Study of Therapeutic Efficacy of Anti-CD19 Chimeric Antigen Receptor T Lymphocytes (CAR-T) Cells in Patients With Multi-drug Resistant SRNS
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- The safety of CAR-T cell therapy in patients with MDR SRNS
研究概览
简要总结
This is an investigator-initiated trial aimed at assessing the safety and efficacy of anti-CD19 CAR-T cells in the treatment of patients with Multi-drug resistant SRNS
详细描述
At present, there is no effective treatment for Multi-drug resistant steroid resistant nephrotic syndrome (MDR-SRNS), which has a high risk of progression to kidney failure, and about 55% of patients will have disease recurrence after receiving kidney transplantation, which is in urgent need of new treatment methods.
CAR-T therapy is an adoptive cell therapy that uses genetic modification technology to reprogram T cells and eliminate target cells expressing disease-related antigens through antigen-specific recognition.Since 2019, CAR-T cell therapy has been successfully applied to autoimmune diseases. Although no clinical data related to CAR-T treatment of nephrotic syndrome has been disclosed, CAR-T is effective for systemic lupus erythematosus and systemic sclerosis.Many kinds of autoimmune diseases such as chemical syndrome and idiopathic inflammatory dermatomyositis have good therapeutic effect. These results suggest that the therapeutic effect of CAR T cells may not be limited to systemic lupus erythematosus, but may also play a role in several different B-cell-mediated and autoantibody-driven human autoimmune diseases, which is expected to bring breakthroughs in the treatment of MDR-SRNS.The purpose of this study is to assess the safety and efficacy of the anti-CD19 CAR-T cells in the treatment of patients with MDR-SRNS.
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
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Age ≥2 years old, gender unlimited;
- •2.Diagnosed with SRNS according to the 2021 Kidney Disease: Improving Global Outcomes （KDIGO） Guidelines and have not achieved a complete response after 12 months of treatment with two standard doses of hormone replacement drugs with different mechanisms of action or relapse of disease activity after remission (at least one of the two drugs is a calcineurin inhibitor such as cyclosporine or tacrolimus; Other hormone replacement drugs include Mycophenolate Mofetil, cyclophosphamide, Taitacept or rituximab); Or if no remission has been achieved after 3 to 6 months of adequate treatment with one calcineurin inhibitor, if the researcher judges that the benefits outweigh the risks and the patient or guardian has fully informed consent, the patient can be considered for inclusion.Patients with other diseases, such as systemic lupus erythematosus, requiring long-term systemic treatment with glucocorticoids or immunosuppressants, may be considered for inclusion after the investigator determines that the benefits outweigh the risks and the patient or guardian has fully informed consent;
- •3. Renal biopsy was performed and the pathological type was determined to be minimal lesion nephropathy(MCD) or focal segmental glomerulosclerosis (FSGS);
- •4. The functions of important organs are basically normal: Cardiac function: Left ventricular ejection fraction (LVEF) ≥55% with no obvious abnormality in electrocardiogram; Renal function: eGFR≥30ML/min/1.73m2# Liver function: Asparagus cochinchinensis transaseminase (AST) and Alanine Aminotransferase (ALT)≤3.0 upper limit of normal, Total Bilirubin (TBIL) in serum ≤2.0×upper limit of normal; Lung function: No serious lung lesions, SpO2≥92%;
- •5. Met the standards of leukapheresis or intravenous blood collection, No contraindication for cell collection;
- •6. Negative pregnancy test for female Subjects of childbearing age, agree to take effective contraceptive measures the first year after CAR-T infusion;
- •7. Participants or their guardians agrees to participate in the clinical trial and sign the informed consent form which indicating that he/she understands the purpose and procedure of the clinical trial and is willing to participate in the study.
排除标准
- •1. Received CAR T cell therapy or other gene-modified cell therapy previously;
- •2. Patients had a cerebrovascular accident or seizure, or other active central nervous system disease within 6 months;
- •3. Genetic tests have confirmed hereditary kidney disease;
- •4. Renal biopsy has been confirmed as immunoglobulin A nephropathy, idiopathic membranous nephropathy or membranoproliferative glomerulonephritis;
- •5. Renal replacement therapy has been or is being performed within 3 months prior to transfusion. (if acute kidney injury factors were considered, patients with chronic kidney disease were excluded, and the benefits outweighed the risks as determined by the investigator and with the full and informed consent of the patient or guardian could be considered for inclusion);
- •6. Renal replacement therapy has been or is being performed within 3 months prior to transfusion;
- •7. Have a history of congenital heart disease or acute myocardial infarction within 6 months prior to screening; Or severe arrhythmias (including multisource frequent supraventricular tachycardia, ventricular tachycardia, etc.); Or combined with moderate to massive pericardial effusion, serious myocarditis, etc; Or patients with unstable vital signs who need hypertensive drugs;
- •8. Received solid organ transplantation or hematopoietic stem cell transplantation within 3 months prior to screening; Acute graft-versus-host disease (GVHD) of grade 2 or above was present within 2 weeks prior to screening;
- •9. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer greater than the normal reference value range; Or hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA titer greater than the normal reference value range; Or positive for human immunodeficiency virus (HIV) antibodies; Or syphilis test positive; Or cytomegalovirus (CMV) DNA test positive;
- •10. Macrophage activation syndrome occurred within 1 month prior to screening;
- •11. Received live vaccine within 4 weeks before screening;
- •12. Patients with malignant diseases such as tumors before screening, or with other serious life-threatening diseases;
- •13. Tested positive in Blood pregnancy test;
- •14. Patients who participated in other clinical study within 1 months prior to enrollment;
- •15. Any other conditions that the investigators deem it unsuitable for the study.
研究组 & 干预措施
CAR-T treatment group
This study employs a '3+3' design with three dosage groups (0.3×10^5/kg, 1×10^5/kg, and 3×10^5/kg). Each dosage group will enroll 3 to 6 patients, starting from the lowest dosage and escalating to explore a safe and effective dose. Once a dosage group completes enrollment without observing any serious unexpected adverse reactions, and based on the efficacy and cell kinetics data, the investigator and the technical team together may consider escalating to the next dosage group to explore the optimal effective dose. The trial is expected to enroll a total of 9 to 18 patients
干预措施: anti-CD19 CAR-T cells (Biological)
结局指标
主要结局
The safety of CAR-T cell therapy in patients with MDR SRNS
时间窗: 3 months
Incidence and severity of Adverse Events (AEs) and Serious Adverse Event（SAEs）,including changes in laboratory values,Electrocardiograph(ECG) and vital signs assessed by CommonTerminology Criteria for Adverse Events (CTCAE) v5.0.
The efficiency of CAR-T cell therapy in patients with MDR SRNS
时间窗: 3 months
Complete response and partial response rate (complete response defined as Urinary protein/creatinine ratio (uPCR) ≤200 mg/g for 3 consecutive days, partial response is defined as a 50% or more reduction in proteinuria from baseline and 200mg/g \< uPCR \<2000mg/g)
次要结局
- Effectiveness of other visit points(24 months)
- Pharmacokinetic Outcome Cmax(3 months)
- Pharmacokinetic Outcome Tmax(3 months)
- Pharmacokinetic Outcome AUC(3 months)
- Pharmacodynamics Outcome(3 months)
研究者
Mao Jianhua
Principal Investigator
The Children's Hospital of Zhejiang University School of Medicine