CAR T-cell therapy shows promise in treating refractory autoimmune rheumatic diseases by targeting CD19 for faster, more significant effects and potential drug-free remission.
CAR T-cell therapy is an innovative cell-based immunotherapy that has revolutionized the treatment landscape for hematologic malignancies. Over the past two years, CD19-targeted CAR T-cell therapy has been successfully applied in refractory autoimmune rheumatic diseases, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and anti-synthetase syndrome (ASyS). Compared to B-cell depletion therapies, CD19 CAR T-cell therapy demonstrated faster and more significant effects, achieving drug-free remission with manageable adverse events. These promising results require validation through long-term, large-scale randomized controlled trials. Future clinical research aims to confirm the role of CAR T-cell therapy in refractory rheumatic diseases and to establish its safety, efficacy, and durability of remission. Optimizing engineering strategies and improving patient selection are also crucial for the further successful clinical implementation of CAR T-cell therapy.
What is CAR T-cell therapy?
Adoptive cellular immunotherapy involves modifying T lymphocytes via viral transduction or gene editing to engineer synthetic receptors on their surface. These receptors, called CAR (chimeric antigen receptors), feature an extracellular domain that binds specifically to antigens and a variable intracellular costimulatory domain that triggers CAR T-cell expansion and persistence in the body, effectively eliminating targeted tumor cells. The efficacy and tolerance of CAR T-cells were confirmed in early clinical trials, leading to their approval for clinical use in 2017. As of July 2023, six CAR-T products have been authorized by the European Medicines Agency and the U.S. Food and Drug Administration (FDA). These include CD19-targeted CAR T-cells for the treatment of relapsed or refractory large B-cell lymphoma (LBCL), follicular lymphoma(FL), mantle cell lymphoma (MCL), and acute lymphoblastic leukemia (ALL), as well as B-cell maturation antigen (BCMA)-targeted CAR-T cells for relapsed or refractory multiple myeloma.
Currently, all approved CAR-T cells are autologous and are classified as second-generation cells, with CD28 or 4-1BB costimulatory domains inserted into the CAR. After collecting autologous T lymphocytes via leukapheresis, the cells are sent fresh or cryopreserved to a laboratory for processing. In the lab, T cells undergo activation, expansion, and transduction (using lentiviral or retroviral vectors), followed by CAR-T cell expansion. The cells are then transported to the treatment center for cryopreservation and stored at -196°C. Currently, the turnaround time for CAR-T cell production in the lab is around one month. During this period, patients may receive bridging chemotherapy to manage their hematologic condition. Prior to CAR-T cell administration, lymphodepleting therapy is given (typically fludarabine and cyclophosphamide in current protocols). After 48 hours, the CAR-T cells are thawed and immediately infused intravenously into the patient.
Progress of CAR-T therapy in autoimmune rheumatic diseases
Mougiakakos and colleagues first reported a case of a 20-year-old female patient with refractory SLE treated with autologous CD19-targeted CAR-T cells. The patient presented with active lupus nephritis, pericarditis, endocarditis, pleuritis, rash, and arthritis, and had previously failed high-dose corticosteroids and various immunosuppressive treatments, including two B-cell-targeting biologics: rituximab and belimumab. After receiving fludarabine (25 mg/m²/day intravenously [IV], from day -5 to day -1) and cyclophosphamide (1000 mg/m²/day IV, on day -3), the patient was administered a single dose of CAR-T cells at 1.1 × 10⁶ cells/kg, resulting in a rapid remission within 44 days. Anti-double-stranded DNA (dsDNA) antibodies became negative, low C3 and C4 levels normalized, urine protein decreased from >2000 mg/g to <250 mg/g, and the SLEDAI-SELENA score dropped from 16 to 0. No adverse events were observed during the 7-week follow-up period. Low-dose steroids were the only medication used after lymphodepletion, and they were successfully discontinued for up to 18 months without any relapse.
The same team further reported a series of five successful cases of SLE treated with CD19-targeted CAR T-cell therapy. The patients, aged between 18 and 24, had disease durations of at least one year and had previously been treated with corticosteroids, hydroxychloroquine, mycophenolate mofetil, cyclophosphamide, and other immunosuppressive drugs. Notably, all five patients had received belimumab, and one had been treated with rituximab. Each patient had multi-organ involvement, with biopsy-proven glomerulonephritis and active disease at baseline, reflected by SLEDAI-2K scores ranging from 8 to 16. The treatment process was similar to the first case, but these patients achieved drug-free remission with a slightly lower CAR-T dose of 1.0 × 10⁶ cells/kg. Significant improvements in SLEDAI-2K scores, proteinuria, C3 levels, anti-dsDNA antibody levels, and self-reported fatigue were observed within three months. Circulating B cells were fully depleted from day 2 and remained undetectable for an extended period, while other circulating immune cells recovered within 10 days post-treatment. Mild adverse events were observed in 3 out of 5 patients, limited to grade 1 cytokine release syndrome (CRS), which was effectively managed. All five patients remained drug-free without SLE relapse during the follow-up period. In summary, autologous CD19-targeted CAR T-cell therapy demonstrated both efficacy and tolerability in patients with active SLE, with relatively long-term follow-up supporting these findings.
In a recent report, a team from Erlangen, Germany, administered CD19-targeted CAR-T therapy to 8 patients with refractory systemic lupus erythematosus (SLE) (with the longest follow-up period extended to 24 months), 3 patients with idiopathic inflammatory myopathy, and 4 patients with systemic sclerosis (SSc). They also reported on 3 severe refractory SLE patients enrolled in an open-label, single-arm, multicenter phase I/II study (NCT05798117). Notably, these patients were older than those in previous SLE reports, aged 58, 48, and 38. Although the longest follow-up was 106 days, the data revealed preliminary efficacy and manageable tolerability. Additionally, CAR-T therapy has been reported in severe and refractory SSc and refractory anti-synthetase syndrome (ASyS).
Based on the success observed in lupus and initial case reports, clinical research exploring the potential applications of this innovative therapy has significantly increased over the past two years, aiming to test the broader applicability of CAR-T cells in various autoantibody-mediated autoimmune diseases. As of November 2023, a comprehensive search on ClinicalTrials.gov using the keywords “autoimmune disease” and “CAR-T cells” identified 29 ongoing clinical studies. These studies highlight the focus on systemic autoimmune diseases, particularly connective tissue diseases, with lupus being a major area of interest, comprising 17 of the 29 studies. Lastly, it is worth noting that most of these studies are currently being conducted in China.
CAR was first constructed in the early 1990s and has gone through several iterations. CAR-T therapy was originally designed to target and kill tumor cells. In 2017, the first CD19-targeted CAR-T product was approved for the treatment of hematological malignancies. In 2021, the first case of refractory SLE successfully treated with CD19-targeted CAR-T was reported, and case reports of CAR-T treatment of autoimmune rheumatic diseases continued to emerge.
Advantages and challenges of CAR T-cell therapy
Published cases of autoimmune rheumatic diseases (ARD) treated with CAR-T therapy have involved patients with refractory diseases and significant organ involvement. Before receiving CAR-T therapy, these patients had undergone various immunosuppressive treatments but failed to achieve long-term remission or low disease activity. Some had also received B-cell-targeted therapies, such as anti-CD20 monoclonal antibodies and anti-BAFF monoclonal antibodies, but these either produced poor responses or only transient and partial improvements. One possible reason for the varied responses to B-cell-targeted therapies is incomplete B-cell depletion. Unlike CD20, CD19 is expressed more broadly across all stages of B-cell development, including pro-B cells, antibody-secreting plasmablasts, and plasma cells. Targeting CD19 is therefore expected to result in faster, broader, and more profound B-cell depletion than anti-CD20 monoclonal antibodies, including the depletion of long-lived plasma cells residing in the bone marrow, enhancing the potential of CD19-targeted therapies.
Moreover, despite B-cell and immunoglobulin recovery, drug-free remission has persisted during follow-up. Notably, in reported cases of SLE, B-cell reconstitution occurred around 100 days after CAR-T infusion, and immunophenotyping and B-cell receptor sequencing indicated that these B cells displayed a naive phenotype, suggesting successful resetting of the B-cell compartment. On the other hand, the recovery of immunoglobulin levels suggests that, unlike conventional treatments such as high-dose corticosteroids, CAR-T therapy does not lead to broad immunosuppression despite the pre-treatment lymphodepletion. Although experience in oncology shows that disease relapse can occur after CAR-T infusion, the drug-free remission observed in the case reports of SLE has far exceeded expectations. In follow-up after CAR-T therapy, persistent serologic remission was reported, with vaccine-related immune responses preserved. If remission or low disease activity can be maintained over a longer period, the medication burden for patients, including the long-term side effects of corticosteroids, could be greatly reduced.
Due to the limited preclinical studies and clinical reports, several questions remain regarding the implementation of CAR-T therapy. Two major adverse events have been reported in autoimmune rheumatic diseases (ARD), namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which are commonly observed in malignant hematological tumors. The involvement of different organs in ARD patients may pose challenges in managing these adverse events; for example, fever, a common symptom of CRS, can complicate the management of patients with interstitial lung disease (ILD). Other factors to consider include the waiting time required for ex vivo engineering and the efficacy of bridging therapies. Disease exacerbation has been observed during the washout of immunosuppressants prior to lymphocyte depletion treatment. Furthermore, the risk of life-threatening infections due to lymphodepletion preconditioning raises additional safety concerns.
Additionally, B cells may represent only a part of the disease mechanisms rather than the entirety of the pathogenesis. Cases of anti-synthetase syndrome (ASyS) exemplify this complexity, where enhanced CD8 T cells were detected in circulation after CAR-T therapy, prompting the inclusion of additional T cell-suppressive medications due to concerns of potential relapse. Recent reports of failed CD19-targeted CAR-T therapy in a systemic sclerosis (SSc) animal model further suggest that CAR-T design should align with the pathogenesis of the disease. This study utilized a Fra-2 transgenic mouse model that effectively simulates the fibrosis and vasculopathy of SSc but lacks typical autoimmune responses. Although CD19-targeted CAR-T combined with anti-CD20 monoclonal antibodies achieved deeper B cell depletion in the peripheral blood and lungs of Fra-2 mice compared to anti-CD20 monoclonal antibodies alone, it did not improve overall outcomes and even worsened lung fibrosis and pulmonary hypertension. One reason for this may be that B cells do not play a crucial role in the pathogenesis of the Fra-2 transgenic mouse model, as evidenced by the lack of significant differences between the anti-CD20 monoclonal antibody group and the control group. Additionally, the absence of lymphodepletion preconditioning may lead to T cell activation. This report reinforces the importance of CAR-T design and the selection of study participants.
To fully understand the safety and efficacy of this novel treatment, longer follow-up observations and randomized controlled trials are necessary. Moreover, the current high costs limit its widespread application, particularly considering the potential need for repeat treatments. The persistence and tolerability of repeated CAR-T therapy in ARD remain unclear.
In conclusion, CAR T-cell therapy represents a promising treatment option for autoimmune rheumatic diseases, and the success of future clinical trials will depend on the development of CAR-based immune cells tailored to various pathomechanisms, the use of appropriate CAR engineering techniques to minimize toxicity and maximize therapeutic efficacy, and the selection of suitable participant populations for these studies. These clinical trials will gradually clarify the efficacy and safety of CAR-T therapy in this context.
References:
- Xia, Lyu,Latika, Gupta,Eleni, Tholouli et al. Chimeric antigen receptor T cell therapy: a new emerging landscape in autoimmune rheumatic diseases.[J] .Rheumatology (Oxford), 2023, 63: 0.
- Aurélien, Guffroy,Léa, Jacquel,Blandine, Guffroy et al. CAR-T cells for treating systemic lupus erythematosus: A promising emerging therapy.[J] .Joint Bone Spine, 2024, 91: 0.
