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.
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.
eGFR < 60 ml/min/1.73m² and/or persistent proteinuria > 8g/d for more than 6 months.
Secondary membranous nephropathy (e.g., due to SLE, malignancy, drugs, infection).
HBV: HBsAg (+) and/or HBcAb (+) with detectable HBV DNA.
HCV: HCV Ab (+) with detectable HCV RNA.
HIV Ab (+).
Single group
All patients will receive CD19 CAR-T cell therapy on the basis of standard symptomatic and supportive treatment.
Other interventionPrior 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.
Incidence of DLT in rMN subjects after a single infusion of CD19 CAR-T cells
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
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.
Overall response rate (CR+PR) in rMN subjects after cell infusion
1. Definition of rMN CR: Disappearance of the patient's clinical symptoms and signs; urine protein reduced to \<0.3 g/day or UACR \<300 mg/g; with normal levels of serum albumin (ALB) and serum creatinine (Scr). 2. Definition of rMN PR: Improvement in clinical symptoms and signs; urine protein decreased by more than 50% compared with baseline, and reduced to 0.3-3.5 g/day or UACR 300-3500 mg/g.
Proportion of rMN subjects achieving CR after cell infusion
Definition of rMN CR: Disappearance of the patient's clinical symptoms and signs; urine protein reduced to \<0.3 g/day or UACR \<300 mg/g; with normal levels of serum albumin (ALB) and serum creatinine (Scr).
Proportion of rMN subjects achieving PR after cell infusion
Definition of rMN PR: Improvement in clinical symptoms and signs; urine protein decreased by more than 50% compared with baseline, and reduced to 0.3-3.5 g/day or UACR 300-3500 mg/g.
rMN recurrence after cell infusion
Definition of rMN recurrence: After NR or PR, the patient's urine protein rises again to \>3.5 g/day or UACR \>3500 mg/g; frequent recurrence is defined as more than 2 recurrences within 6 months or more than 4 recurrences within 12 months.
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