Background

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can affect multiple organ systems and is heterogenous in its presentation and response to therapy. SLE remains incurable and has significant negative impacts on the function and quality of life of affected individuals. While the current therapies used to treat SLE have led to an improvement in morbidity and mortality, many patients with SLE remain refractory to available treatment regimens [1, 2]. Additionally, when diagnosed in childhood, SLE is associated with increased morbidity and mortality compared to adult SLE [3, 4]. SLE is known to be more aggressive in non-white ethnicities [5]. Lupus nephritis (LN) in particular carries significant morbidity and has an increased prevalence and severity in children and adolescents compared to adults [6, 7].

Despite advances in therapy [8, 9], the survival rates for SLE and LN have plateaued over recent decades [10]. In the United States, SLE is the tenth leading cause of death and the number one cause of death from a chronic inflammatory disease for females in the 15–24 year age group [11]. Complete remission of LN is achieved in only 40–60% of youth despite aggressive therapy [12]. Children who develop end stage kidney disease (ESKD) due to LN have a 5-year mortality of approximately 22% [13]. Compared to other children on hemodialysis, those with LN have an increased mortality rate and are less likely to receive renal transplant despite the fact that post-transplant, graft survival and infection rates are comparable [14].

Due to increased disease severity, most children with SLE require prolonged treatment with high dose glucocorticoids and aggressive immunosuppression often with cyclcophosphamide (CYC). They can have high cumulative exposure to these therapies that carry significant morbidity and mortality, particularly from infection [15]. Glucocorticoids carry a significant morbidity risk in SLE in particular with increased risk of lupus-related damage as well as adverse effects like cataracts, hypertension, hyperglycemia, dyslipidemia, avascular necrosis, obesity and poor growth, and osteoporosis [16]. Therefore, there remains a significant unmet need for new therapies that can improve disease control and reduce glucocorticoid and other toxic medication exposure for these patients.

Disease pathogenesis and targeted treatments

Both the innate and adaptive immune responses are implicated in the pathogenesis of SLE [17,18,19]. The innate immune system includes complement proteins, macrophages, neutrophils, antigen presenting cells, and various antimicrobial molecules and support cells. In SLE, there is poor clearance of apoptotic material allowing for the presentation of intracellular substances that then trigger the inflammatory cascade [20,21,22,23]. Abnormalities and defects in the complement pathway [24] and the Fas ligand pathway [25,26,27] are also involved in its pathogenesis. Defects in neutrophil apoptosis result in increased antigen production and triggering of inflammation [28]. The adaptive immune system includes T cells, B cells, and natural killer cells. In SLE, B cells are dysregulated and produce autoantibodies, which are a hallmark of SLE [29,30,31]. Autoantibodies are thought to contribute to SLE pathogenesis in many ways, including from deposition as well as direct damage to tissues, stimulation of interferon production and signaling, and binding to and increasing the immunogenicity of neutrophil extracellular traps [32, 33].

Despite a multimodal approach to target the different aspects of the immune system involved in SLE pathogenesis, many patients have refractory disease, defined as a “failure to improve within 3–4 months or the inability to achieve partial remission after 5–12 months or complete remission after 2 years of treatment” [34, 35]. In most studies, SLE is also considered refractory when patients do not respond to 1–3 immunosuppressive medications in addition to corticosteroids [35]. Given that so many therapeutic options are exhausted in these patients, they are often reliant on glucocorticoids for disease control.

Widespread implementation of treatments such as CYC has improved outcomes for patients with refractory disease, but gains have been more modest in patients with severe kidney disease [10, 36].

B cell-directed therapies

Recent research has turned to B cell therapies to try and improve outcomes in SLE and LN [37, 38]. B cells produce autoantibodies, which are known to play a critical role in SLE pathogenesis [39, 40] In addition, B lymphocytes indirectly affect antigen-presenting activity in SLE [41]. Rituximab, a monoclonal antibody that targets CD20-expressing B cells, is used to treat lupus with mixed effects [42]. In the LN Assessment with Rituximab (LUNAR) trial for adults with SLE, rituximab was not shown to be effective in reaching the endpoints of improved clinical renal outcomes after 1 year of therapy [43]. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial sought to evaluate if there was a major or partial clinical response for moderate to severe extrarenal manifestation of adult SLE [44]. Likewise, it did not reach its end goal. Despite these studies not reaching their endpoints, rituximab has continued to be used clinically for the treatment of lupus due to real-world experience supporting its efficacy. Trial design may have contributed to the LUNAR and EXPLORER studies not meeting their primary endpoints– including poorly targeted patient selection, inclusion of patients on excessively high doses of corticosteroids, and inadequate study time to reach ambitious endpoints [35]. In a meta-analysis that included 31 studies involving over a thousand SLE patients, the global response to rituximab was 72% with a complete response in 46% and a partial response rate of 32% [41].

Belimumab is a fully humanized monoclonal antibody against B lymphocyte stimulator (BAFF), an essential survival factor for B cells, that is used as an adjunct B cells depleting agent for lupus treatment. Two international phase III clinical trials, BLISS-52 [45] and BLISS-76 [46], of adults with SLE led to the U.S. Food and Drug Administration FDA approval of belimumab for lupus in 2011, the first new treatment for lupus in over 50 years. Subanalysis of those studies suggested its benefit in LN. BLISS-LN was conducted and randomized 448 adult SLE patients with active, biopsy-proven class III, IV and/or V LN 1:1 to receive belimumab or placebo, plus standard of care therapy, for 104 weeks. The primary endpoint was met by 43% of patients receiving belimumab compared to 32% on placebo. A pediatric trial of belimumab, PLUTO [47], showed similar efficacy compared to the adult data with 41.2% achieving SRI response rate [48]. Thus, numerous studies have shown that anti-B cell therapies may serve as a potent treatment for SLE [49], even though we do not always see an adequate response in every patient. It has been postulated that the failure of current B cell therapies is largely related to transient or incomplete depletion of B cells, as has been seen in both rheumatoid arthritis and in SLE [50, 51].

Chimeric antigen receptor T Cells

Chimeric antigen receptor T cells (CAR T) are T cells that are genetically engineered to express a CAR to target specific surface antigens without the need for MHC presentation. A CAR combines an antibody derived scFV extracellular domain with an intracellular domain designed to stimulate T cell activation. The most common clinically utilized CAR T cells have an intracellular domain composed of a CD3𝛇 stimulatory domain combined with either 4-1BB or CD28 costimulatory domains. CAR T cells were first developed in the 1980s, however, the major clinical breakthrough occurred over 20 years later with the first human trials of anti-CD19 CAR T cells for B cell malignancies [52]. Tisagenlecleucel, an autologous anti-CD19 CAR T cell product, was the first CAR T cell product utilized in pediatric cancer. In phase I/II clinical trials of tisagenlecleucel in pediatric patients with relapsed/refractory acute lymphoblastic leukemia, complete response rates were > 80% after a single dose [53]. These dramatic response rates led to FDA approval of tisagenlecleucel in 2017, and since then 5 other CAR T cell products have been approved for adults with B cell lymphomas and multiple myeloma. The majority of CAR T cell studies utilize autologous T cells collected via apheresis. CAR T cell manufacturing times vary but may take up to 2 weeks for CAR transduction and T cell expansion. Prior to infusion, patients undergo lymphodepleting chemotherapy to enhance CAR T cell in vivo expansion and persistence. Typical regimens for lymphodepletion include both CYC and fludarabine.

As CD19 CAR T cells can deplete both normal and pathogenic B cells, as well as plasmablasts, there is promise in utilizing this novel therapeutic avenue for SLE [52]. It is hypothesized that by potently eliminating both B cells and plasmablasts, CAR T therapy can halt autoimmunity and prevent organ damage in patients refractory to current B cell-depleting treatments.

To that end, CD19 CAR T cells have demonstrated efficacy in proof-of-concept murine models of lupus [54, 55]. MRL-lpr is a spontaneous SLE murine model with severe lupus nephritis. Infusion of syngeneic anti-mouse CD19 CAR T cells into 13-week-old MRL-lpr mice after low dose irradiation resulted in nearly complete eradication of circulating CD19 + B cells in the blood, which correlated with improved survival and less active disease [54]. Importantly, the mice spared total body irradiation prior to the CD19 CAR T infusion did not exhibit such robust B cell depletion. Similarly, it was demonstrated that infusion of anti-CD19 CD8 + T cells into MRL-lpr and NZB/W mice led to profound and prolonged depletion of CD19 + B cells with aplasia lasting more than one year post therapy [55]. Anti-DNA IgG and IgM antibodies that were detectable before CAR T cell injections declined to undetectable levels after treatment and remained low to undetectable in most of the CAR T cell-treated mice for at least 19 weeks post infusion. These results correlated to a drastic improvement in survival and reversal of high-grade proteinuria in the CAR T treated mice [55].

CAR T cells in human SLE

Given this promising pre-clinical data and substantial clinical experience with CD19 CAR T cells for hematologic malignancies, there is a large interest in utilizing CD19 CAR T cells for autoimmune disease. Early clinical success has been demonstrated in patients with SLE, anti-synthetase syndrome, and myasthenia gravis [56,57,58]. In 2023, Schett and colleagues, published a comprehensive review about CAR T therapy in autoimmune disease including lupus. The first report of CAR T to treat human SLE was published by a group in Germany in 2021. Mougiakakos, D et al., reported a case of a 20-year-old woman with severe and refractory SLE who presented with active LN (class IIIA), nephrotic syndrome, pericarditis, pleurisy, rash, arthritis, and a history of Libman–Sacks endocarditis whose lupus was inadequately controlled despite treatment with hydroxychloroquine, high-dose glucocorticoids, CYC, mycophenolate mofetil (MMF), tacrolimus, belimumab, and rituximab [59]. After lymphodepletion with fludarabine and CYC, a single dose of 1.1 × 106 CD19 CAR T cells/kg (CD4 + to CD8 + T cell ratio of 3:1) was administered. The common side effects of CAR T therapy including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias were not observed in this patient. She had complete depletion of circulating B cells that was maintained for more than 44 days. Her double-stranded DNA (dsDNA) autoantibodies and complement levels normalized. Clinically, she had improvement in proteinuria and her SLEDAI score improved from 18 to 0 post treatment [59].

Five young adult patients with refractory lupus were enrolled in a compassionate use trial of autologous CD19 CAR T cell therapy after previously failing management with conventional immunosuppressives [60]. The patients, aged 18 to 24 years, had disease durations ranging from 1 to 9 years and high baseline lupus disease activity as measured by the SLEDAI (scores 8 to 16). All had LN (stages III, IV, or III/V). In brief, the patients received lymphodepleting chemotherapy with fludarabine and CYC from day − 5 to day − 3 followed by 1 × 106 CAR T cells/kg. All five patients had an in vivo expansion of the infused CD19 CAR T cells and rapid and sustained depletion of circulating B cells. All patients achieved control of LN and SLEDAI scores decreased to inactive levels (range 0–2) by 3 months. Nephritis resolved in all five of the patients, as demonstrated by normalization of proteinuria. Other manifestations including arthritis, fatigue, and fibrosis of cardiac and pulmonary valves resolved after the administration of CD19 CAR T cells. Complement C3 levels normalized, and anti-dsDNA and ANA levels significantly declined in all patients. The patients were able to discontinue both corticosteroids and hydroxychloroquine and demonstrated a durable mean remission of 9.8 months (5–17 months). Severe CRS was not observed in any of the patients, although 3 patients developed grade 1 CRS (fever alone) lasting 2–3 days that was successfully treated by administration of methimazole in four of the patients and a single infusion of tocilizumab (8 mg/kg) in one patient. No patients had signs of ICANS, or infections reported during the short-term period of the study (5–17 months). No SLE flare has been reported in any of the patients thus far despite reconstitution of patients peripheral B cells [61]. More recently, long-term follow up data up to 29 months post infusion demonstrated a lasting remission in all patients without any immunosuppressive medications [62].

Additionally, a 32 year old woman with SLE was successfully treated with CD19-targeted CAR T cells [63]. Lupus was diagnosed during pregnancy. Clinical manifestations included serositis, nephritis, cytopenias, immunologic findings (ANA, dsDNA, hypocomplementemia), and concern for central nervous system involvement. She remained refractory to treatment with multiple agents including tacrolimus, belimumab, CYC, and rituximab. Prior to undergoing conditioning treatment for cell retrieval, she was weaned off immunosuppression three weeks prior to leukapheresis except for glucocorticoids, which were tapered to 5 mg daily. She tolerated CAR T cell treatment with no reported adverse effects, and after three months she achieved lupus low disease activity per low lupus disease activity state (LLDAS) criteria, proteinuria normalized, and she no longer had detectable circulating anti-dsDNA antibodies three months after treatment. Of note, B cells returned to the peripheral blood within 2 months without associated disease recurrence.

Importantly, the feasibility of manufacturing autologous CAR T cells from patients with lupus has been demonstrated to be achievable [64]. Manufacturing failures can occur in patients with active malignancy who are heavily immunosuppressed and are often cytopenic. Similar concerns exist in patients with SLE. All SLE patients studied were on glucocorticoids and received a wide array of immunosuppressive treatment prior to cell collection for CAR T generation. Glucocorticoids were tapered to a maximum of 10 mg/day one week prior to apheresis while other immunosuppressive agents were held two weeks beforehand. Despite patients being on low dose glucocorticoids, enough autologous T cells were successfully collected to generate ten times the minimum amount of CAR T cells needed for a single clinical infusion [64].

CAR T cells targeting the B cell Maturation Antigen (BCMA) receptor are FDA approved in patients with multiple myeloma and have a similar safety profile to CD19 CAR T cells. One strategy is to deplete both pathogenic B cells and antibody producing plasma cells by targeting both BCMA and CD19. To this end, Zhang et al. developed a CD19-BCMA compound CAR T cell product that has been successfully to eliminate donor specific alloantibodies prior to stem cell transplantation [65]. The use of the compound CD19-BCMA CAR T cells in a patient with SLE and stage IV diffuse large B cell lymphoma was reported [66]. She received fludarabine and CYC lymphodepleting chemotherapy followed by an infusion of 5.3 × 106 CD19-BCMA CAR T cells/kg. B cell depletion was rapid and complete through 198 days after treatment. The patient was able to discontinue glucocorticoid therapy and achieved normal complement levels and undetectable ANA levels after treatment. She remained in remission 23 months after treatment despite B cell reconstitution, but specific immunophenotyping of the reconstituted B cells was not reported [66]. Safety and preliminary efficacy of a combination of CD19 and BCMA CAR T cells in SLE has also been reported [67]. 12 patients with SLE refractory to multiple lines of immunosuppressive therapies including rituximab and belimumab were enrolled in a clinical trial. Patients received 1 or 2 × 10^6 of each CD19 and BCMA CAR T cells. The infusions were safe with only mild grade 1 CRS and no neurologic toxicity. Anemia was reported in all (Table 1). Mild infections were reported in 4 patients within 6 months of infusion [67]. After infusion of CD19/BCMA CAR T cells all patients met LLDAS criteria and were able to discontinue all immunosuppression including glucocorticoids. B cell aplasia was noted for approximately 3 months after CAR T cell therapy and no SLE flares have occurred at a median follow up of 118.5 (45–524) days [67].

Table 1 A review of CAR T therapy for humans patients with SLE:
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Discussion and conclusions

In conclusion, despite recent expansion of available treatments for SLE, remission rates remain unacceptably low, and morbidity and mortality rates remain unacceptably high. This is especially true for patients with SLE onset in childhood who have worse disease severity and outcomes when compared to adult-onset SLE. B cell directed CAR T cell therapy offers significant promise for improving outcomes for refractory pediatric disease in particular. As described above, CAR T cell therapy has demonstrated safety and efficacy in treating refractory SLE in young adults with durability reported to last 2 years after receiving a single infusion. Novel therapeutics have recently been approved to treat lupus nephritis, including in the induction phase of therapy; however, most of these agents serve as add-on therapies [68]. The potential of CAR T cell therapies to reduce the need for other potentially toxic medications including glucocorticoids in children and adolescents with SLE is therefore particularly encouraging. The safety profile to date for the SLE population is more favorable compared to the oncology population due to a smaller target T cell population, and therefore a lower underlying risk of CRS.

CAR T cells enable the elimination of tissue-resident B cells that may still contribute to disease pathogenesis after treatment with the other currently available B cell depleting agents such as Rituximab and Belimumab. However, the peripheral B cell compartment most often does recover, and no significant side effects have been reported to date in this patient population. Notably, the recently reported safety signal of T cell lymphomas from CAR T is rare and has not been reported in patients without an underlying primary malignancy [69]. As limited numbers of patients have underwent CAR T therapy for autoimmune diseases, further data is required to assess its long-term safety. Controlled clinical trials of CAR T therapy in both adult and pediatric lupus will provide further insight into the efficacy, safety, and durability of this therapy (Table 2).

Table 2 A review of the current clinical trials of CAR T for SLE
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