Safety and Efficacy of CD19 Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) in the Treatment of Refractory Membranous Nephropathy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Incidence of DLT in rMN subjects after a single infusion of CD19 CAR-T cells
研究概览
简要总结
This study is a single-center, prospective, exploratory Phase I clinical trial initiated by the team led by Associate Professor He Lijie from the Department of Nephrology, Xijing Hospital.
Prior to receiving CAR-T cell therapy, patients will undergo lymphodepletion chemotherapy with cyclophosphamide (fludarabine will be added if necessary). After prophylactic administration of antihistamines and acetaminophen, patients will be infused with CD19 CAR-T cells at a dose of 1×10⁶ cells/kg.
In the subsequent 2 weeks, patients will be hospitalized for monitoring of vital signs and adverse reactions. The planned follow-up duration of this study is 1 years.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed as primary membranous nephropathy (PMN) by renal biopsy.
- •Classified as moderate-risk or high-risk refractory membranous nephropathy (rMN).
- •Moderate-risk rMN is defined as: eGFR ≥ 90 ml/min/1.73m² AND 24-hour urinary protein > 3.5g/d, with a reduction of no more than 50% within 6 months of receiving renin-angiotensin system inhibitor (RASi) therapy.
- •High-risk rMN is defined as meeting one of the following:
- •eGFR < 60 ml/min/1.73m² and/or persistent proteinuria > 8g/d for more than 6 months.
- •Normal eGFR with proteinuria > 3.5g/d and ≤50% reduction after 6 months of RASi therapy, PLUS at least one of the following: Serum albumin < 25g/L; PLA2R antibody > 50 RU/mL; Urinary α1-microglobulin > 40 μg/min; Urinary IgG > 1 μg/min; Urinary β2-microglobulin > 250 mg/d; IgG/albumin clearance ratio > 0.
- •Diagnosis of rMN requires failure of adequate first-line immunosuppressive therapy (≥6 months of steroids+cyclophosphamide, CNI, or rituximab), defined by any of the following: persistent high-titer anti-PLA2R antibody; for antibody-negative patients, persistent nephrotic syndrome (protein >3.5g/d, albumin <30g/L); <50% reduction in proteinuria.
- •Age ≥ 18 years.
- •Adequate organ function, defined as:
- •Renal: eGFR ≥ 30 ml/min/1.73m².
- •Hepatic: ALT and AST ≤ 2.5 x ULN; Total bilirubin ≤ 1.5 x ULN.
- •Cardiac: LVEF ≥ 50%; NYHA Class I or II; No significant arrhythmias requiring intervention; No major cardiovascular events within the past 6 months.
- •Respiratory: SpO2 > 92% on room air.
- •Ability to understand and willingness to sign an Informed Consent Form.
排除标准
- •Secondary membranous nephropathy (e.g., due to SLE, malignancy, drugs, infection).
- •Active infection requiring IV antibiotics, active tuberculosis, or positive viral serology indicating active infection, including:
- •HBV: HBsAg (+) and/or HBcAb (+) with detectable HBV DNA.
- •HCV: HCV Ab (+) with detectable HCV RNA.
- •HIV Ab (+).
- •Active EBV or CMV infection (IgM+ or DNA above normal).
- •Positive syphilis (Treponema pallidum) antibody (requires evaluation for active infection).
- •Severe uncontrolled comorbidities, including:
- •Uncontrolled hypertension (persistent SBP > 160 mmHg or DBP > 100 mmHg).
- •Uncontrolled diabetes (HbA1c > 8% or random glucose ≥11.1 mmol/L) or diabetic nephropathy.
- •Symptomatic deep vein thrombosis or pulmonary embolism within the past 6 months.
- •Active peptic ulcer or gastrointestinal bleeding within the past 6 months.
- •Severe congenital or acquired immunodeficiency.
- •Severe CNS diseases (e.g., catastrophic APS, uncontrolled epilepsy).
- •End-stage organ failure not attributable to PMN.
- •History of malignancy within the past 5 years, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ, or thyroid cancer.
- •Specific treatment history or plans, including:
- •Prior receipt of any cell therapy (e.g., MSCs, HSCT).
- •Major surgery within 24 weeks before or planned within 24 weeks after enrollment.
- •Planned kidney transplantation within 3 years.
- •History of substance abuse.
- •Participation in another interventional clinical trial within 3 months prior to enrollment.
- •Pregnant or lactating women.
- •Inability to understand the study or provide informed consent (e.g., severe dementia, mental illness).
- •Any other condition deemed by the investigator to increase risk, interfere with assessment, or affect compliance.
结局指标
主要结局
Incidence of DLT in rMN subjects after a single infusion of CD19 CAR-T cells
时间窗: 28 days and 3 months after infusion
Definition: The DLT evaluated in this study is assessed within two time windows: 28 days (Day 0 to Day 28) and 3 months (Day 28 to Month 3) after CAR-T cell infusion. These time windows are selected based on the typical timeline of CAR-T cell expansion, activity, and potential occurrence of major toxicities in vivo. The determination of DLT must meet all the following criteria:1.DLT must be an adverse event judged by the investigator as probably or definitely related to CAR-T cell infusion, and cannot be attributed to underlying diseases, comorbidities, or toxicities from concomitant medications;2.The adverse event must reach a severity grade of ≥ Grade 3 (per CTCAE v5.0) or ≥ Grade 3 specific toxicity grading criteria (e.g., IEC-HS grading).
Incidence of AE in rMN subjects after a single infusion of CD19 CAR-T cells
时间窗: 12 months after infusion
Severity grading is based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: Mild; asymptomatic or mild symptoms; only clinically or diagnostically detectable; no treatment required. Grade 2: Moderate; requires minor, local, or non-invasive treatment; limitation in age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; results in hospitalization or prolongation of existing hospitalization; disabling; limitation in self-care activities of daily living. Grade 4: Life-threatening; requires urgent treatment. Grade 5: Death related to complications.
次要结局
- Overall response rate (CR+PR) in rMN subjects after cell infusion(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- Proportion of rMN subjects achieving CR after cell infusion(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- Proportion of rMN subjects achieving PR after cell infusion(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- rMN recurrence after cell infusion(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- Urine protein(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- Ferritin level(Day 2, Day 7, Day 10 or 14, Day 21, Day 28 (1 month) after infusion)
- The surface of peripheral blood B cell subsets(Day 2, Day 5, Day 7, Day 10 or 14, Day 21, Day 28 (1 month) after infusion)
- eGFR(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- UACR(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- anti-PLA2R antibody(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- Scr, CysC(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- Routine blood test(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- CRP(Day 2, Day 7, Day 10 or 14, Day 21, Day 28 (1 month) after infusion)
- Serum complements C3, C4(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- IgE、IgA、IgG、IgM(Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- CAR copy number(Day 2, Day 5, Day 7, Day 10 or 14, Day 21, Day 28 (1 month), Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion)
- Cytokine panel(Day 2, Day 7, Day 10 or 14, Day 21, Day 28 (1 month) after infusion)
- Peripheral blood lymphocyte subset count(Day 2, Day 5, Day 7, Day 10 or 14, Day 21, Day 28 (1 month) after infusion)
研究者
Li Jipeng
Research associate
The First Affiliated Hospital of Air Force Medicial University