Safety and Efficacy of CD19 Chimeric Antigen Receptor T-Cell (CAR-T) in the Treatment of Refractory Membranous Nephropathy

Phase 1RecruitingNCT07266181

The First Affiliated Hospital of Air Force Medicial University5 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Refractory Membranous Nephropathy

Interventions

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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: 1. eGFR \< 60 ml/min/1.73m² and/or persistent proteinuria \> 8g/d for more than 6 months. 2. 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 \> 0.20. * 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: 1. Renal: eGFR ≥ 30 ml/min/1.73m². 2. Hepatic: ALT and AST ≤ 2.5 x ULN; Total bilirubin ≤ 1.5 x ULN. 3. Cardiac: LVEF ≥ 50%; NYHA Class I or II; No significant arrhythmias requiring intervention; No major cardiovascular events within the past 6 months. 4. Respiratory: SpO2 \> 92% on room air. * Ability to understand and willingness to sign an Informed Consent Form. Exclusion Criteria: * 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: 1. HBV: HBsAg (+) and/or HBcAb (+) with detectable HBV DNA. 2. HCV: HCV Ab (+) with detectable HCV RNA. 3. HIV Ab (+). 4. Active EBV or CMV infection (IgM+ or DNA above normal). 5. Positive syphilis (Treponema pallidum) antibody (requires evaluation for active infection). * Severe uncontrolled comorbidities, including: 1. Uncontrolled hypertension (persistent SBP \> 160 mmHg or DBP \> 100 mmHg). 2. Uncontrolled diabetes (HbA1c \> 8% or random glucose ≥11.1 mmol/L) or diabetic nephropathy. 3. Symptomatic deep vein thrombosis or pulmonary embolism within the past 6 months. 4. Active peptic ulcer or gastrointestinal bleeding within the past 6 months. 5. Severe congenital or acquired immunodeficiency. 6. Severe CNS diseases (e.g., catastrophic APS, uncontrolled epilepsy). 7. 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: 1. Prior receipt of any cell therapy (e.g., MSCs, HSCT). 2. Major surgery within 24 weeks before or planned within 24 weeks after enrollment. 3. Planned kidney transplantation within 3 years. 4. 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.

Outcomes

Primary Outcomes

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).

Time frame: 28 days and 3 months after infusion

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.

Time frame: 12 months after infusion

Secondary Outcomes

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.