CAR-T IS ONE OF THE MOST PROMISING STRATEGIES FOR REFRACTORY AUTOIMMUNE DISEASES: THERAPY ABOUT TO BE APPROVED BY THE FDA

M. Trakatelli^1*, M. Di Emidio² and C. Mortellaro³

¹ Second Department of Dermatology-Venerology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece;
² University of L’Aquila, L’Aquila, Italy;
³ Saint Camillus International University of Health Sciences, Rome, Italy.

*Correspondence to:
Myrto Trakatelli,
Second Department of Dermatology-Venerology,
Papageorgiou Hospital,
Aristotle University of Thessaloniki,
Thessaloniki, Greece.
e-mail: mtrakatelli@hotmail.com

Received: 06 April, 2026 Accepted: 18 May, 2026

ISSN 2279-5855 print / 3103-7364 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Autoimmune diseases occur when the immune system mistakenly attacks the body’s own healthy cells instead of protecting it from harmful invaders such as viruses and bacteria. Current treatments mainly rely on immunosuppressive and biologic drugs to reduce inflammation and immune activity, but they do not provide a definitive cure. Chimeric antigen receptor T-cell (CAR-T) therapy is a form of cellular immunotherapy in which a patient’s T cells are genetically engineered to express artificial receptors that recognize specific targets on diseased cells. These chimeric receptors combine antibody-based antigen recognition with T-cell activation and costimulatory signalling domains, enabling direct and highly specific immune responses. Upon binding to the target antigen, CAR-T cells become activated, proliferate, release cytokines, and destroy target cells through cytotoxic mechanisms independently of the major histocompatibility complex (MHC). In CAR-T therapy, a patient’s T cells are genetically modified to express a chimeric receptor consisting of an extracellular antigen-recognition domain, a transmembrane domain, and intracellular signalling domains that activate the T cell upon target recognition. The receptor combines an scFv antibody fragment for specific antigen binding with activation (CD3ζ) and costimulatory molecules (such as CD28 or CD137) that promote T-cell proliferation, survival, and cytotoxic activity. CAR-T therapy is approved for several hematological cancers and has recently shown promising results in severe, treatment-resistant autoimmune diseases, leading to the development of multiple Federal Drug Administration (FDA)-approved personalized CAR-T products. The use of CAR-T cells in autoimmune diseases is still under clinical development, but early results suggest they may represent one of the most promising advances in immunotherapy by targeting and eliminating autoreactive CD19-positive B cells.

KEYWORDS: CAR-T therapy, CD19, autoimmune disease, B lymphocyte, immunotherapy, T cell signalling

INTRODUCTION

Autoimmune diseases are a group of conditions in which the immune system, which normally protects us from viruses and bacteria, mistakenly attacks the body’s healthy cells (1).  These diseases are diverse and can affect various organs and tissues, causing chronic inflammation and systemic damage. Physiologically, the immune system recognizes what belongs to the body (self-proteins) and what is foreign to the body (non-self-proteins), such as viruses, bacteria, fungi, parasites, and foreign cells (for example, those from a heterologous transplant) (2).  In autoimmune diseases, this specific recognition mechanism no longer occurs, and the immune system begins to view certain cells in the body as enemies and attacks them, causing inflammation, damage, and cell death (3). Furthermore, the symptoms of autoimmune diseases vary greatly depending on the specific disease (4). However, they may present some common symptoms, such as joint or muscle pain, chronic fatigue, skin or internal organ problems, persistent low-grade fever, and frequent inflammation (5).  Specific clinical tests can identify autoimmune diseases, although symptoms can be confused with other conditions, making diagnosis difficult. Today, autoimmune diseases require treatments that aim to reduce inflammation and slow disease progression (6).  Additionally, immunosuppressive drugs or biologics are used to reduce the immune system’s attack. However, these are nonspecific therapies with unwanted side effects that cannot eradicate the diseases. (7).

Chimeric antigen receptor T-cell (CAR-T) therapy is a cellular immunotherapy in which a patient’s T cells are genetically modified to recognize and kill tumor cells (8). The mechanism involves both molecular aspects and the use of a chimeric receptor, which is an artificial receptor created by combining elements from different proteins to achieve a new or enhanced function (9).  Generally, a chimeric receptor is a receptor artificially obtained by fusing functional domains from different molecules to confer new recognition or signalling capabilities (10). CAR-T is an immunotherapy that designs receptors that allow immune cells to recognize specific targets. The molecular mechanism of CAR-T cells involves the expression of a chimeric receptor that combines direct antibody recognition of a tumor antigen with the T-cell signalling machinery (CD3ζ and costimulatory domains) (9). Binding between the receptor and antigen induces intracellular activation, clonal expansion, cytokine secretion, and perforin/granzyme and Fas/FasL-mediated cytotoxicity, a reaction that leads to the elimination of target cells without the involvement of the major histocompatibility complex (MHC) (11).

CAR-T therapy is already approved for treating several hematological cancers and recent studies have yielded promising results for treating severe, treatment-resistant autoimmune diseases such as systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, and dermatomyositis (Table I). This has led to the development of multiple personalized CAR-T products approved by the Federal Drug Administration (FDA).

Table I. List of the most common autoimmune diseases that could potentially be treated with CAR-T therapy.

DISCUSSION

In CAR-T therapy, an immune T cell is genetically modified to express a receptor composed of an external portion that recognizes a molecule present on the tumor cell; a transmembrane portion that crosses the cell membrane; and an internal portion that activates the T cell when the target is recognized (12).

The extracellular recognition domain is generally composed of a single-chain variable fragment (scFv) derived from a monoclonal antibody that directly recognizes an antigen expressed on the tumor cell surface (e.g., CD19 in B-cell tumors) (13).  The hinge region, or spacer, is a segment of the chimeric antigen receptor (CAR) that connects the antigen-recognition domain (scFv) to the transmembrane domain (14). This gives the receptor flexibility and determines the optimal distance between the T cell and the target cell.

The transmembrane domain binds the CAR to the lymphocyte’s plasma membrane, while the intracytoplasmic domain is a signalling domain and includes CD3ζ, the main activation signal (Signal 1), and costimulatory molecules such as CD28, CD137 (more rarely OX40, ICOS) (Signal 2), which are necessary for proliferation and survival (15).

CAR-T therapy can be applied to the treatment of certain blood cancers, such as lymphomas and leukemias, and to the research of autoimmune diseases. In recent years, CAR-T therapy used for hematological diseases has also shown satisfactory results in severe and refractory autoimmune diseases (16).

Several personalized CAR-T immunotherapies, in which a patient’s own T cells are harvested, genetically modified to recognize target cells, and then reinfused into the patient, have been approved by the FDA (Table II) (17).

Table II. CAR-T therapy for cancer, lymphoma, and multiple myeloma already approved by the FDA.

All CAR-Ts approved in the United States are still intended for hematological cancers, and now, after convincing laboratory trials, the FDA is expected to approve CAR-T therapy for autoimmune diseases (16). Many autoimmune diseases are driven by B lymphocytes (CD19) that produce autoantibodies directed against the body’s own tissues (18).  This experimental therapy uses CAR-T cells directed against CD19, a protein present on the surface of B lymphocytes (19). CAR-T cells eliminate these cells, allowing the immune system to respond appropriately, using a new population of B lymphocytes with less reactivity toward self-cells (20).  The advantages of using CAR-T therapy in autoimmune diseases have been convincingly demonstrated by several independent groups of researchers (21). This therapy selectively eliminates autoreactive cells, an effect due to the elimination of CD19 lymphocytes and, consequently, the harmful antibodies they produce (19).  It has been observed that even after a single treatment, a long-lasting remission can be achieved, unlike traditional immunosuppressive therapies that require long-term treatment (22).

After depletion of autoreactive CD19 B lymphocytes, the immune system reboots and can generate a less pathological B lymphocyte population. This therapy leads to a reduction in the use of immunosuppressive drugs such as corticosteroids and reduces the side effects of long-term therapies. CAR-T therapy has proven particularly attractive in patients who have failed multiple standard treatments, offering a new therapeutic option. For example, patients with very severe systemic lupus erythematosus (SLE) refractory to conventional therapies, treated with CAR-T therapy in Europe (Germany, University Hospital Erlangen), led by rheumatologist and immunologist Georg Schett and Fabian Müller’s team, achieved clinical remission after the use of an anti-CD19 drug (23).

Another important example where CAR-T therapy has been very promising is in rheumatoid arthritis (24). Rheumatoid arthritis is a chronic, debilitating disease, and the use of CAR-T therapy has proven to be a highly innovative strategy, especially in patients with severe disease resistant to other conventional therapies (25).  In rheumatoid arthritis, B lymphocytes actively participate in the disease by producing self-reacting antibodies. CAR-T therapy can inhibit the production of these antibodies, the presentation of antigens to T lymphocytes, and reduce the production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) (26).

CONCLUSIONS

Currently, the use of CAR-T cells in autoimmune diseases is still in the clinical development phase, but the results already obtained are considered among the most promising advances in immunotherapy. CAR-T therapy is an innovative treatment that reduces autoreactive CD19 lymphocytes in autoimmune diseases, interrupting the immunopathological cascade. However, the available data comes mainly from preliminary studies and small patient groups, a gap that will certainly be filled in future studies.

Conflict of interest

The authors declare that they have no conflict of interest.

REFERENCES

1. Abeles I, Palma C, Meednu N, Payne AS, Looney RJ, Anolik JH. B Cell-Directed Therapy in Autoimmunity. Annual review of immunology. 2024;42(1):103-126. doi:https://doi.org/10.1146/annurev-immunol-083122-044829
2. Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB. T Cell Response in Experimental Autoimmune Encephalomyelitis (EAE): Role of Self and Cross-Reactive Antigens in Shaping, Tuning, and Regulating the Autopathogenic T Cell Repertoire. Annual Review of Immunology. 2002;20(1):101-123. doi:https://doi.org/10.1146/annurev.immunol.20.081701.141316
3. Cao G, Lin MY, Gu W, et al. The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts. Life Sciences. 2023;328:121877-121877. doi:https://doi.org/10.1016/j.lfs.2023.121877
4. Carabotti M, Lahner E, Esposito G, Sacchi MC, Severi C, Annibale B. Upper gastrointestinal symptoms in autoimmune gastritis. Medicine. 2017;96(1):e5784. doi:https://doi.org/10.1097/md.0000000000005784
5. Paik JJ, Vencovský J, Charles-Schoeman C, et al. Brepocitinib, a potent and selective TYK2/JAK1 inhibitor: scientific and clinical rationale for dermatomyositis. Clinical and experimental rheumatology. 2024;43(2):354-363. doi:https://doi.org/10.55563/clinexprheumatol/eeglsa
6. Robinson WH, Lepus CM, Wang Q, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nature Reviews Rheumatology. 2016;12(10):580-592. doi:https://doi.org/10.1038/nrrheum.2016.136
7. Jansen MHA, Rondaan C, Legger GE, et al. EULAR/PRES recommendations for vaccination of paediatric patients with autoimmune inflammatory rheumatic diseases: update 2021. Annals of the Rheumatic Diseases. 2022;82(1):35-47. doi:https://doi.org/10.1136/annrheumdis-2022-222574
8. Shimoyama T. Rinsho Ketsueki. 2023;64(11):1447-1455. doi:https://doi.org/10.11406/rinketsu.64.1447
9. Haradhvala NJ, Leick MB, Maurer K, et al. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nature Medicine. 2022;28(9):1848-1859. doi:https://doi.org/10.1038/s41591-022-01959-0
10. Choi T, Kang Y. Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma. Pharmacology & Therapeutics. 2021;232:108007. doi:https://doi.org/10.1016/j.pharmthera.2021.108007
11. Appleman LJ, Tzachanis D, Grader-Beck T, van Puijenbroek AAFL, Boussiotis VA. Helper T cell anergy: from biochemistry to cancer pathophysiology and therapeutics. Journal of Molecular Medicine. 2001;78(12):673-683. doi:https://doi.org/10.1007/s001090000180
12. Giraudo M, Jackson Z, Das I, Abiona O, Wald D. Chimeric Antigen Receptor (CAR)-T Cell Therapy for Non-Hodgkin’s Lymphoma. Pathogens & immunity. 2024;9(1):1-17. doi:https://doi.org/10.20411/pai.v9i1.647
13. Hudecek M, Sommermeyer D, Kosasih PL, et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer immunology research. 2015;3(2):125-135. doi:https://doi.org/10.1158/2326-6066.CIR-14-0127
14. Goebeler ME, Bargou RC. T cell-engaging therapies — BiTEs and beyond. Nature Reviews Clinical Oncology. 2020;17(7):418-434. doi:https://doi.org/10.1038/s41571-020-0347-5
15. Wu W, Zhou Q, Masubuchi T, et al. Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy. Cell. 2020;182(4):855-871.e23. doi:https://doi.org/10.1016/j.cell.2020.07.018
16. Brudno JN, Maus MV, Hinrichs CS. CAR T Cells and T-Cell Therapies for Cancer. JAMA. 2024;332(22). doi:https://doi.org/10.1001/jama.2024.19462
17. Kattamuri L, Lal BM, Vojjala N, et al. Safety and efficacy of CAR-T cell therapy in patients with autoimmune diseases: a systematic review. Rheumatology International. 2025;45(1). doi:https://doi.org/10.1007/s00296-024-05772-5
18. Abramson JS. Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. Transfusion Medicine Reviews. 2020;34(1):29-33. doi:https://doi.org/10.1016/j.tmrv.2019.08.003
19. Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. The Lancet. 2023;402(10416). doi:https://doi.org/10.1016/s0140-6736(23)01126-1
20. Hunter TL, Bao Y, Zhang Y, et al. In vivo CAR T cell generation to treat cancer and autoimmune disease. Science. 2025;388(6753):1311-1317. doi:https://doi.org/10.1126/science.ads8473
21. Scherlinger M, Nocturne G, Radic M, et al. CAR T-cell therapy in autoimmune diseases: where are we and where are we going? The Lancet Rheumatology. 2025;7(6):e434-e447. doi:https://doi.org/10.1016/s2665-9913(24)00377-1
22. Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up. The New England Journal of Medicine. 2024;390(8):687-700. doi:https://doi.org/10.1056/nejmoa2308917
23. Müller F, Hagen M, Wirsching A, et al. CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial. Nature Medicine. 2026;32:1142-1151. doi:https://doi.org/10.1038/s41591-025-04185-6
24. Freeley M. CAR T Cell Therapy for Rheumatoid Arthritis. Clinical Reviews in Allergy & Immunology. 2025;68(1):100-100. doi:https://doi.org/10.1007/s12016-025-09113-7
25. Nie W, Yang X, Ma M, Xu X, Hou J. Chimeric antigen receptor T cell therapy for autoimmune diseases. Current Opinion in Immunology. 2025;95:102596. doi:https://doi.org/10.1016/j.coi.2025.102596
26. Dec P, Kubisa A, Plewa P, Pawlik A. Chimeric antigen receptor T-cell therapy in rheumatoid arthritis. The Journal of Pharmacology and Experimental Therapeutics. 2026;393(7):104951. doi:https://doi.org/10.1016/j.jpet.2026.104951