CD19-Directed CAR-T Cell Therapy in Refractory Systemic Lupus Erythematosus

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.

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.