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

Official title

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

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.

Interventions

• Other All patients will receive CD19 CAR-T cell therapy on the basis of standard symptomatic and supportive treatment.
  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.

Primary outcome measures

• Incidence of DLT in rMN subjects after a single infusion of CD19 CAR-T cells [Time frame: 28 days and 3 months after infusion]
• Incidence of AE in rMN subjects after a single infusion of CD19 CAR-T cells [Time frame: 12 months after infusion]

Secondary outcome measures (12)

• Overall response rate (CR+PR) in rMN subjects after cell infusion [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion]
• eGFR [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Day 2, Day 7, Day 10 or 14, Day 21, Day 28 (1 month) after infusion]
• Serum complements C3, C4 [Time frame: Week 2, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18 (if applicable), Month 24 (if applicable) after infusion]

Eligibility criteria

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:

• 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 > 0.20.
• 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:

• 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.

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:

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Department of Nephrology, Xijing Hospital — Xi'an

Identifiers

NCT: NCT07266181 · KY20252388-F-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗