Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which the immune system mistakenly attacks the body's own tissues and organs. The disease can affect the skin, joints, kidneys, blood cells, brain, and other organs, leading to significant health problems and reduced quality of life. Although several treatments are available, some patients continue to have active disease despite receiving standard therapies.

Recent research has shown that B cells, a type of immune cell, play a central role in the development and persistence of SLE. CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an innovative treatment that uses a patient's own immune cells, genetically modified to recognize and eliminate B cells. This approach has already shown remarkable success in certain blood cancers and has recently produced encouraging results in patients with severe autoimmune diseases, including SLE.

The CLEVER-SLE study is a Phase I/II clinical trial designed to evaluate the safety and potential effectiveness of CD19-directed CAR-T cell therapy produced at Ribeirao Preto Blood Bank in patients with SLE who have not responded adequately to conventional treatments. Participants will undergo the collection of their own immune cells, which will be modified in a specialized laboratory to produce CAR-T cells. After receiving preparatory chemotherapy, participants will receive a single intravenous infusion of these CAR-T cells.

The main goal of this study is to evaluate the safety of this treatment. Researchers will also assess its effects on disease activity, symptoms, organ involvement, medication requirements, immune system markers, and the duration of clinical responses. The study aims to determine whether CD19-directed CAR-T cell therapy can provide a new treatment option for patients with refractory SLE and contribute to the development of CAR-T therapies for autoimmune diseases.

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by loss of immune tolerance, production of pathogenic autoantibodies, and immune-mediated tissue injury. The disease can affect virtually any organ system, including the skin, joints, kidneys, hematologic system, cardiovascular system, and central nervous system. Despite major advances in the understanding of disease pathogenesis and the availability of immunosuppressive and biologic therapies, many patients continue to experience persistent disease activity, recurrent flares, progressive organ damage, reduced quality of life, and increased mortality.

B lymphocytes play a central role in the pathogenesis of SLE. Beyond their ability to differentiate into antibody-producing plasma cells, B cells contribute to disease development through antigen presentation, cytokine production, and maintenance of autoreactive immune responses. The persistence of autoreactive B-cell populations is believed to be a key driver of chronic disease activity and treatment resistance.

Several therapeutic strategies targeting B cells have been developed for SLE, including anti-CD20 monoclonal antibodies and inhibitors of B-cell survival pathways. Although these approaches have improved outcomes for many patients, a substantial proportion of individuals fail to achieve sustained remission. One potential limitation of antibody-based therapies is their inability to completely eliminate autoreactive B-cell populations residing within inflamed tissues and specialized immune niches. In contrast, CD19-directed CAR-T cells are living immune effectors capable of expanding in vivo, trafficking to affected tissues, and mediating deep depletion of B cells not only in the peripheral blood but also within sites of ongoing autoimmune inflammation. This broader and more profound tissue-level B-cell depletion may contribute to more durable disease control and potentially restore immune tolerance. In addition, existing therapies often require continuous administration and may be associated with cumulative toxicities, incomplete disease control, or relapse after treatment discontinuation.

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy represents a novel therapeutic strategy that enables a patient's own T lymphocytes to recognize and eliminate CD19-expressing B cells. This approach has demonstrated unprecedented efficacy in B-cell malignancies and has transformed the treatment landscape of several hematologic cancers. More recently, emerging clinical evidence has suggested that deep B-cell depletion induced by CD19-directed CAR-T cells may also be capable of resetting abnormal immune responses in autoimmune diseases.

Early clinical experiences in patients with severe refractory autoimmune diseases, including systemic lupus erythematosus, have reported rapid and profound reductions in disease activity, sustained clinical remissions, normalization of serological markers, and significant reductions in the need for immunosuppressive medications. These findings have generated considerable interest in the potential application of CAR-T cell therapy beyond oncology and have established a strong scientific rationale for further investigation in autoimmune disorders.

The CAR-T product evaluated in this study consists of autologous T lymphocytes genetically modified to express a chimeric antigen receptor directed against CD19. The product is manufactured at the Ribeirão Preto Blood Center (Hemocentro de Ribeirão Preto), one of the leading academic cell therapy centers in Brazil. This manufacturing platform has previously demonstrated feasibility, safety, and clinical activity in patients with hematologic malignancies and serves as the foundation for the present investigation.

The CLEVER-SLE study was developed to evaluate the use of CD19-directed CAR-T cell therapy manufactured at the Ribeirão Preto Blood Center in patients with refractory systemic lupus erythematosus. The study seeks to expand current knowledge regarding the safety profile and therapeutic potential of CAR-T cells in autoimmune diseases while generating clinical evidence to support the development of advanced cellular therapies for patients with severe disease who have limited treatment options.

By investigating a strategy capable of directly targeting the cellular drivers of autoimmunity, this study aims to contribute to the development of transformative therapies that may achieve sustained disease control and improve long-term outcomes for patients with refractory SLE.

Inclusion Criteria:

• Adults aged 18 to 50 years, inclusive.

• Diagnosis of systemic lupus erythematosus (SLE) according to the 2019 ACR/EULAR classification criteria.

• Active disease at screening, defined as SLEDAI-2K ≥4 and Physician Global Assessment (PGA) ≥0.5.

• Inadequate response, intolerance, or contraindication to corticosteroids and at least two of the following therapies: azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, belimumab, rituximab, or tacrolimus.

• Adequate organ function, including:

  • Hepatic function: AST and ALT ≤3× upper limit of normal (ULN); total bilirubin ≤2× ULN (participants with documented Gilbert syndrome are eligible).
  • Hematologic function: neutrophils ≥1,000/mm³; hemoglobin ≥8 g/dL without transfusion within 14 days; lymphocytes ≥500/mm³; platelets ≥20,000/mm³ without transfusion within 14 days.
  • Renal function: estimated creatinine clearance ≥30 mL/min (CKD-EPI).
  • Cardiac function: left ventricular ejection fraction ≥40%.
  • Pulmonary function: oxygen saturation ≥92% on room air.

• Women of childbearing potential must agree to use highly effective contraception during study participation and for 12 months after CAR-T cell infusion.

• Male participants must agree to use barrier contraception during study participation and for 12 months after CAR-T cell infusion.

• Ability to understand and provide written informed consent.

Exclusion Criteria:

• Severe pulmonary hypertension (estimated pulmonary artery systolic pressure >50 mmHg).
• Requirement for systemic anticoagulation at screening.
• Clinically significant cardiovascular disease, including NYHA Class III/IV heart failure, myocardial infarction, unstable arrhythmias, or unstable angina within the previous 6 months.
• Active neurological disease (stroke, epilepsy, or neurodegenerative disorders) within the previous 12 months.
• History of malignancy within 2 years prior to screening, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, ductal carcinoma in situ of the breast, or stage I uterine cancer.
• Previous or suspected hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
• Active or uncontrolled bacterial, viral, fungal, or other infection.
• Active hepatitis B infection or detectable HBV DNA.
• Active hepatitis C infection or detectable HCV RNA.
• Human immunodeficiency virus (HIV) infection.
• Pregnancy, breastfeeding, or plans to become pregnant during the study or within 12 months after CAR-T cell infusion.
• Major surgery within 4 weeks prior to screening.
• Administration of a live attenuated vaccine within 4 weeks prior to screening.
• Prior allogeneic or autologous hematopoietic stem cell transplantation or prior solid organ transplantation.
• Inability or unwillingness to comply with study procedures and follow-up requirements.
• Any medical condition that, in the investigator's judgment, could compromise participant safety or interfere with study assessments.