---
title: "CAR-T cell therapy in autoimmune diseases: progress, challenges, and emerging technologies"
id: "plos-medicine-0-progress-and-promise-of-car-t-cell-treatment-in-autoimmune-diseases"
canonical_url: "https://medichelpline.com/clinical-feed/plos-medicine-0-progress-and-promise-of-car-t-cell-treatment-in-autoimmune-diseases"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "PLOS Medicine"
source_url: "https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005179"
published_at: "2026-07-20T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CAR-T cell therapy in autoimmune diseases: progress, challenges, and emerging technologies
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-medicine-0-progress-and-promise-of-car-t-cell-treatment-in-autoimmune-diseases
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** PLOS Medicine
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005179)
- **Published At:** 2026-07-20T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Chimeric antigen receptor (**CAR-T cells**) are living-cell therapies that combine immune cell physiology with a redirected pharmacologic function to target B cells in autoimmune disease (AID). - Autologous CD19-targeted CAR-T cells deeply deplete circulating and tissue B cells, disrupting germinal centers and inducing an **immune reset** associated with sustained, drug-free remission in many patients. - The first use of CD19 CAR-T in refractory systemic lupus erythematosus was reported in 2021; since then CD19-CAR-T applications have expanded to diverse AIDs including rheumatic, neuroinflammatory, cytopenias and inflammatory bowel disease. - Advantages include comprehensive B cell elimination, potential restoration of immune homeostasis, and lower rates of high-grade cytokine release syndrome or severe neurologic and hematologic toxicity compared with oncology experience, though published patient numbers remain limited. - Key clinical uncertainties include the need to target long-lived plasma cells (which lack CD19), optimal lymphodepletion regimens for AID, risks of late-onset neutropenia and persistent B cell aplasia, and long-term infection, secondary malignancy, and cardiovascular risks. - BCMA-targeted CAR-T cells can deplete plasma cells and have been used in some AID cases, but may necessitate immunoglobulin replacement and re-vaccination due to loss of humoral memory. - Vaccination responsiveness after CAR-T therapy depends on timing: absent during B cell aplasia but preliminary data suggest normal humoral responses after reconstitution with a predominantly naïve B cell repertoire. - Barriers to autologous CAR-T include manufacturing costs and limited treatment centers; however, oncology-derived strategies, hospital exemption programs, and improved production are easing access, and preliminary analyses suggest healthcare cost reductions after successful therapy. - Emerging approaches include allogeneic off-the-shelf CAR-T/CAR-NK products from iPSCs, and in vivo CAR generation via targeted lipid nanoparticles delivering CAR-encoding RNA; these promise scalability but require evaluation of durability, safety, and capacity to induce immune reset. - mRNA-based transient CAR expression offers genomic-safety advantages and has shown efficacy in ex vivo applications, but achieving sufficient magnitude and persistence of CAR expression is critical for complete B cell depletion and immune reset. - Multiple pivotal trials of autologous and early-stage studies of allogeneic, CAR-NK, and in vivo CAR approaches are underway; identifying patient populations most likely to benefit and timing before irreversible damage will be important for clinical placement.
## Clinical Analysis & Structured Key Points
SKIP TO MAIN CONTENT Advertisement plos.org Create account Sign in About Browse Publish advanced search 0 Save 0 Citation 17 View 0 Share OPEN ACCESS PERSPECTIVE Progress and promise of CAR-T cell treatment in autoimmune diseases Jule Bachl, Melanie Hagen, Georg Schett Published: July 20, 2026 https://doi.org/10.1371/journal.pmed.1005179 Article Authors Metrics Comments Media Coverage Abstract Introduction Considerations and questions for CAR-T cell therapy for AID Can new technologies pave the way to the clinic? Conclusions References Reader Comments Figures Chimeric antigen receptor (CAR)-expressing cells bear a great potential for the treatment of autoimmune diseases. While numerous challenges persist, recent technological developments have demonstrated the potential for CAR cells to reset dysfunctional immune systems and transform care for patients with autoimmune disease. Figures Citation: Bachl J, Hagen M, Schett G (2026) Progress and promise of CAR-T cell treatment in autoimmune diseases. PLoS Med 23(7): e1005179. https://doi.org/10.1371/journal.pmed.1005179 Published: July 20, 2026 Copyright: © 2026 Bachl et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Deutsche Forschungsgemeinschaft (Leibniz Award to G.S.; CRC1755-CASCAID; grant number 550296805; projects 01 to J.B. and project #02 to G.S.) and the Lupus Research Alliance (Lupus Insight Award to G.S.). M.H. received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Abbreviations: AID, autoimmune disease; BCMA, B cell maturation antigen; CAR, chimeric antigen receptor; iPSCs, inducible pluripotent stem cells; NK, natural killer Introduction Chimeric antigen receptor (CAR) T cells are cell-based therapies for the treatment of malignant and autoimmune diseases [1,2]. In contrast to other drugs, such as chemical compounds or monoclonal antibodies, CAR-T cells are “living drugs” conveying the physiological properties of a human immune cell (e.g., migration, activation, proliferation) and combining them with a redirected pharmacological function. This redirected function is based on the expression of the CAR, which allows these therapeutic cells to specifically bind B cells through recognition of the B cell-specific surface molecule CD19 (or alternatively B cell maturation antigen, BCMA) and successively kill target cells (see Fig 1). CAR-T cells are highly effective B cell killers in all human tissues; they not only eliminate circulating B cells but also eradicate the entire pool of tissue B cells in the secondary lymphatic tissues and in target organs affected by autoimmune disease (AID) [3]. This deep depletion—together with a revamping of the entire immune cell landscape after CAR-T cell treatment—has been described as “immune reset”, which clinically manifests in deep and sustained drug-free remission [2]. The most established form of CAR-T cell treatment is autologous therapy [4,5], which is outlined in Fig 1. Download: PNG larger image TIFF original image Fig 1. Generation and application of autologous CAR-T cells in autoimmune diseases. (A) Generation of CAR-expressing cells by isolation and ex vivo expansion of autologous T cells, and transduction by a lentivirus encoding the CAR. These cells are then re-infused in the same patient after lymphodepletion with cyclophosphamide (Cy) and fludarabine (Flu), which allows CAR-T cells to appropriately expand in the patient and establish a population large enough to kill all B cells. The structure of the CAR is shown with specific domains. (B) Deep B cell depletion by CAR-T cells. (C) Features of immune reset after treatment with CAR-T cells in patients with AID. In the vast majority of patients, B cells reappear at a median time of 3 months, showing a virtually exclusive naïve phenotype, which sustains over many months, or even years [5,6]. GPA, Granuloamatosis with Polyangiitis; IIM, Idiopathic Inflammatory Myopathy; ITP, Idiopathic Thromobocytopenic Purpura; MG, Myasthenia Gravis; MS, Multiple Sclerosis; NMOSD, Neuromyelitis Optica Spectrum Disorder; RA, Rheumatoid Arthritis; SLE, Systemic Lupus Erythematosus; SPS, Stiff Person Syndrome; SSc, Systemic Sclerosis; UC, Ulcerative Colitis. https://doi.org/10.1371/journal.pmed.1005179.g001 Treatment with autologous CAR-T cells targeting CD19 has been approved in B cell malignancies and was first used in AID in 2021, when a patient with refractory systemic lupus erythematosus was treated with CD19 CAR-T cells [6]. Since then, CD19-CAR-T cell treatment has not only rapidly expanded to other autoimmune rheumatic diseases [4,5], but also neuroinflammatory disorders, immune-driven cytopenia and inflammatory bowel disease. Advantages of CAR-T cell therapy are based on their possibility to eliminate the entire B cell compartment and thereby also autoimmune B cells. By their ability to deeply deplete B cells, CAR-T cells also disrupt germinal center structures, eliminate follicular dendritic cells and block antigen presentation, which affects the T cell and myeloid compartments. This process induces a state of immune homeostasis (“immune reset”; Fig 1C), which needs further characterization but appears to permit sustained remission of AID in the absence of further immune suppression [2]. This effect may have crucial long-term benefits for patients treated with CAR-T cells, i.e., a lower infection risk and higher flexibility for family planning due to the absence of further immune suppression. In addition, the low risk for higher-grade cytokine release syndrome, neurological side effects, and hematotoxicity supports the feasibility of CAR-T cell therapy for AID [7]. However, further data are required to better characterize their long-term safety profile; notably, to date the overall number of published cases on patients with AID treated with CAR-T cells is still limited and further consolidation of their safety and efficacy profile is needed. Key questions concern the emergence of late-onset neutropenia (low numbers of neutrophils) and persistent B cell aplasia (reduction or absence of B cells). Additionally, clinical attention must focus on the long-term risks of infection, secondary malignancies, and cardiovascular disease—conditions that are exacerbated in patients with AID. Considerations and questions for CAR-T cell therapy for AID Despite promising results, the rapid advent of CAR-T cell therapy for AIDs means that several questions remain unanswered. For example, it is currently unknown whether in some patients long-lived plasma cells will need to be eliminated to induce sustained immune reset. These cells are not eliminated by CD19-CAR-T cells, as plasma cells lack expression of CD19. While CAR-T cells targeting BCMA-expressing plasma cells are available and have been successfully used in AID [8–10], eradication of immune memory and the necessity to substitute immunoglobulins in conjunction with BCMA-CAR-T cell therapy poses additional challenges. An additional open question is the level of lymphodepletion that is needed to make CAR-T cell therapy successful. Lymphodepletion regimens, consisting of cyclophosphamide and fludarabine, have been adopted from oncology but have not been developed for AID. Hence, lower-dose lymphodepletion regimens may be feasible and sufficient to allow the expansion of CAR-T cells in vivo. Considering that CAR-T cell therapy induces a virtually complete B cell depletion in patients, which is followed by reconstitution with a naïve B cell repertoire, responsiveness to vaccination is of critical interest, and may impact the long-term safety of this approach. While no humoral immune response to vaccination can be expected in the B cell aplasia phase, preliminary data suggest normal humoral immune responses after B cell reconstitution [4]. However, structured assessment of vaccination with de novo and recall antigens will be necessary to define vaccination responses in a situation where the memory B cell pool is substantially contracted. Furthermore, while CD19-targeted CAR-T cells do not target long-lived plasma cells and leave most existing vaccination responses intact [5,6], BCMA-targeted CAR-T cells also deplete long-lived plasma cells and therefore interfere with existing humoral vaccination responses. Hence, re-vaccination may be obligatory after BCMA-targeted CAR-T cell therapy, and its efficacy will need to be investigated. Potential barriers for autologous CAR-T cell treatment include the high manufacturing costs and the limited number of advanced treatment centers. Nonetheless, some of these barriers have been overcome in oncology by more accurate selection of high-risk patients, hospital exemption programs and advanced CAR-T cell production methods. Similar developments are currently seen in the treatment of patients with AID with autologous CAR-T cells. Furthermore, medical costs have shown to decrease by more than 90% after successful CAR-T cell therapy in AID, which results from a sharp decrease in drug therapy, lower need for inpatient and outpatient management of complications, and a diminished requirement of rehabilitative and organ-support measures [11]. Considering that the majority of patients with AID treated with CAR-T cells indeed maintain drug-free remission over years, the benefits of this treatment may outweigh the costs. Can new technologies pave the way to the clinic? New technologies are rapidly evolving. These include allogeneic CAR-T cells, which are usually produced from inducible pluripotent stem cells (iPSCs) differentiated into T cells or natural killer (NK) cells expressing a CAR. These “off-the-shelf” cell therapy products are gene-edited to remove critical antigenic surface structures in order to prevent their immediate rejection, as well as to reduce graft-versus-host disease. Allogeneic CAR-T cell products can be readily used in larger patient populations and do not require individual cell manufacturing. Meanwhile, a very recent approach is in vivo CAR-T cell therapy, whereby CAR-T cells are formed directly in the patient by infusing targeted lipid nanoparticles that contain the RNA payload for the CAR. Once administered, these nanoparticles fuse with target cells (usually T cells) and induce the expression of the CAR. Killing of B cells then functions in a similar way as with ex vivo CAR-T cell therapy. While the principal feasibility of allogeneic and in vivo CAR-T cell therapy in AID has been demonstrated [12,13], it is currently unclear whether these approaches can induce sustained immune reset in patients and allow long-term drug free remission. A transient mRNA-based CAR expression is principally well suited for its use in AID, avoiding genomic integration and ascertaining reversibility of the CAR expression. In fact, ex vivo mRNA-based CAR-T cells have shown clinical efficacy in myasthenia gravis [8]. In the context of in vivo approaches, dimension and durability of CAR expression need to be sufficiently high enough to achieve complete B cell depletion and thereby trigger an immune reset. As CAR expression is diluted with each cell division in mRNA-based expression approaches—showing no genomic integration—upfront generation of sufficient numbers of CAR-T cells seems to be critical, while the proliferation of existing CAR-T cells in vivo, which is the most powerful process in autologous ex vivo CAR-T cell therapy, seems less important. Repeated injection of targeted mRNA-CAR carrying lipid nanoparticles, as well as vector-based in vivo CAR-T cell therapies, may overcome these issues. Vector-based in vivo therapies are in development, but require stringent safety considerations due to in vivo DNA integration. Overall, these new methods will push forward the CAR-T cell field and eventually allow improved scalability of treatment. Conclusions With the first autoimmune patient reaching 5 years drug-free remission after a single infusion of CAR-T cell in March 2021, cure of AID has become within reach for the first time. It is widely accepted that cancer can be cured and a 5-year cancer-free survival is used as a benchmark by the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program [14]. Further data are necessary to support the concept of cure after more than 5 years absence of AID; however, with the growing insights from CAR-T cell therapy, a gradual shift of therapeutic expectations from remission to cure will likely occur. Based on the preliminary but encouraging safety and efficacy data, several pivotal studies with autologous CAR-T cells—alongside early studies with allogeneic CAR-T and CAR-NK cells, as well as in vivo CAR-T cells—are currently underway, which will considerably extend the knowledge on this new therapy. It is yet too early to say where these treatments are best placed in the treatment landscape, but it is likely that patients with severe forms of AID or those showing inadequate responses to conventional treatments are the ones who may profit the most. Identification of such patient populations will be critical in order to initiate timely treatment before substantial irreversible damage accrues. References 1. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73. pmid:29972754 View Article PubMed/NCBI Google Scholar 2. Schett G, Xu H. Resetting autoimmune disease by CAR-expressing cells. Nat Med. 2026. View Article Google Scholar 3. Tur C, Eckstein M, Velden J, Rauber S, Bergmann C, Auth J, et al. CD19-CAR T-cell therapy induces deep tissue depletion of B cells. Ann Rheum Dis. 2025;84(1):106–14. pmid:39874224 View Article PubMed/NCBI Google Scholar 4. Müller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Völkl S, et al. CD19 CAR T-Cell therapy in autoimmune disease - a case series with follow-up. N Engl J Med. 2024;390(8):687–700. pmid:38381673 View Article PubMed/NCBI Google Scholar 5. Müller F, Hagen M, Wirsching A, Kharboutli S, Aigner M, Völkl S, et al. CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial. Nat Med. 2026;32(3):1142–51. pmid:41501497 View Article PubMed/NCBI Google Scholar 6. Mougiakakos D, Krönke G, Völkl S, Kretschmann S, Aigner M, Kharboutli S, et al. CD19-targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med. 2021;385(6):567–9. pmid:34347960 View Article PubMed/NCBI Google Scholar 7. Schwingen NR, Mueller F, Scholz JK, Aigner M, Hagen M, Wirsching A, et al. Distinct safety and toxicity profile of CD19-directed CAR T-cell therapy in systemic lupus erythematosus versus B-cell lymphoma - a single-center experience. Blood. 2024;144(Supplement 1):4835–4835. View Article Google Scholar 8. Qin C, Dong M-H, Zhou L-Q, Chu Y-H, Pang X-W, He J-Y, et al. Anti-BCMA CAR-T therapy in patients with progressive multiple sclerosis. Cell. 2025;188(23):6414-6423.e11. pmid:41101309 View Article PubMed/NCBI Google Scholar 9. Feng J, Huo D, Hong R, Jin X, Cao H, Shao M, et al. Co-infusion of CD19-targeting and BCMA-targeting CAR-T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial. Nat Med. 2025;31(11):3725–36. pmid:40993243 View Article PubMed/NCBI Google Scholar 10. Fedak RR, Ruggerie RN, Shan Y, Curvino EJ, de Sousa JF, Daniel S, et al. BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial. Nat Med. 2026;32(3):1118–30. pmid:41514039 View Article PubMed/NCBI Google Scholar 11. Taubmann J, Hagen M, Müller F, Wirsching A, Temiz A, Völkl S, et al. Effects of CD19 CAR T cell therapy on quality of life and direct healthcare costs in systemic lupus erythematosus: a preliminary analysis. J Rheumatol. 2026;53(1):33–7. pmid:40953960 View Article PubMed/NCBI Google Scholar 12. Wang X, Wu X, Tan B, Zhu L, Zhang Y, Lin L, et al. Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis. Cell. 2024;187(18):4890-4904.e9. pmid:39013470 View Article PubMed/NCBI Google Scholar 13. Wang Q, Xiao ZX, Zheng X, Wang G, Yang L, Shi L, et al. In vivo CD19 CAR T-cell therapy for refractory systemic lupus erythematosus. N Engl J Med. 2025;393(15):1542–4. pmid:40961420 View Article PubMed/NCBI Google Scholar 14. National Cancer Institute. Surveillance, epidemiology, and end results program [Internet]. SEER; 2018. Available from: https://seer.cancer.gov/ Download PDF Print Share ADVERTISEMENT Subject Areas ? Autoimmune diseases B cells Cancer treatment Vaccination and immunization Antigens Plasma cells Drug therapy Stem cell therapy Publications PLOS Aging and Health PLOS Biology PLOS Climate PLOS Complex Systems PLOS Computational Biology PLOS Digital Health PLOS Ecosystems PLOS Genetics PLOS Global Public Health PLOS Medicine PLOS Mental Health PLOS Neglected Tropical Diseases PLOS One PLOS Pathogens PLOS Sustainability and Transformation PLOS Water Home Blogs Collections Give feedback LOCKSS Privacy Policy Terms of Use Advertise Media Inquiries Contact PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in California, US Cookie Preference Center Our website uses different types of cookies. Optional cookies will only be set with your consent and you may withdraw this consent at any time. Below you can learn more about the types of cookies PLOS uses and register your cookie preferences. Accept All Cookies Customize Your Cookie Preference + Strictly Necessary Always On + Functional Off + Performance and Analytics Off + Marketing Off Save Selected Preferences and Close For more information about the cookies and other technologies used by us, please read our Cookie Policy.
## Related Clinical Research

- [Epstein–Barr virus mechanisms driving autoimmunity: shared pathways and disease-specific vulnerabi](https://medichelpline.com/clinical-feed/frontiers-in-immunology-12-mechanisms-of-epstein-barr-virus-associated-autoimmunity-a-comparative-overview.md)
- [Emergency diagnosis frequency and outcomes across 13 non-cancer conditions in England: analysis of](https://medichelpline.com/clinical-feed/plos-medicine-2-frequency-and-prognostic-outcomes-of-emergency-diagnosis-in-13-non-neoplastic.md)
- [Climate change worsens health for people with chronic illness](https://medichelpline.com/clinical-feed/stat-news-1-opinion-climate-change-is-making-people-with-chronic-illness-even-sicker.md)
- [MicroRNAs in Immune-Related Diseases: Mechanisms, Functions and Therapeutic Perspectives](https://medichelpline.com/clinical-feed/frontiers-in-immunology-14-micrornas-in-immune-related-diseases-mechanism-functions-and-therapeutic.md)
- [Brief-COPE Questionnaire Shows Five-Factor Structure in Seropositive Rheumatoid Arthritis](https://medichelpline.com/clinical-feed/medrxiv-1-validation-of-the-brief-cope-questionnaire-in-a-seropositive-rheumatoid.md)

## Navigation
- [← Back to General Feed](https://medichelpline.com/clinical-feed/general.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.