this author Hao Zhou Xiangya Hospital Central South University View all articles by this author Xiuli Zhang Hunan University of Chinese Medicine View all articles by this author Sugimoto Kazuo Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital View all articles by this author Jia Liu Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital View all articles by this author Lan-xin Lin Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Xu-hui Kang Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Dai-yi Jiang Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Yong Peng 0000-0001-8390-7668 [email protected] Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Metrics & Citations Metrics Article Usage 274 views 218 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shun-yu Yao, Miao-qiao Du, Huan Yang, et al. 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