CAR T-cell therapy in systemic lupus erythematosus: a scoping review

CAR T-cell therapy in systemic lupus erythematosus: a scoping review* Russka Shumnalieva1,2,3 , Ivan Padjen4,5 , Simeon Monov1,2 , Tsvetelina Velikova3 1 Clinic of Rheumatology, University Hospital St. Anna, Blvd. Dimitar Mollov 1, 1709 Sofia, Bulgaria 2 Department of Rheumatology, Faculty of Medicine, Medical University – Sofia, “St. Georgi Sofiyski” Str. 1, 1431 Sofia, Bulgaria 3 Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak str., 1407 Sofia, Bulgaria 4 University of Zagreb, School of Medicine, Salata 3, 10000 Zagreb, Croatia 5 Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Croatian Referral Centre for SLE and Related Disorders, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Corresponding author: Russka Shumnalieva (rsh[email protected]m) Received 1 August 2025♦ Accepted 25 August 2025♦ Published 6 November 2025 Citation: Shumnalieva R, Padjen I, Monov S, Velikova T (2025) CAR T-cell therapy in systemic lupus erythematosus: a scoping review. Pharmacia 72: 1–13. https://doi.org/10.3897/pharmacia.72.e167410 Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatic disease affecting more women than men. Although the etiology of SLE remains unknown, recent advances in understanding disease pathogenesis have revealed important aspects of immune system dysregulation and disruption of immune tolerance. The abnormal activation of B lymphocytes, with subsequent production of autoantibodies against self-antigens, leads to complement activation, immune complex formation, and tissue deposits, resulting in cell migration, tissue damage, and organ failure. Current treatment options for SLE include the use of nonspecific immunosuppressants, as well as targeted therapies against activation markers and signaling pathways. In this scoping review, we explore the emerging role of chimeric antigen receptor (CAR) T-cell therapy in the treatment of autoimmune rheumatic diseases (AIRD), with a specific focus on SLE, translated from its well-established applications in cancer research and therapy. The review highlights the underlying mechanisms, clinical advancements, and therapeutic potential of CAR T-cell technology in modulating immune responses and targeting disease-specific pathways in SLE. We also discuss the challenges and future directions of CAR T-cell therapy as a transformative approach in the management of AIRD. Keywords autoantibodies, autoimmune rheumatic, B lymphocytes, chimeric antigen receptor, dysregulation, immunosuppressants, systemic lupus erythematosus * This article is part of: “Bridging Science and Innovation: Advances in Diagnosis, Therapy, and Translational Medicine: Insights from the Second SUMMIT Conference“, edited by Georgi Momekov, Ivan Padjen, Naim Mahroum. Introduction Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune rheumatic disease affecting more women than men (Tsokos 2011; Justiz Vaillant et al. 2023). Although the etiology of SLE remains unknown, recent advances in understanding disease pathogenesis have revealed important aspects of immune system dysregulation and disruption of immune tolerance (Shumnalieva et al. 2018; Crow 2023). There is abnormal activation of B Copyright Shumnalieva R et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Pharmacia 72: 1–13 DOI 10.3897/pharmacia.72.e167410 Research Article Shumnalieva R et al.: CAR T-cell therapy in SLE2 lymphocytes, leading to the production of autoantibodies against self-antigens and cytokine secretion, which in turn triggers complement activation, immune complex formation, and tissue deposits, resulting in cell migration, tissue damage, and organ failure (Nashi et al. 2010; Dai et al. 2025). Autoantibodies against double-stranded DNA are present in a high percentage of patients with SLE and have diagnostic utility. Specific subtypes of autoantibodies in SLE have been found to be related to disease activity, tissue damage, and organ manifestations (Gómez-Bañuelos et al. 2023). The multifactorial pathogenic mechanisms involved in SLE pose significant challenges in the treatment, management, and prevention of disease-related complications. The pivotal role of B cells in pathogenesis has led to the development of B cell-targeted therapies for patients with SLE who exhibit high immunological activity and are resistant to state-of-the-art treatments with synthetic disease-modifying anti-rheumatic drugs (Ma et al. 2019; Su et al. 2024). Even though B cell-targeted therapies have significantly improved survival rates, a considerable proportion of patients remain resistant. This may be due to autoreactive B cells residing in tissues that are inaccessible to drugs or to the presence of CD20-negative B cells contributing to autoantibody production. These limitations have driven the development of specific antigen-targeted T cells, which, depending on the target, lead to cell depletion and diminished autoantibody production in patients with SLE (Salmon 2022; Velikova et al. 2024). Search strategy The research strategy for this paper focused on a comprehensive review of the literature to explore cell-targeted therapies in SLE. PubMed, MEDLINE, Scopus, and Web of Science databases were used to gather evidence-based data. Key topics included biological therapies, B cell-targeted therapies, therapeutic approaches in patients with SLE, and adverse events. Emphasis was placed on management strategies and the integration of cell-specific biological therapies in SLE. The search terms included combinations of the following keywords with Boolean operators: („B cell therapies in SLE“ OR „B cell targeted therapies in SLE“ OR „drug against B cells in SLE“) AND („systemic autoimmune diseases“ OR „autoimmune systemic disorders“) AND („therapy“ OR „treatment“ OR „therapeutic challenges“ OR „cell therapy“) AND („chimeric antigen receptor T cell“ OR „CAR T cells“ OR „CD19+ targeted T cells“ OR „BCMA targeted T cells“) AND („CAR T cell trials“ OR „CAR T cell research“ OR „BCMA targeted T cell trials“ OR „BCMA targeted T cell research“). The search was limited to articles published in English and included original research, clinical trials, and review articles focusing on the role of CAR T-cell therapy in SLE. Articles were critically reviewed for relevance, methodology, and outcomes. This approach ensured a robust synthesis of current knowledge while identifying strengths and limitations of CAR T-cell therapy in clinical practice. SLE–treatment overview Pharmacological treatment of SLE is based on four types of medications: glucocorticoids, antimalarials, conventional immunosuppressive drugs, and, more recently, biologics (Fanouriakis et al. 2024). Glucocorticoids have been the cornerstone of treatment for decades; however, growing awareness of their contribution to organ damage has led to the use of lower initial doses, rapid tapering protocols, and lower maintenance doses (Martin-Iglesias et al. 2024). Antimalarials (primarily hydroxychloroquine) remain a mainstay of treatment due to their proven effects on multiple outcomes in SLE, including the prevention of flares, increased long-term survival, and slowing of damage accrual (Ruiz-Irastorza et al. 2010). Conventional immunosuppressants (i.e., methotrexate and azathioprine in mild to moderate disease, mycophenolate mofetil in moderate to severe lupus, and cyclophosphamide in severe disease) have been used for decades and continue to play a crucial role in the current therapeutic approach (Fanouriakis et al. 2024). Their use has been shown to improve outcomes across several organ systems, although with varying levels of evidence (Pego-Reigosa et al. 2013). Most data are available for lupus nephritis, where immunosuppressive regimens have significantly improved the disease course, although partial and complete remission remain unmet needs for a relatively high proportion of patients (Chan 2015). Calcineurin inhibitors, such as the historically used cyclosporine, as well as tacrolimus and the more recently introduced voclosporine, are not only effective T-cell inhibitors but also exert potent effects on podocytes, with a clinically meaningful impact on proteinuria-related outcomes in patients with lupus nephritis (Ponticelli et al. 2021). The introduction of agents targeting specific biological pathways in SLE has further expanded the therapeutic armamentarium and improved overall outcomes (Moysidou et al. 2023). Given the pathogenic role of B cells, therapeutic options targeting them have been developed and studied for years. There are two main approaches: interference with B cell activation through blockade of crucial cytokines involved in B cell transition and maturation (B cell-activating factor, BAFF, or B lymphocyte stimulator, BLyS, and/or A proliferation-inducing ligand, APRIL), or depletion of B cells through interference with cell-surface cluster of differentiation markers, including CD19, CD20, or CD22 (Bernal et al. 2015; Li et al. 2025). Although rituximab (an anti-CD20 antibody) failed to meet primary endpoints in randomized trials, subsequent evidence has demonstrated its efficacy, particularly in refractory SLE and lupus nephritis (Piantoni and Korsten 2022). Pharmacological depletion of circulating B cells has been confirmed in a randomized prospective trial of another anti-CD20 agent, obinutuzumab, in patients with lupus nephritis (Furie et al. 2025). Belimumab, a biologic agent targeting BLyS, was the first to receive approval for SLE (Dubey et al. 2011). Its effects have been demonstrated in both non-renal and renal Pharmacia 72: 1–13 3 lupus, where it serves as an add-on therapy with conventional immunosuppressive regimens (Joy et al. 2022). Anifrolumab has recently been approved for non-renal SLE (Deeks 2021). It inhibits type I interferon receptors, with efficacy most pronounced in patients with a type I interferon gene signature, such as those with cutaneous manifestations, arthritis, and active serology (Vital et al. 2022). The role of biological agents in current practice may become increasingly relevant due to their potential to prevent damage accrual, especially in patients who do not respond adequately to standard immunosuppressive regimens (Zhang et al. 2017; Touma et al. 2025). CAR-T cell therapy–history, generations, mode of action Chimeric antigen receptor and generations of CAR-T therapy The discovery of chimeric immunoreceptors, known as chimeric antigen receptors (CARs), at the end of the twentieth century led to major breakthroughs in cellular immunotherapy (Wu et al. 2020; Bui et al. 2024). Through recombinant technology, T cells are coupled with an engineered T cell receptor or CAR, allowing specific antigen targeting. The structure of CAR T cells includes an extracellular domain for antigen recognition (independent of MHC–peptide complexes), a transmembrane domain, and an intracellular signal transduction fragment for cell activation (Wu et al. 2020; Tomasik et al. 2022; Labanieh and Mackall 2023a, b). Since the discovery of CARs, their structure has been continuously refined based on efficacy and safety data. Currently, five generations of CAR T cells are recognized (Fig. 1) (Tokarew et al. 2019; Asmamaw et al. 2022; Zheng et al. 2023). The first generation of CARs comprises an extracellular antigen-recognizing domain that binds to a single CD3ζchain or FcεRIγ intracellular domain. One of the major issues with the first-generation CARs is their inability to stimulate sufficient interleukin-2 (IL-2) secretion. The second-generation CARs consist of an extracellular antigen-recognizing domain and two intracellular domains: a CD3ζ-chain and co-stimulatory molecules (CD28, 4-1BB, or OX-40), which enhance cell proliferation and cytotoxicity. The third-generation CARs combine an extracellular antigen-recognizing domain with three intracellular domains: the CD3ζ-chain and two additional co-stimulatory signaling domains (CD3ζ-CD28-OX40 or CD3ζ-CD2841BB). However, their efficacy was similar to that of second-generation CARs. The fourth-generation CARs–also called armored CAR T cells, cytokine-expressing CAR T cells, or T cells redirected for universal cytokine-mediated killing (TRUCKs)–were based on the second generation. In these, the cells were modified to express a transgenic protein (a cytokine) or a suicide gene, improving both safety and efficacy. After the modified CD3ζ-containing CAR T cells bind to their specific target, the transgenic product is transcribed and secreted into the extracellular fluid, stimulating CAR T-cell activity and supporting the formation of memory T cells. The fifth (and most recent) generation of CAR T cells contains a membrane receptor, such as the IL-2 receptor, which facilitates antigen-dependent activation of the JAK/STAT pathway (Fig. 1). CAR T-cell therapy–mode of action Cells expressing CAR can bind to and destroy specific cell types that present the target antigen on their surface (Abdalhadi et al. 2024). By coupling their extracellular domain to an antigen, CAR T cells can eliminate target popuFigure 1. Structure of chimeric antigen receptors (CARs) (A) and mechanism of action (B). Created in BioRender. Velikova T (2025) https://BioRender.com/oa86zic. Shumnalieva R et al.: CAR T-cell therapy in SLE4 lations based solely on antigen recognition, such as CD19, B cell maturation antigen (BCMA), fibroblast activation protein (FAP), or urokinase plasminogen activator receptor (uPAR), among others (Fischer and Bhattarai 2021). Progress in CAR T-cell therapies for cancer and systemic autoimmune diseases has also led to novel approaches in which the extracellular domain of CAR contains not an antibody but an autoantigen–enabling recognition of autoantibody-expressing B cells. These engineered cells are known as chimeric autoantigen receptor T cells (CAAR T cells) (Ellebrecht et al. 2016). CAR-T cell therapy–clinical application in cancer–a short overview CAR T-cell therapy has been successfully applied in clinical practice for relapsed or refractory B cell malignancies. These include CD19-targeted CAR T-cell therapy for B cell acute lymphocytic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), as well as BCMA-targeted CAR T-cell therapy for multiple myeloma (MM) (Zhao et al. 2018). Since 2017, the US Food and Drug Administration (FDA) has approved seven CAR T-cell therapies for clinical usage (Goyco et al. 2024). These include tisagenlecleucel (Kymriah; Novartis, in 2017), axicabtagene ciloleucel (Yescarta; Gilead, in 2017), brexucabtagene autoleucel (Tecartus; Gilead, in 2020), lisocabtagene maraleucel (Breyanzi; Bristol Myers Squibb, in 2021), idecabtagene vicleucel (Abecma; Bristol Myers Squibb and Bluebird Bio, in 2021), ciltacabtagene autoleucel (Carvykti; Legend and Janssen, in 2022), and obecabtagene autoleucel (Aucatzyl; Autolus Therapeutics, in 2024) (Table 1) (King and Orozco 2019; Bouchkouj et al. 2022; Sharma et al. 2022; Abramson et al. 2024; Elmacken et al. 2024; Khvorost et al. 2024; Natrajan et al. 2024; Lee 2025; Rampotas and Roddie 2025). The nature of solid tumors makes the application of CAR T cells in this area more complicated due to tumor-associated factors, including the immunosuppressive tumor microenvironment (TME) (Albelda 2024; Du et al. 2025). Among these are the physical barrier of the tumor, hypoxia and nutrient deficiency, the presence of immunosuppressive cells, inhibitory enzymes, and cytokines, and the use of checkpoint inhibitors, which can interfere with CAR T-cell trafficking and infiltration and antigen binding and cause their anergy and exhaustion. Overcoming the TME is an area of research interest, and approaches for modifying CAR structure or combination or adjuvant treatment strategies are under development (Chen et al. 2024). Interesting applications of CAR T-cell therapy include the possibility of direct local delivery of CAR T cells (locoregional therapy) or priming the TME before CAR T-cell infusion (Sagnella et al. 2022). CAR-T cell therapy in autoimmune rheumatic diseases–G. Schett’s groundbreaking discovery The advantages of CAR T-cell therapy in the treatment of B-cell-related hematological malignancies have led to the idea of possible application of CAR T cells as a therapeutic strategy in B-cell-driven systemic autoimmune rheumatic diseases (Shumnalieva et al. 2024; Rampotas et al. 2025). In the ideal scenario, eliminating pathogenic B cells could lead to complete and sustained clinical and immunological remission of the disease. The use of genetically reprogrammed allogeneic or autologous T cells against specific targets has shown potential benefits in preclinical and early clinical studies in SLE (Nie et al. 2025). In experimental models of lupus, there was complete B-cell depletion and reduction in autoantibodies, which was associated with better disease outcomes. The use of anti-CD19 CAR T cells has shown promising results in the prevention and treatment of the disease (Jin et al. 2021). CD19-targeted CAR T cells have the advantage of depleting a significant fraction of B cells, including pre-B cells and antibody-producing plasmablasts and plasma cells, which play a pivotal role in SLE pathogenesis (Schett et al. 2024). The use of hypoimmune CD19 CAR T cells in a mouse model of spontaneous SLE resulted in sustained deep tisTable 1. CAR T-cell therapies approved by the FDA for clinical use by 2025. Name Pharmaceutical company Target Indication Ref. Tisagenlecleucel Kymriah; Novartis CD19 Relapsed/Refractory large B-cell ALL, relapsed/ refractory FL Rampotas and Roddie 2025; Khvorost et al. 2024 Axicabtagene ciloleucel Yescarta; Gilead CD19 Relapsed/refractory large B-cell lymphoma or FL King and Orozco 2019 Brexucabtagene autoleucel Tecartus; Gilead CD19 Relapsed/refractory mantle cell lymphoma; relapsed/ refractory B-cell precursor ALL Bouchkouj et al. 2022 Lisocabtagene maraleucel Breyanzi; Bristol Myers Squibb CD19 Relapsed/refractory large B-cell lymphoma, DLBCL Elmacken et al. 2024; Abramson et al. 2024 Idecabtagene vicleucel Abecma, Bristol Myers Squibb and Bluebird Bio BCMA Relapsed/refractory multiple myeloma Sharma et al. 2022 Ciltacabtagene autoleucel Carvykti; Legend and Janssen BCMA Relapsed/refractory multiple myeloma Natrajan et al. 2024 Obecabtagene autoleucel Aucatzyl; Autolus Therapeutics CD19 Relapsed or refractory B-cell precursor acute lymphoblastic leukemia Lee 2025 Legend: ALL – acute lymphoblastic leukemia; BCMA – B-cell maturation antigen; CAR – chimeric antigen receptor; CD – cluster of differentiation; DLBCL – diffuse large B-cell lymphoma; FDA – Food and Drug Administration; FL – follicular lymphoma. Pharmacia 72: 1–13 5 sue B-cell depletion, decreased levels of autoantibodies and cytokines, and improvement in disease manifestations, including proteinuria, without inducing immune activation or allograft rejection (Hu et al. 2025). The first published experience with the use of CAR T cells in inflammatory rheumatic diseases is a series of five SLE patients reported by a research group from Germany, led by Professor Georg Schett. The authors described the use of chimeric CAR T cells in patients with SLE who were refractory to standard immunosuppressive treatment. Following a course of lymphodepletion with fludarabine and cyclophosphamide, patients were reinfused with autologous T cells transduced with a lentiviral anti-CD19 CAR vector. These reports revealed promising results, achieving DORIS remission in all patients three months after treatment, with an acceptable safety profile. Drugfree remission persisted even after the reappearance of naïve B cells that occurred after a mean of 110 days (Mougiakakos et al. 2021; Mackensen et al. 2022a, b). The findings described above were reiterated in a more recent case series of 15 patients with different systemic autoimmune diseases, including eight patients with refractory SLE. Other diagnoses included idiopathic inflammatory myositis (three patients) and systemic sclerosis (four patients). All SLE patients had proliferative lupus nephritis and were refractory to two standard immunosuppressive agents, including mycophenolate mofetil as one of the two drugs. This study demonstrated a steep decline in disease activity and rapid elimination of CD19-positive B cells from the circulation. All patients achieved DORIS drug-free remission by six months following CAR T-cell infusion, with SLEDAI-2k = 0 (including negative dsDNA and normal complement levels) throughout the follow-up period. In a single patient, proteinuria was reported four months after CAR T-cell infusion; however, the subsequent kidney biopsy revealed podocytopathy with no histologically active lupus nephritis. Despite the absence of SLE-specific antibodies (including dsDNA and other antinuclear antibodies assessed in the study), IgG responses to standard vaccines remained stable. Reconstitution of circulating B cells was confirmed at 4 and 12 months following CAR T-cell treatment. Most of the B cells exhibited a naïve phenotype, in contrast to the CD19+CD27+ memory cells, whose count was markedly lower. There was no moderate – or high-grade cytokine release syndrome, immune-effector cell-associated neurotoxicity syndrome (ICANS), or significant bone marrow toxicity. Only one SLE patient experienced pneumonia seven weeks after CAR T-cell treatment (Müller et al. 2024). Unlike CAR T-cell treatment of hematological malignancies, CAR T-cell-mediated killing of B cells in the tissues of patients with inflammatory rheumatic conditions may lead to a newly described side effect, termed “local immune effector cell-associated toxicity syndrome (LICATS).” The syndrome was described in a recently published extension of the previous patient series from Germany, now including 39 patients (20 with SLE). LICATS has been defined as a local and self-limited impairment of organ function after treatment, following the pre-treatment pattern of organ involvement. LICATS was observed in 30 of 39 (77%) patients. Notably, most patients with two or more LICATS manifestations were those with SLE. Given that most episodes resolved spontaneously or after a short course of glucocorticoids, the authors concluded that LICATS is an entity of its own, not representing a disease relapse (Hagen et al. 2025). In addition to the potential therapeutic effects and the understanding of the consequences of deep tissue B-cell depletion, studies on CAR T cells have improved knowledge of the interplay between two therapeutically important aspects of SLE pathogenesis: B-cell activation and autoreactivity, and the expression of interferon-induced genes. Since CAR T cells reduced the type I interferon gene signature in monocytes and T cells (PBMCs), the same group of authors concluded that autoreactive B cells and their activation may be the initiating point causing (or at least preceding) an increase in interferon expression, rather than the reverse (Wilhelm et al. 2024). Therefore, the pivotal work of Schett et al. (2024) has not only introduced a new therapeutic concept but also provided novel insights into the role of B cells and their associations with other aspects of adaptive and innate immunity relevant to SLE pathogenesis. In 2024, Hagen et al. reported a 21-year-old neuropsychiatric SLE patient presenting with transverse myelitis, arthritis, and skin vasculitis whose condition deteriorated despite corticosteroid and immunosuppressive treatment. He was treated with autologous CD19-targeted CAR T cells, showing good tolerability and no treatment-related side effects. Clinical and laboratory improvements included seroconversion of anti-dsDNA antibodies, marked improvement in neurological and muscle functions, and improvements in MRI images and skin manifestations (Hagen et al. 2024). Since the first report on the clinical use of CAR T-cell therapy for treating patients with AIRD, there has been an increasing number of reports and clinical trials exploring the potential, safety, and efficacy of autologous CAR T cells in rheumatology. On the other hand, allogeneic CAR T cells offer several advantages, including homogeneity and cost-effectiveness. However, the risks of graft-versus-host disease and allogeneic rejection must be considered (Yang et al. 2025). In a pilot study assessing the safety and efficacy of allogeneic CD19-targeting CAR T cells in severe, refractory SLE patients, Yang et al. demonstrated significant clinical efficacy, with SELENA-SLEDAI scores of 0 at 3–6 months, decreased anti-dsDNA antibodies, reduced proteinuria, drug-free remission in one patient, and low-dose corticosteroids with slow tapering as maintenance therapy in the others. The safety profile was characterized by CRS grade 1 in all patients, and none experienced ICANS or GVHD (Yang et al. 2025). Wang et al. (2025) reported the use of allogeneic CD19-targeting CAR T cells in three patients with SLE and multiorgan involvement who had failed previous Shumnalieva R et al.: CAR T-cell therapy in SLE6 treatment regimens. After CAR T-cell infusion, there was a significant decrease in both the percentage and absolute circulating B-cell count, as well as a decline in SLE activity scores. There were no side effects related to CAR T-cell therapy, although one patient was withdrawn due to severe thrombocytopenia (Wang et al. 2025). CAR-T-cell therapy in children with SLE The first reports on the use of CAR T-cell therapy in patients with SLE under 18 years of age were published in 2024. The first case was a 15-year-old girl with severe, refractory SLE and an SLEDAI score of 23. At her 6-month follow-up visit, she remained in drug-free remission with a SLEDAI score of 0 (Krickau et al. 2024). The second adolescent patient with SLE treated successfully with CAR T-cell therapy was reported in Italy. This 15-year-old girl had a baseline SLEDAI score of 22 and remained in drugfree remission at follow-up visits, with a SLEDAI score of 2 at 6 weeks (Marasco et al. 2024). Recently, the Integrated Multidisciplinary Paediatric Autoimmunity and Cell Therapy (IMPACT) working group was established to study CAR T-cell therapy in children with rheumatic diseases, aiming to address all aspects of cell therapy use in this patient population (Wobma et al. 2025). CAR-T cell therapy in SLE– clinical trials (ongoing, including lupus nephritis and immune thrombocytopenia) The potential of CAR T-cell therapy as a novel treatment strategy in SLE is under investigation in clinical trials worldwide. A thorough search using the terms “systemic lupus erythematosus” and “CAR T-cell therapy” was performed on clinicaltrials.gov, identifying 79 studies by June 2025 (www.clinicaltrials.gov). Of these, six had an unknown status, two were withdrawn, and the rest were either recruiting or not yet recruiting (Table 2). CAR T-cell therapy is being explored as an innovative therapeutic option in autoimmune rheumatic diseases, including SLE and specific SLE manifestations such as lupus nephritis and immune thrombocytopenia. CAR T-cell adverse effects and toxicities One of the main issues regarding the clinical use of CAR T cells is the occurrence of severe and potentially life-threatening adverse events (AEs), including tumor lysis syndrome (TLS), hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), acute kidney injury (AKI), cytopenia, infections, anaphylaxis, and unique AEs such as cytokine release syndrome (CRS), CRS-related coagulopathy, CAR T-cell-related encephalopathy syndrome (CRES), immune effector cell-associated neurotoxicity syndrome (ICANS), and, as previously mentioned, LICATS (Adkins 2019; Gatto et al. 2023; Guffroy et al. 2024). The most common side effect of CAR T-cell therapy is CRS, which results from the release of proinflammatory cytokines and chemokines from targeted cells, followed by a cytokine storm. Typically, it occurs within 3 weeks after CAR T-cell infusion and ranges from mild to severe. The clinical presentation includes fever, nausea, hypotension, tachypnea, and tachycardia, and in severe cases, pulmonary edema. In such cases, tocilizumab (TCZ)–an interleukin (IL)-6 receptor antagonist–may be used, as approved by the FDA. However, there are reports of resistant CRS that does not respond to TCZ or high-dose corticosteroids (CS) (Frey and Porter 2019; Jain et al. 2023). Patients with AIRD treated with CAR T-cell therapy who developed CRS generally had mild symptoms and did not require aggressive treatment (Müller et al. 2024). Toxicity affecting the central nervous system (CNS) may accompany CRS or appear during its resolution (Velasco et al. 2023). It usually develops within 8 weeks after CAR T-cell infusion, with manifestations ranging from mild to severe. The clinical presentation includes neuropsychiatric symptoms with qualitative or quantitative disturbances of CNS function (Fleischer et al. 2024). A possible pathogenic mechanism is dysfunction of the blood–brain barrier (BBB) due to cytokine and chemokine secretion, which leads to further activation of neuronal cells and the release of neurotoxic mediators. MAS/HLH is another possible complication of CAR T-cell therapy, regarded as a variant of CAR T-cell-related CRS. It is characterized by interferon (IFN)-γ-driven hyperinflammation, presenting with life-threatening cytopenias, splenomegaly, and hypercoagulability (Martín-Rojas et al. 2022). Evidence of MAS/HLH in patients with AIRD remains limited. TLS has been observed in patients with hematological malignancies treated with CAR T-cell therapy. It has been reported in association with higher tumor burden, and close monitoring of treated patients is recommended. Particular attention should be paid to uric acid, creatinine, and lactate dehydrogenase (LDH) levels, as well as proinflammatory cytokines and CRS development (Zhang et al. 2023). Another reported side effect is AKI, especially in patients with pre-existing kidney injury due to the underlying disease. Possible mechanisms include hypoperfusion in the setting of hypotension, increased vascular permeability, and complications of CRS, TLS, or HLH, accompanied by secretion of proinflammatory cytokines. Notably, toxicity of drugs used for lymphodepletion prior to CAR T-cell infusion has also been implicated (Gutgarts et al. 2020; Russo et al. 2024). CAR T-cell therapy has been linked to hematological toxicities, such as severe cytopenias, along with conditions like neutropenia-related infections, which typically Pharmacia 72: 1–13 7 Table 2. Clinical trials exploring CAR T-cell therapy in the field of SLE by June 2025. Condition www.clinicaltrial.gov Number Compound name Type of CAR Phase Country Sponsor Status SLE NCT07038447 KITE-363 Anti-CD19/CD20 CAR T-cell Phase 1 Not yet provided Kite, A Gilead Company Not yet recruiting SLE NCT07031713 ct1192 CD19/20 CAR-T cell Phase 1 China Wuhan Union Hospital, China Not yet recruiting SLE NCT07015983 CC-97540 (BMS986353) D19-Targeted NEX-T CAR T Cells Phase 2 70 locations worldwide Juno Therapeutics, Inc., a Bristol-Myers Squibb Company Not yet recruiting SLE +/- lupus nephritis NCT06984341 P-CD19CD20ALLO1 allogeneic CD19/ CD20-specific CAR-T cells Phase 2 Not yet provided Genentech, Inc. Not yet recruiting SLE NCT06980597 OL-108 gamma delta (γδ) CAR-T Phase 2 China Beijing GoBroad Hospital recruiting SLE NCT06978738 universal allogeneic anti-CD19/BCMA CAR T-cells Phase 1 China Changzhou No.2 People‘s Hospital Not yet recruiting Lupus nephritis (SLE-LN) NCT06947473 umbilical cord blood CD19-BCMA CAR-T cells Phase 1; Phase 2 Not yet provided Beijing GoBroad Hospital Not yet recruiting Lupus nephritis (SLE-LN) NCT06947460 CD19-BCMA CAR-T cells Phase 1; Phase 2 China Beijing GoBroad Hospital recruiting SLE NCT06946485 CHT101 Universal CAR-T Cells Early phase 1 Not yet provided The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School Not yet recruiting Lupus nephritis (SLE-LN) NCT06935474 C-CAR168 autologous antiCD20/BCMA CAR-T therapy Phase 1 Phase 2 United States AbelZeta Inc. Not yet recruiting Childhood-onset SLE NCT06934447 BCMA/CD70 CAR-T cells Phase 1 China The Children‘s Hospital of Zhejiang University School of Medicine recruiting SLE NCT06925542 CTX112 Anti-CD19 Allogeneic CRISPRCas9-Engineered T Cells Phase 1 United States and Germany RISPR Therapeutics recruiting SLE NCT06920433 universal CD19/ BCMA CAR T-cells Early phase 1 China Zhejiang University recruiting SLE NCT06913608 CLBR001 and SWI019 switchable CAR-T cell combination therapy Phase 1 Not yet provided Calibr, a division of Scripps Research Not yet recruiting Lupus nephritis (SLE-LN) in children NCT06904729 CAR-T cells Phase 3 China Guangzhou Women and Children‘s Medical Center recruiting SLE NCT06902844 Equecabtagene Autoleucel Injection (Eque-cel) autologous BCMA CAR-T cells Not Applicable China Tongji Hospital recruiting SLE NCT06900764 CAR-T Cells Not Applicable China Wuhan Union Hospital, China Not yet recruiting SLE NCT06897930 AZD0120 CD19/BCMA dual CAR T cell therapy Phase 1b/2 AstraZeneca recruiting SLE NCT06892145 MC-1-50 CD19-targeting CAR T Lymphocyte Phase 1 China Chongqing Precision Biotech Co., Ltd Not yet recruiting SLE NCT06886919 C19 CAR-T Allogeneic CD19targeting CAR T cells Early phase 1 Not yet provided Beijing Immunochina Medical Science & Technology Co., Ltd. Not yet recruiting SLE NCT06866080 LCAR-AIO CAR-T Cells Early phase 1 China Nanjing Legend Biotech Co. recruiting SLE NCT06852573 ZM001 CAR-T Cells Phase 1 Not yet provided Beijing Immunochina Medical Science & Technology Co., Ltd. Not yet recruiting SLE-related immune thrombocytopenia NCT06826430 Inaticabtagene Autoleucel autologous CD19specific CAR T-cell Phase 1 Not yet provided Juventas Cell Therapy Ltd. Not yet recruiting SLE NCT06822881 CT1190B CAR-T Therapy Phase 1 China Beijing GoBroad Hospital recruiting Shumnalieva R et al.: CAR T-cell therapy in SLE8 Condition www.clinicaltrial.gov Number Compound name Type of CAR Phase Country Sponsor Status SLE NCT06794008 BCMA-CD19 CAR-T Therapy Phase 2 China Peking University People‘s Hospital recruiting Lupus nephritis (SLE-LN) NCT06785519 CD19/BCMA CAR-T Cells Early phase 1 China He Huang recruiting SLE with a cohort with SLE-LN and extrarenal lupus (ERL) NCT06752876 CB-010 CRISPR-Edited Allogeneic AntiCD19 CAR-T Cell Therapy Phase 1 Not yet provided Caribou Biosciences, Inc. Not yet recruiting SLE NCT06711146 Meta10-19 Metabolically Armed CD19 CAR-T Cells Early phase 1 China Zhejiang University recruiting SLE NCT06710717 autologous CD19 CAR T-cell Phase 1 Malaysia National University of Malaysia recruiting SLE-Non renal, SLE-LN NCT06708845 zamtocabtagene autoleucel (zamtocel) autologous tandem CD20CD19-directed non-cryopreserved CAR-T cell product Phase 1 Not yet provided Miltenyi Biomedicine GmbH Not yet recruiting SLE NCT06691152 CD19 Universal CAR-T cells Phase 1 cHINA The Children‘s Hospital of Zhejiang University School of Medicine recruiting SLE NCT06685042 CD19-CAR_Lenti autologous CAR T-cell product targeting CD19positive B cells Phase 1; Phase 2 Italy Fondazione Policlinico Universitario Agostino Gemelli IRCCS recruiting Lupus nephritis (SLE-LN) NCT06681337 Universal BCMA CART + CD19 CART Early Phase 1 Not yet provided Bioray Laboratories Not yet recruiting SLE NCT06653556 LCAR-AIO T cells Early Phase 1 China Wuhan Union Hospital, China recruiting SLE NCT06585514 CD19 CAR T cells Phase 1; Phase 2 China Beijing GoBroad Hospital recruiting SLE NCT06567080 JWCAR201 CD19/CD20 CAR-T product Phase 1 China RenJi Hospital Not yet recruiting SLE NCT06549296 RD06-04 CAR-T Cells Targeting CD19 Early Phase 1 China Nanjing Bioheng Biotech Co., Ltd. recruiting SLE NCT06544330 SYNCAR-001 + STK-009 a Combination Autologous CD19 CAR T Cell Therapy (SYNCAR-001 + STK-009) Phase 1 United States Synthekine recruiting SLE NCT06530849 GC012F autologous CAR T-cell therapy that targets both BCMA and CD19 Phase 1; Phase 2 China Gracell Biotechnologies (Shanghai) Co., Ltd. recruiting SLE NCT06513429 IM19 CAR-T cells n/a China Peking University Third Hospital recruiting SLE NCT06503224 SCAR02 Anti-BCMA and CD19 CART cells n/a China The First Affiliated Hospital of the University of Science and Technology of China recruiting Lupus nephritis (SLE-LN) NCT06497387 PRG-1801 BCMA-targeting CAR-T Cells) Early Phase 1 China Tongji Hospital recruiting Lupus nephritis (SLE-LN) NCT06497361 PRG-2311 CD19/BCMAtargeting CAR-T Cells Early Phase 1 China Tongji Hospital recruiting SLE NCT06465147 CD19-targeting CART cells Phase 1 United States Seattle Children‘s Hospital recruiting SLE NCT06462144 IMPT-514 Autologous AntiCD19/20 CAR T Therapy Early Phase 1 China The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School recruiting Pharmacia 72: 1–13 9 Condition www.clinicaltrial.gov Number Compound name Type of CAR Phase Country Sponsor Status SLE NCT06428188 BAH247 BCMA/CD19 CAR-T cells Phase 1; Phase 2 China Essen Biotech recruiting SLE NCT06420154 anti-CD19-CAR-T cells Early Phase 1 China First Affiliated Hospital of Wenzhou Medical University Not yet recruiting SLE NCT06417398 UTAA09 CD19-targeting CART cells Early Phase 1 Not yet provided PersonGen BioTherapeutics (Suzhou) Co., Ltd. Not yet recruiting SLE NCT06373081 anti-CD19-CD3ECAR-T cells n/a China Shanghai Changzheng Hospital recruiting SLE NCT06361745 UTAA09 CD19-targeting CART cells n/a China PersonGen BioTherapeutics (Suzhou) Co., Ltd. recruiting SLE NCT06349343 CD19/BCMA CAR-T cell therapy Phase 1 China Wuhan Union Hospital, China recruiting SLE NCT06350110 BAH242 CD19-BCMA CAR-T cells Phase 1; Phase 2 China Essen Biotech recruiting SLE NCT06347718 anti-CD19 CAR T cell therapy Phase 1; Phase 2 Germany University of Erlangen-Nürnberg Medical School recruiting Lupus nephritis (SLE-LN) NCT06342960 KYV-101 An autologous fully human anti-CD19 CAR T-cell therapy Phase 1 Phase 2 Germany Kyverna Therapeutics recruiting SLE NCT06340490 RJMty19 allogeneic CD19CAR-DNT cells Phase 1 China Guangdong Ruishun Biotech Co., Ltd Not yet recruiting SLE NCT06340750 LMY-920 BAFF-ligand CAR-T cells Phase 1 United States Luminary Therapeutics recruiting SLE NCT06333483 obecabtagene autoleucel (obe-cel) autologous CD19targeting CAR T cells Phase 1 Spain, United Kingdom Autolus Limited recruiting SLE (lupus nephritis, immune thrombocytopenia) NCT06316791 CNCT19 Anti-CD19 Cell Therapy Early Phase 1 China Juventas Cell Therapy Ltd. recruiting SLE NCT06310811 RD06-04 Anti-CD19 CAR-T Cell Therapy n/a China Wuhan Union Hospital, China recruiting SLE NCT06308978 FT819 iPSC-derived CAR T-cell therapy targeting CD19 Phase 1 United States Fate Therapeutics recruiting SLE NCT06297408 Relmacabtagene autoleucel (relmacel) (JWCAR029) Anti-CD19 CAR-T Cell Therapy Phase 1 Not yet provided Shanghai Ming Ju Biotechnology Co., Ltd. Not yet recruiting SLE NCT06294236 SC291 a Hypoimmune, Allogeneic CD19directed CAR T Cell Therapy Phase 1 United States Sana Biotechnology recruiting Lupus nephritis (SLE-LN) NCT06285279 FKC288 BCMA/CD19 Dual Targeted CAR-T Cell Phase 1 China Nanjing University School of Medicine recruiting Lupus nephritis (SLE-LN) NCT06277427 PRG-1801 BCMA-targeting CAR-T Cells n/a China Lingli Dong recruiting SLE NCT06249438 C-CAR168 CD20/BCMAdirected CAR-T cells Phase 1 China RenJi Hospital recruiting SLE NCT06222853 anti-CD19-CAR-T cells Phase 1 China The Children‘s Hospital of Zhejiang University School of Medicine recruiting SLE NCT06150651 anti-CD19-CAR-T cells Phase 1 Thailand Chulalongkorn University recruiting SLE NCT06121297 CABA-201 autologous CD19specific CAR T Cells Phase 1; Phase 2 United States; Spain Cabaletta Bio recruiting SLE NCT05988216 BRL-301 Allogeneic CAR T Cell Targeting CD19 Gene n/a China Bioray Laboratories recruiting Lupus nephritis (SLE-LN) NCT05938725 KYV-101 An autologous fully human anti-CD19 CAR T-cell therapy Phase 1; Phase 2 United States Kyverna Therapeutics recruiting