Chimeric antigen receptor (CAR)-T cells are considered a powerful therapeutic tool to reset the immune system in patients with autoimmune diseases. Innovative trial designs are needed to allow feasible testing of the safety and efficacy of CAR-T cells in clinical studies. CASTLE (CAR-T cells in systemic B cell mediated autoimmune disease) is a phase 1/2a two-stage optimal design basket study that investigated the safety and efficacy of zorpocabtagene autoleucel (Zorpo-cel, also known as MB-CART19.1), an autologous CD19 CAR-T cell product, in patients with treatment-resistant systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM). The primary safety outcome was the rate of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The secondary clinical efficacy outcomes were remission of SLE according to DORIS criteria, no progression of interstitial lung disease in SSc and American College of Rheumatology (ACR) major/moderate response in IIM after 24 weeks. A total of 24 patients were enrolled (10 with SLE, 9 with SSc and 5 with IIM), all receiving a single infusion of Zorpo-cel after stopping immunosuppressive treatments and receiving standard lymphodepletion with cyclophosphamide and fludarabine. Primary and secondary endpoints of CASTLE were met. Regarding safety, no CRS higher than grade 2 and no ICANS occurred. Regarding efficacy, 22 of the 24 patients achieved predefined efficacy endpoints, with 9 out of 10 patients with SLE reaching DORIS remission, 9 out of 9 patients with SSc showing no disease progression, and 4 out of 5 patients with IIM reaching ACR major/moderate response. Furthermore, all patients remained free of glucocorticoids and any other immunosuppressive treatment over the entire observation period of 24 weeks. CASTLE suggests the feasibility, safety and efficacy of Zorpo-cel in three different autoimmune diseases and paves the way for conducting a pivotal study. ClinicalTrials.gov identifier: NCT06347718, EudraCT identifier: 2022-001366-35.

ABSTRACT:CD19-directed chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) and recently showed effects in autoimmune diseases, such as systemic lupus erythematosus (SLE). Despite high levels of inflammation, toxicity seemed to differ between patients with SLE and B-NHL. We therefore compared the CAR T-cell kinetics and treatment-related side effects to better define the toxicity profiles. In contrast with the similar CAR T-cell expansion, patients with SLE revealed a lower incidence and severity of cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hematotoxicity. Although the neutrophil nadir was lower in patients with SLE after therapy, the platelet counts remained close to normal and hematotoxicity was shorter in SLE than B-NHL. The reduced hematotoxicity correlated with lower acute-phase inflammation, better hematologic reserve before CAR T-cell therapy, and distinct serum cytokine profiles. Interestingly, CAR T-cell persistence was consistently shorter, and the reconstitution of conventional T and B cells was faster in SLE. In both cohorts, B-cell reconstitution correlated with functional CD4+ T-cell recovery, indicating a general biologic process of hematopoietic and immune system regeneration. In summary, similar lymphodepletion and CAR T-cell pharmacokinetics led to distinct toxicity, demonstrating that CAR T-cell therapy had a favorable side-effect profile in SLE, including faster recovery of the adaptive immune system.

O006 / #412 Topic:AS12 - Genetics, Epigenetics, Transcriptomics SCIENTIFIC HYBRID SESSION: CLINICAL TRACK PRESENTATIONS - OUTSTANDING ABSTRACT PRESENTATIONS 23-05-2025 9:00 AM - 10:00 AM Remission, as defined by the Definition of Remission in SLE (DORIS) criteria, is the primary therapeutic target in systemic lupus erythematosus (SLE). While DORIS remission correlates with the reversal of key pathogenic processes,[1] novel approaches like CD19-targeted chimeric antigen receptor (CAR)-T cell therapy have shown potential to induce durable, drug-free remission. Yet, the molecular characteristics of CAR-T cell-induced remission compared to standard immunosuppression-induced remission remain unclear. To delineate unique molecular profiles of CD19 CAR-T cell therapy-induced remission, we performed a comparative analysis of Reactome pathways. Pseudo-bulk expression profiles were generated from single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) in 7 SLE patients post-lymphodepletion and CAR-T cell infusion. As a comparator, transcriptional profiles from 34 SLE patients in DORIS remission on standard immunosuppression from the PRECISESADS project (1) were analyzed. Functional pathway annotations were derived using the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. Of 314 pathways, 22 pathways related to the immune system were significantly differentially regulated, with CAR-T cell-induced remission being associated with a greater suppression of type I interferon, complement activation, and interleukin signaling pathways. Notably, Fc gamma receptor IIIa-mediated IL-10 synthesis and lipid metabolism pathways were selectively upregulated, suggesting enhanced antiinflammatory responses and metabolic rewiring. CD19 CAR-T cell-induced remission was also marked by decreased DNA damage response activation compared to remission on standard immunosuppression. Our findings reveal a distinct immune and metabolic landscape associated with CD19 CAR-T cell-induced remission in SLE, supporting the notion of CD19 CAR-T cell-mediated immunological reset.References:[1] Parodis I. Ann Rheum Dis. 2024;83(7):889-900.

CD19 chimeric antigen receptor (CD19 CAR) T cell therapy has been shown to induce stable drug-free remission in patients with refractory autoimmune disease. The management of potential relapses is currently unclear. Here we report on a 45-year-old woman with treatment-refractory Jo-1-associated anti-synthetase syndrome, who initially achieved disease remission after CD19 CAR T cell therapy but then experienced disease relapse after 9 months. After reinfusion of the same product, CAR T cells failed to expand and T cells targeting the CD19 CAR were detected. Despite full-dose lymphodepletion, no clinical response was observed. After bridging with anti-CD38 antibody daratumumab, which was efficacious with limited durability, plasma-cell-targeting B-cell maturation antigen (BCMA) CAR T cell therapy was performed. BCMA CAR T cells expanded, cleared plasma cells in lymphoid tissue, reduced autoantibody levels and re-induced stable drug-free remission. This case highlights the challenges in CAR T cell reinfusion, the potential of alternative targets and products, and suggests that the depletion of plasma cells may enhance therapeutic outcomes in patients who become treatment-refractory.

Systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and idiopathic inflammatory myositis (IIM) are autoimmune diseases managed with long-term immunosuppressive therapies. Hu19-CD828Z, a fully human anti-CD19 chimeric antigen receptor (CAR) with a CD28 costimulatory domain, is engineered to potently deplete B-cells. In this study, we manufactured Hu19-CD828Z CAR T-cells from peripheral blood of SLE, IIM, and SSc patients and healthy donors (HDs). CAR-mediated, CD19-specific activity of these cells was evaluated in vitro by assessing cytotoxicity, cytokine release, and proliferation assays in response to autologous CD19+ B-cells, the CD19+ NALM-6 B-cell line, or a CD19- U937 non-B-cell line as targets. The results demonstrated an increased proliferation of Hu19-CD828Z CAR T-cells and dose-dependent cytotoxicity against primary autologous and NALM-6 B-cells compared to non-transduced controls or co-cultures with non-B-cells. Notably, autoimmune-patient-derived CAR T-cells produced lower levels of inflammatory cytokines than healthy-donor-derived CAR T-cells in response to CD19+ B-cell targets. These data support the potential of Hu19-CD828Z and its therapeutic cell product KYV-101 as a therapeutic strategy to achieve deep B-cell depletion in SLE, IIM, and SSc patients, and highlights its promise for broader application in B-cell-driven autoimmune disorders.

OBJECTIVES:To assess the efficacy of new protein-based B cell depletion with glyco-engineered anti-CD20 antibody obinutuzumab (OBI) and the CD19/CD3 T cell engager blinatumomab (BLI) in patients with autoimmune diseases (AIDs) in comparison to rituximab (RTX) and CD19 chimeric antigen receptor (CAR) T cell therapy. METHODS:Sequential inguinal lymph node biopsies were taken before and after treatment with OBI-, BLI-, RTX- and CD19-CAR T cells in patients with AID. CD19+ and CD20+ B cells, plasma cells, T cells and macrophages were analysed by immunohistochemistry. Changes in follicular architecture (follicular dendritic cells, T follicular helper cells, proliferation) were also assessed. RESULTS:Baseline and follow-up lymph node biopsies from 24 patients with AID (OBI, 4; BLI, 4; RTX, 4; CD19-CAR T cells, 12) were analysed. B cell depletion was confirmed in all CD19-CAR T cell-treated patients but only in 1 (OBI) out of 12 protein-based B cell-treated patients. Likewise, follicular architecture was disrupted in all CD19-CAR T cell-treated patients but only in 1 (OBI) out of 12 protein-based B cell-treated patients. B cell depletion efficacy in the lymph nodes was 100% for CD19-CAR T cells, 92% for OBI, 86% for RTX and 69% for BLI. Plasma cells were reduced but not depleted in all treatment approaches. CD3+ T cells and CD68+ macrophages remained unaffected. Peripheral blood B cell depletion occurred in all but 1 BLI-treated patient. B cell depletion was associated with stable drug-free remission, whereas a reduction in B cell numbers without depletion required retreatment with immunomodulatory drugs. CONCLUSIONS:Protein-based B cell depletion reduces but usually does not deplete B cells in lymph nodes leaving the follicular architecture intact and being associated with disease recurrence.

Chimäre Antigenrezeptor(CAR)-T-Zellen haben sich als effektive Therapieoption in der Behandlung von B‑Zell-assoziierten Malignomen etabliert. Neben malignen B‑Zellen können auch autoreaktive B‑Zellen ein Ziel der anti-CD19-gerichteten CAR-T-Zellen (CD19-CAR-T-Zellen) darstellen. B‑Zellen sind beim systemischen Lupus erythematodes (SLE) maßgeblich an der Produktion pathogener Autoantikörper beteiligt und fördern sowohl den Krankheitsausbruch als auch das Fortschreiten der Erkrankung. In unseren bisherigen Forschungsarbeiten als auch in weiteren Fallanalysen konnte gezeigt werden, dass der Einsatz der CD19-CAR-T-Zell-Therapie bei schwerem, therapierefraktärem Verlauf des SLE eine vielversprechende Wirksamkeit sowie ein akzeptables Sicherheitsprofil aufweist. Es wird ein Fazit zum aktuellen Stand bezüglich Wirksamkeit und Sicherheit der CD19-CAR-T-Zell-Therapie beim systemischen Lupus erythematodes (SLE) gegeben. PatientInnen mit progredientem, therapierefraktärem SLE erhielten im Rahmen eines individuellen Heilversuches eine autologe CD19-CAR-T-Zell-Therapie (MB19,1, Miltenyi Biotec, Bergisch Gladbach, Deutschland) und werden regelmäßig an unserem Zentrum nachbeobachtet. Elf PatientInnen mit progredientem, therapierefraktärem SLE erhielten im Rahmen eines individuellen Heilversuches eine autologe CD19-CAR-T-Zell-Therapie. Die mediane Nachbeobachtungszeit beträgt 2,5 Jahre (0,5 bis 4 Jahre). Alle PatientInnen erreichten innerhalb von 6 Monaten eine DORIS-Remission (Definition of Remission in SLE). Die immunsuppressive Therapie wurde bei allen PatientInnen vollständig abgesetzt. Fünf der 11 PatientInnen hatten ein „cytokine release syndrome“ (CRS) ersten Grades. CRS Grad 2 wurde nur 1‑malig beobachtet. Höhergradige CRS sind in dieser Kohorte nicht aufgetreten. Bei unseren SLE-PatientInnen war keine Neurotoxizität („immune effector cell-associated neurotoxicity syndrome“ [ICANS]) festzustellen. Alle PatientInnen befinden sich aktuell in einer anhaltenden und medikamentenfreien Remission. Wir verzeichneten bei einer Patientin einen therapiebedürftigen SLE-Schub. Erste Daten deuten trotz ähnlicher CD19-CAR-T-Zell-Expansion und Kinetik auf ein besseres Sicherheitsprofil der CD19-CAR-T-Zell-Therapie bei SLE im Vergleich zu Lymphomkohorten hin. Bei SLE-Patientinnen stellt sich die adaptive Immunität nach einer CD19-CAR-T-Zell-Therapie zudem schnell wieder her. Der Einsatz von CD19-CAR-T-Zellen bei PatientInnen mit schwerem Verlauf des SLE erweist sich als sicher und wirksam.

Introduction: Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM) are characterized by the activation of pathological B-cells and the formation of autoantibodies that trigger damage to cells and organs. Based on previous findings from pilot studies we found that zorpocabtagene-autoleucel (zorpo-cel, MB-CART19.1), an autologous T-cell product expressing the chimeric antigen receptor (CAR) against CD19, induce deep B-cell depletion e.g., in peripheral blood and in tissues such as lymph nodes achieving drug-free remission in these AIDs. Methods: CASTLE is a Phase I/II basket trial that tested the feasibility, safety, and efficacy of zorpo-cel in patients with severe, treatment-resistant SLE, SSc, and IIM. The primary enpoint was safety defined as the rate of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) within the first 4 weeks after zorpo-cel administration, the secondary clinical efficacy endpoints were DORIS remission in SLE, no progression of interstitial lung disease in SSc, and ACR Major/Moderate Response in IIM after 24 weeks. Dose-limiting toxicities were defined as CRS or ICANS of grade 3 or higher, or grade three or higher organ toxicities (including late immune effector cell-associated hematotoxicity, ICA-HT lasting beyond day 28).. Lastly, local immune effector cell associated toxicity syndrome (LICATS) was recorded according to Hagen et al 2025, Lancet Rheumatology. Patients were enrolled in 2 cohorts: 8 patients for Phase I, 16 patients for Phase II with a safety review between Phase I and Phase II. Results: All planned 24 patients with SLE, IIM or SSc were enrolled between July 2023 and February 2025. Ten SLE, nine SSc and five IIM patients had a median disease duration of 4.0 [1.3; 6.5] years and failed a median of 4 [3; 6] immunosuppressive treatments. For all patients, zorpo-cel was successfully produced and infused. CAR T cells peaked at a median of 140 [82; 360] cells/µl after 10 days. B cell depletion was achieved within 7 days and B-cell aplasia lasted a median of 83 [56; 113] days. B cells were mostly naïve in recurrence for all patients. The 8 patients of phase 1 fulfilled predefined safety and efficacy endpoints and 16 additional patients were included in Phase 2. The study met its primary endpoint of safety. No CRS > grade 2 and no ICANS occurred, there was no ICAHT persisting beyond day 28. One patient developed a CMV pneumonitis during a virus reactivation. Kidney biopsy due to reduced organ function showed thrombotic microangiopathy, possibly related to CMV. Persisting reduction of creatinine-clearance resulted in the only DLT of the trial. Twenty-two of 24 patients achieved efficacy endpoints, with 9/10 SLE patients fulfilling DORIS remission, all 9 SSc patients showing no disease progression, and 4/5 IIM patients reaching ACR/EULAR major response after 6 months. One patient with longstanding IIM did not adequately improve in muscle strength and failed ACR Moderate/Major Response Criteria. One patient with SLE did not achieve significant reduction of proteinuria (< 500 mg protein/g creatinine) and therefore did not meet DORIS remission at 6 months. Immunosuppressive therapy could be stopped in all patients. Conclusion: The CASTLE study is the first phase I/II basket trial to demonstrate feasibility, favorable safety, and high efficacy of zorpo-cel in three B-cell driven AIDs. These promising results provide strong rationale to further develop zorpo-cel in AID.

Prescribable digital health applications (DiGAs) present scalable solutions to improve patient self-management in rheumatology, however real-world evidence is scarce. Therefore, we aimed to assess the effectiveness, usage, and usability of DiGAs prescribed by rheumatologists, as well as patient satisfaction. The DiGAReal registry includes adult patients with rheumatic conditions who received a DiGA prescription. Data at baseline (T0) and the 3-month follow-up (T1) were collected through electronic questionnaires. Study outcomes included DiGA-specific outcome assessments as well as generic outcome assessments, including the Patient Global Impression of Change (PGIC), Patient Activation Measure (PAM®), and the German Telehealth Usability and Utility Short Questionnaire (TUUSQ). Changes between T0 and T1 were analyzed using descriptive statistics and paired tests. A total of 191 patients were included between June 2022 and April 2023. Of these, 127 completed the 3-month follow-up, and 114 reported using the prescribed DiGA, with 66

BACKGROUND:CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has advanced treatment strategies for severe autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis, and idiopathic inflammatory myopathy. Data regarding side-effects are mostly generated from patients with malignancies, but little is known about autoimmune disease-specific adverse events. This study aimed to describe autoimmune disease-specific adverse events that occur with CAR T-cell therapy. METHODS:In this observational study, patients of any age with autoimmune disease receiving CD19-targeting CAR T-cell therapy in two centres in Germany with a follow-up of at least 30 days were assessed for local organ-specific reactions occurring after CAR T-cell infusion. Observed reactions were documented according to localisation, time of onset, and duration, and were graded for severity (grade 1: spontaneous resolution; grade 2: glucocorticoid treatment due to symptoms lasting >1 week or presence of relevant inner organ involvement; grade 3: prolonged or new hospitalisation; grade 4: intensive care treatment). People with related lived experience were involved in the study design and implementation. FINDINGS:Between March 1, 2021, and Oct 31, 2024, 39 patients with autoimmune disease were treated with CD19-targeting CAR T cells (20 with SLE, 13 with systemic sclerosis, six with idiopathic inflammatory myopathy). 25 (64%) patients were female and 14 (36%) were male. Median age was 36 years (IQR 22-44). 54 local reactions, which we termed local immune effector cell-associated toxicity syndrome (LICATS), were recorded, affecting 30 (77%) patients with a median time of onset of 10 days (IQR 9-21) from CAR T-cell infusion and a median duration of 11 days (5-14). LICATS exclusively occurred during the B-cell aplasia phase and only involved organs previously affected by the respective autoimmune disease. The most frequently affected organs were the skin (19 [35%] of 54) and the kidneys (12 [22%]). Most cases of LICATS were mild (grade 1: 35 [65%]; grade 2: 16 [30%]). Only three cases were grade 3. All events of LICATS resolved without sequelae. INTERPRETATION:LICATS is a new form of toxicity in patients with autoimmune disease receiving CD19-targeting CAR T-cell therapy, most likely based on the cleansing of immune cells from the affected organs. It is self-limited, organ-specific, and usually mild in its intensity. FUNDING:Deutsche Forschungsgemeinschaft (DFG), German Cancer Aid, Bundesministerium für Bildung und Forschung, European Union, Staedtler Foundation, Lupus Research Alliance, and donations from the Bendel family and the Bleyl family.

Introduction: While CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy is now established as a standard of care in relapsed/refractory B-cell lymphoma, we and others showed its feasibility and effectiveness in adult and adolescent patients with refractory systemic lupus erythematosus (SLE) (Mackensen et al., Nat Med 2022; Müller et al., NEJM 2024; Krickau et al., Lancet 2024). Furthermore, we recently demonstrated that - despite similar CAR T-cell kinetics – patients with SLE experience less severe adverse events than patients with B-cell lymphoma (Müller et al., Blood 2025). While side effects of CAR T-cell therapy are widely studied, resolution of CAR T-cell-induced but also disease-specific inflammation is still poorly understood. Methods: We performed deep serum proteomics in SLE patients (N=18; all patients in CR) and lymphoma patients [DLBCL NOS (N=39), MCL (N=3), other types of NHL (N=6); 50% in lasting CR > 6 months] before and at day +7, +14, +30, +90, and +365 after CAR T-cell therapy. In addition, healthy control samples of age-matched donors (SLE controls: n=18; lymphoma controls: n=30) were also analyzed. Persistence of CAR T-cells within patients and reconstitution of T- and B-cells were measured by flow cytometry and linked to serum proteome profiles. All patients received either commercial CAR T-cell products or the investigational medicinal product MB-CART19.1 (in-house manufactured 2nd generation anti-CD19 CAR T-cells with a 4.1BB co-stimulatory domain) in our center. Results: To characterize inflammatory signatures, we performed serum proteomics using the Olink® Target 96 Immuno-Oncology Panel across the CAR T-cell treatment course. Prior to CAR T-cell therapy, both B-cell lymphoma and SLE patients exhibit an inflammatory serum milieu - characterized by elevated levels of IL-6, IL-1α, IFN-γ, and CXCL10 - compared to age- and sex-matched healthy donors (HDs). One-year after CAR T-cell therapy, lymphoma patients maintained elevated pro-inflammatory cytokine levels compared to HDs, whereas SLE patients demonstrated resolution of IL-6-driven inflammation and reduction of SLE-associated cytokines including IL-8, CXCL13, MCP-1, and MCP-3. Concurrently, SLE patients showed increased expression of cytokines linked to immune cell reconstitution (TGF-b1, TRAIL, CXCL5, CXCL12, IL-7). This immune-restorative shift coincided with the loss of CAR T-cell persistence in SLE patients, suggesting a link between the persistence of CAR T-cells and resolution of inflammation. Principal component analysis (PCA) of serum proteins identified that angiogenic markers ANGPT-1 and VEGF-2 as well as immune-reconstituting cytokines CXCL5 and CXCL12, contributed to distinct clustering of SLE patients one-year post-CAR T-cell therapy, aligning them more closely with HDs. In contrast, no such clustering was observed in B-cell lymphoma patients prior to or post CAR T-cell therapy compared with HDs. Notably, the shift of cytokine expression and the resolution of IL-6–driven inflammation in SLE patients are further supported by the rapid reconstitution of T and B cells after CAR T-cell therapy, with upregulated serum IL-7 and CXCL12 likely contributing to T-cell and B-cell recovery, respectively. This pattern was specific to SLE patients, whereas persistent inflammation and ongoing B-cell aplasia could be observed in patients with B-cell lymphoma. Conclusion: Taken together, our data reveal a resolution of systemic inflammation specific to SLE patients following CAR T-cell therapy, compared to patients with B-cell lymphoma. This resolution might be linked to the shorter persistence of CAR T-cells in SLE patients and thus benefit the reconstitution of the adaptive immune system.

BACKGROUND:Chimeric antigen receptor T-cells (CAR T-cells) are an effective therapeutic approach in the treatment of B-cell driven malignancies. In addition to malignant B-cells, autoreactive B-cells are important targets for CD19 CAR T-cells, as they are a source of autoantibody production and support both the onset and progression of systemic lupus erythematosus (SLE). We and others have shown that their use in severe and therapy-refractory cases of SLE is effective and, moreover, safe. OBJECTIVE:The current status and an interim analysis of the efficacy and safety of CD19-CAR T‑cell therapy in SLE. MATERIAL AND METHODS:Patients with severe, treatment-refractory, and active SLE received autologous CD19-CAR T‑cell therapy (MB19.1, Miltenyi Biotec, Bergisch Gladbach, Germany) as part of an individual compassionate treatment attempt and are regularly followed up at our center. RESULTS:11 patients with progressive, therapy-refractory SLE received an autologous CD19 CAR T-cell therapy as part of an individual treatment attempt. The median follow-up time is 2.5 years [0.5 - 4 years]. All patients achieved a DORIS remission within 6 months. Immunosuppressive therapy was completely discontinued in all patients. Five out of the 11 patients experienced grade 1 cytokine release syndrome (CRS). Grade 2 CRS was observed only once. No higher-grade CRS occurred in this cohort. So far, no neurotoxicity (immune effector cell-associated neurotoxicity syndrome, ICANS) has been observed in our SLE patients. All patients remain in a sustained and drug-free remission to date. One patient experienced an SLE flare. Initial data, despite similar CD19 CAR T-cell expansion and kinetics, suggest a better safety profile of CD19 CAR T-cell therapy in SLE compared to lymphoma cohorts. Additionally, adaptive immunity in SLE patients recovers rapidly after CD19 CAR T-cell therapy. CONCLUSION:The use of CD19-CAR T‑cells in patients with severe SLE proved to be safe and effective.

Chimeric antigen receptor (CAR) T cells are highly effective at targeting and eliminating cells of the B cell lineage. CAR T cell therapy has become a standard-of-care treatment for patients with relapsed or refractory B cell malignancies. In addition, the administration of genetically modified T cells with the capacity to deplete B cells and/or plasma cells has tremendous therapeutic potential in autoimmune diseases. In the past few years, CD19-based and B cell maturation antigen (BCMA)-based CAR T cell therapies have been applied to various B cell-mediated autoimmune diseases including systemic lupus erythematosus, idiopathic inflammatory myopathy, systemic sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis and multiple sclerosis. The scientific rationale behind this approach is that deep depletion of B cells, including autoreactive B cell clones, could restore normal immune function, referred to as an immune reset. In this Review, we discuss important aspects of CAR T cell therapy in autoimmune disease, including considerations relating to patient selection, safety, efficacy and medical management. These considerations are based on the early experiences of CAR T cell therapy in autoimmune diseases, and as the field of CAR T cell therapy in autoimmune diseases continues to rapidly evolve, these issues will remain subject to ongoing refinement and adaptation.