Evaluation of the Safety and Efficacy of CD19 CAR T-Cell Therapy for the Treatment of Refractory Systemic Lupus Erythematosus: A Phase I Clinical Trial
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Assessment of Frequency and Severity of Adverse Events and Serious Adverse Events
研究概览
简要总结
The goal of this Phase I clinical trial is to evaluate the safety and tolerability of autologous CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy in adults with refractory systemic lupus erythematosus who have demonstrated inadequate response to standard-of-care immunosuppressive treatments.
The primary questions this study aims to address are:
What is the incidence, nature, and severity of treatment-emergent adverse events following CD19 CAR-T cell infusion? Is administration of CD19 CAR-T cell therapy feasible and tolerable in patients with refractory systemic lupus erythematosus? This study is conducted as a single-arm trial without a comparison group.
Participants will:
Undergo leukapheresis for collection of autologous peripheral blood mononuclear cells Receive a protocol-defined lymphodepleting chemotherapy regimen prior to CAR-T cell infusion Receive a single intravenous infusion of approximately 1.0 × 10⁶ CD19 CAR-T cells per kilogram of body weight Undergo scheduled clinical evaluations, laboratory testing, and longitudinal follow-up to assess safety, tolerability, and clinical parameters
详细描述
This is a Phase I, single-center, open-label clinical trial evaluating the safety of autologous CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy in patients with refractory systemic lupus erythematosus (SLE).
Systemic lupus erythematosus is a chronic autoimmune disease characterized by immune dysregulation and pathogenic autoantibody production, with B lymphocytes playing a central role in disease pathophysiology. Targeting CD19-expressing B cells represents a potential therapeutic strategy for patients with disease refractory to standard immunosuppressive therapies.
Autologous CD19 CAR-T cells will be generated from peripheral blood T cells collected by leukapheresis. Cells will be genetically modified ex vivo to express a CD19-specific chimeric antigen receptor, expanded, and released for clinical administration following protocol-defined quality control testing and regulatory requirements.
Participants will receive a lymphodepleting chemotherapy regimen prior to a single intravenous infusion of CD19 CAR-T cells. Treatment administration and post-infusion monitoring will be conducted according to the protocol-specified safety and observation plan.
Following infusion, participants will be monitored for treatment-emergent adverse events, including CAR-T-associated toxicities such as cytokine release syndrome, immune effector cell-associated neurotoxicity, cytopenias, and infections. Safety evaluations will include serial clinical assessments and laboratory monitoring.
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
- 16 Years 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 16 to 55 years, male or female
- •Diagnosis of systemic lupus erythematosus (SLE) according to the 2019 EULAR/ACR classification criteria with a total score ≥ 10
- •SLEDAI-2K score ≥ 8 at screening (with at least 4 points derived from laboratory parameters; excluding points attributable to central nervous system involvement)
- •Positive antinuclear antibody (ANA ≥ 1:80) OR positive anti-dsDNA OR positive anti-Sm antibody at screening or documented in medical history
- •Refractory systemic lupus erythematosus or refractory lupus nephritis defined as one of the following:
- •Refractory SLE:
- •- Failure to achieve adequate response, partial response, or stable disease control after ≥ 6 months of standard-of-care therapy (documented compliance). Standard therapy includes corticosteroids plus hydroxychloroquine and at least two of the following: calcineurin inhibitors, cyclophosphamide, mycophenolate mofetil, azathioprine, or B-cell-targeted therapy (e.g., rituximab, belimumab).
- •Refractory Lupus Nephritis:
- •Persistent active lupus nephritis after two induction regimens, including intravenous cyclophosphamide and mycophenolate mofetil administered for ≥ 6 months (with or without calcineurin inhibitors, rituximab, or belimumab), AND:
- •Histopathologic confirmation of Class III or Class IV lupus nephritis, with or without Class V (ISN/RPS 2003 classification); isolated Class V is excluded
- •Proteinuria > 1 g/24 hours OR urine protein-to-creatinine ratio > 1 mg/mg
- •Adequate organ function:
- •ALT ≤ 5 × upper limit of normal; total bilirubin ≤ 34 μmol/L (≤ 2.0 mg/dL)
- •Pulmonary function: FVC ≥ 60% predicted OR FEV1 ≥ 60% predicted
- •Cardiac function: LVEF ≥ 50%, no uncontrolled arrhythmia, no intracardiac thrombus, no heart failure
- •Adequate hematologic parameters:
- •Absolute neutrophil count ≥ 0.8 × 10⁹/L (without growth factor support)
- •Absolute lymphocyte count ≥ 0.3 × 10⁹/L
- •Platelet count ≥ 50 × 10⁹/L
- •Hemoglobin ≥ 80 g/L (≥ 8.0 g/dL)
- •Ability to provide written informed consent
- •Agreement to use effective contraception during the study period (for participants of reproductive potential)
排除标准
- •History of significant neurologic disorders (e.g., traumatic brain injury, seizure disorder, hemorrhagic conditions, impaired consciousness)
- •Significant cardiovascular disease within 3 months prior to screening (e.g., uncontrolled hypertension, NYHA Class III-IV heart failure, severe arrhythmia, unstable angina, myocardial infarction)
- •Prior kidney transplantation
- •Severe asthma requiring long-term treatment or respiratory failure
- •Severe hemolytic anemia requiring transfusion at intervals ≤ 7 days
- •Active viral infections (e.g., hepatitis B or C, HIV, tuberculosis, malaria, syphilis, CMV, EBV) or other life-threatening infectious diseases
- •Active bacterial infection confirmed by clinical evaluation, imaging, or laboratory testing
- •Use of the following prior to leukapheresis:
- •Anti-CD20 therapy, cyclophosphamide, live or attenuated vaccines within 1 month
- •Systemic corticosteroids > 10 mg/day (prednisone equivalent), T-cell-targeted therapy (e.g., mycophenolate mofetil, calcineurin inhibitors), immunosuppressive agents, or antimalarial agents within 7 days
- •Prior anti-CD19 therapy
- •Prior T-cell-based cellular therapy or gene therapy, including CAR-T therapy
- •Current or prior malignancy
- •Known hypersensitivity to study-related agents
- •Pregnant or breastfeeding women
- •Active antiphospholipid syndrome (stable antiphospholipid antibody positivity without active APS is permitted)
- •Participation in another clinical trial at the time of screening
- •Any condition that, in the investigator's judgment, would interfere with protocol compliance or study participation
研究组 & 干预措施
CD19 CAR-T Cell Therapy
Participants will receive autologous CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy following leukapheresis and protocol-defined lymphodepleting chemotherapy. A single intravenous infusion of CD19 CAR-T cells will be administered, with subsequent safety monitoring and follow-up according to the study protocol.
干预措施: Autologous CD19-Targeted CAR-T Cells (Biological)
结局指标
主要结局
Assessment of Frequency and Severity of Adverse Events and Serious Adverse Events
时间窗: From CAR-T cell infusion through Day 360
Incidence, type, and severity of adverse events (AEs) and serious adverse events (SAEs) graded according to CTCAE v5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) will be graded according to ASTCT criteria.
次要结局
- Proportion of Participants Achieving Remission According to DORIS Criteria(Day 90 and Day 360)
- Proportion of Participants Achieving Lupus Low Disease Activity State (LLDAS)(Day 90 and Day 360)
- Proportion of Participants Experiencing Disease Relapse(From Day 90 through Day 360)
- Manufacturing Success Rate of Autologous CD19 CAR-T Cells(From leukapheresis through product release, up to 12 days)
- Peripheral CD19+ B-Cell Depletion and Reconstitution(Baseline, Day 7, Day 14, Day 28, Day 90, Day 180, and Day 360)
- CAR-T Cell Expansion and Persistence(Baseline, Day 7, Day 14, Day 28, Day 90, Day 180, and Day 360)