CD19-targeted Lymphocyte Engineering Validation for the trEatment of Refractory Systemic Lupus Erythematosus
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 16
- 试验地点
- 2
- 主要终点
- Incidence and Severity of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
排除标准
- •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.
研究组 & 干预措施
Autologous CD19-Directed CAR-T Cells
Participants with refractory systemic lupus erythematosus will undergo leukapheresis for the manufacture of autologous CD19-directed CAR-T cells, followed by lymphodepleting chemotherapy and a single intravenous infusion of the CAR-T cell product.
干预措施: Autologous CD19-Directed CAR-T Cells Manufactured at Ribeirão Preto Blood Center (Biological)
结局指标
主要结局
Incidence and Severity of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
时间窗: 30 days after CAR-T cell infusion
Incidence and maximum grade of CRS and ICANS following infusion of autologous CD19-directed CAR-T cells, assessed according to ASTCT consensus criteria.
次要结局
- Incidence of Grade ≥3 Cytopenias(Up to 90 days after CAR-T cell infusion)
- Time to Hematologic Recovery(Up to 12 months after CAR-T cell infusion)
- Incidence and Severity of Infections(Up to 12 months after CAR-T cell infusion)
- Incidence of Serious Infections(Up to 12 months after CAR-T cell infusion)
- Changes in Serum Immunoglobulin Levels(Baseline, Day 30, Day 90, Day 180, and Day 360)
- Incidence of Other CAR-T Cell-Associated Toxicities(Up to 12 months after CAR-T cell infusion)
- Deep Remission Rate(6 months after CAR-T cell infusion)
- SRI-4 Response Rate(6 months after CAR-T cell infusion)
- Lupus Low Disease Activity State (LLDAS) Achievement Rate(6 and 12 months after CAR-T cell infusion)
- DORIS Remission Rate(6 and 12 months after CAR-T cell infusion)
- Renal Response Rate(6 and 12 months after CAR-T cell infusion)
- Cutaneous Lupus Response Rate(6 and 12 months after CAR-T cell infusion)
- Articular Response Rate(6 and 12 months after CAR-T cell infusion)
- Anti-dsDNA Serologic Response(6 and 12 months after CAR-T cell infusion)
- Corticosteroid and Immunosuppressant-Free Remission(6 and 12 months after CAR-T cell infusion)
研究者
Diego Villa Clé
MD, MBA, PhD
University of Sao Paulo