A Single-Arm, Open-Label Clinical Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of CD19 CAR-T Cell Therapy in Patients With Moderate-to-Severe Refractory Pemphigus Vulgaris
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Incidence and Severity of Treatment-Emergent Adverse Events
研究概览
简要总结
This is an investigator-initiated, single-center, single-arm, open-label exploratory clinical study designed to evaluate the safety, tolerability, and preliminary efficacy of autologous CD19 CAR-T cell therapy in patients with refractory pemphigus vulgaris.
详细描述
This is an investigator-initiated, open-label, single-center, single-arm exploratory interventional study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immune reconstitution, and preliminary clinical efficacy of autologous CD19 CAR-T cell therapy in adult patients with moderate-to-severe refractory pemphigus vulgaris.
Eligible participants are adults with refractory pemphigus vulgaris. After enrollment, participants will undergo leukapheresis for ex vivo manufacturing of autologous CD19 CAR-T cells. After product release, participants will receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide within 2 to 7 days prior to CAR-T infusion.
Participants will receive a single intravenous infusion of autologous CD19 CAR-T cells at a protocol-defined dose (1 X 10^6 CAR-positive T cells per kilogram of body weight). Premedication may be administered at investigator discretion. No comparator group is included.
Participants will be followed for up to 96 weeks after infusion. Safety assessments include monitoring for cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, infections, cytopenias, organ toxicities, and other treatment-emergent adverse events.
Efficacy assessments include changes in PDAI score, disease control, Physician Global Assessment (PGA), Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), relapse rate, time to relapse, and corticosteroid-sparing effects.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria:
- •Ability to provide written informed consent.
- •Age 18 to 70 years at screening, male or female.
- •Diagnosis of pemphigus vulgaris confirmed by clinical presentation, histopathology, direct immunofluorescence (DIF), and positive anti-desmoglein 3 and/or anti-desmoglein 1 antibodies.
- •Moderate-to-severe disease activity defined as Pemphigus Disease Area Index (PDAI) ≥ 15 at screening.
- •Refractory pemphigus vulgaris is defined as inadequate response, disease relapse, or treatment dependence following systemic corticosteroids and rituximab-based therapy for at least 6 months, with persistent disease activity meeting at least one of the following criteria:
- •Ongoing active disease with the appearance of new erythema, blisters, or erosions;
- •Persistently elevated anti-desmoglein 1 or anti-desmoglein 3 antibody titers > 100 U/mL;
- •Inability to taper systemic corticosteroids to < 20 mg/day prednisone equivalent (i.e., ≥ 4 tablets/day of standard prednisone dosing).
- •Requirement for systemic therapy at screening due to active disease.
- •Adequate vascular access for leukapheresis.
- •Life expectancy greater than 6 months.
- •Participants must have adequate organ function as defined below:
- •Hematologic function: absolute neutrophil count ≥ 1.0 × 10⁹/L, platelet count ≥ 50 × 10⁹/L, hemoglobin ≥ 80 g/L.
- •Renal function: Creatinine clearance ≥ 40 mL/min.
- •Hepatic function: ALT and AST ≤ 2.5 × upper limit of normal; total bilirubin ≤ 1.5 × upper limit of normal.
- •Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% with no clinically significant cardiac dysfunction.
- •Pulmonary function: Dyspnea ≤ Grade 1 (CTCAE v5.0) and oxygen saturation (SpO₂) ≥ 92% on room air.
- •Coagulation function: international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × upper limit of normal, with no clinically significant coagulopathy.
- •9. No evidence of clinically significant active infection at baseline evaluation.
- •10. Reproductive Criteria: Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) test within 48 hours prior to initiation of lymphodepleting chemotherapy. Women of childbearing potential must agree to use effective contraception during study participation and for at least 12 months after CAR-T infusion. Male participants must agree to use effective contraception and avoid sperm donation during study participation and for at least 12 months after infusion.
排除标准
- •Participants meeting any of the following criteria will be excluded:
- •Active uncontrolled infection at screening, requiring systemic antimicrobial therapy. Participants with active tuberculosis, hepatitis C virus (HCV), human immunodeficiency virus (HIV), or syphilis infection will be excluded. Participants with hepatitis B surface antigen and/or hepatitis B core antibody positivity may be eligible only if HBV DNA is below the lower limit of quantification and appropriate antiviral prophylaxis is provided at the investigator's discretion.
- •History of other active autoimmune disease requiring systemic immunosuppression.
- •Previous treatment with any gene-modified cellular therapy, including CAR-T or CAR-NK therapy.
- •Prior allogeneic stem cell or solid organ transplantation.
- •Severe or uncontrolled cardiovascular, pulmonary, hepatic, or renal disease that would increase risk associated with lymphodepleting chemotherapy or CAR-T cell infusion.
- •Use of high-dose systemic corticosteroids (>1 mg/kg/day prednisone equivalent) within 7 days prior to leukapheresis.
- •Use of rituximab or other B-cell-targeted biologics within protocol-defined washout period.
- •Use of intravenous immunoglobulin, plasma exchange, or other intensive immunomodulatory therapy within 2 weeks prior to leukapheresis.
- •Received live vaccine within 8 weeks prior to screening.
- •History of malignancy within 5 years prior to enrollment, except adequately treated non-melanoma skin cancer or in situ carcinoma.
- •Pregnancy or breastfeeding.
- •Known hypersensitivity to any component of lymphodepleting chemotherapy or CAR-T cell product.
- •Any condition that, in the investigator's judgment, would compromise patient safety or study integrity.
结局指标
主要结局
Incidence and Severity of Treatment-Emergent Adverse Events
时间窗: From initiation of lymphodepleting chemotherapy through Day 90 after CAR-T cell infusion
Treatment-emergent adverse events, serious adverse events, dose-limiting toxicities, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, infections, cytopenias, organ toxicities, infusion-related reactions, and clinically significant laboratory abnormalities will be assessed. Adverse events will be graded according to CTCAE v5.0, and immune effector cell-related toxicities will be assessed according to applicable consensus grading criteria.
Change From Baseline in PDAI Score at Week 12
时间窗: Baseline and Week 12
The change from baseline in Pemphigus Disease Area Index (PDAI) score at Week 12 will be assessed to evaluate preliminary clinical efficacy of autologous CD19 CAR-T cell therapy in patients with refractory pemphigus vulgaris.
Proportion of participants achieving disease control at Week 4 after CAR-T infusion
时间窗: Week 4
Disease control is defined as cessation of new active cutaneous or mucosal lesions with established lesion healing or no further progression of existing lesions, as assessed by the investigator. This endpoint evaluates the early clinical response following CD19 CAR-T cell therapy and reflects initial disease stabilization after B-cell depletion.
次要结局
- Change From Baseline in Pemphigus Disease Area Index （PDAI） Score Over Time (Range 0-263)(Baseline through Week 96 after CAR-T cell infusion)
- Change From Baseline in Physician Global Assessment Score (PGA) (Range 0-10)(Baseline through Week 96 after CAR-T cell infusion)
- Change from Baseline in Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) (Range 0-206)(Baseline through Week 96 after CAR-T cell infusion)
- Proportion of participants achieving disease control at Week 12(Week 12)
- Change From Baseline in Anti-Desmoglein 1 and Anti-Desmoglein 3 Antibody Levels(Baseline through Week 96 after CAR-T cell infusion)
- Peripheral CD19-Positive B-Cell Depletion and Reconstitution(Baseline through Week 96 after CAR-T cell infusion)
- Number of Circulating CAR-Positive T Cells in Peripheral Blood(From CAR-T cell infusion through Week 96)
- CAR Transgene Copy Number in Peripheral Blood(From CAR-T cell infusion through Week 96)
- Duration of Detectable CAR-T Cells in Peripheral Blood(From CAR-T cell infusion through Week 96)
- Change From Baseline in Serum Cytokine Levels(Baseline through Week 96 after CAR-T cell infusion)
- Change From Baseline in Lymphocyte Subset Counts(Baseline through Week 96 after CAR-T cell infusion)
- Change From Baseline in B-Cell Subset Counts(Baseline through Week 96 after CAR-T cell infusion)
- Relapse Rate Through Week 96(From disease control through Week 96 after CAR-T cell infusion)
- Time to First Relapse(From disease control through Week 96 after CAR-T cell infusion)
- Change From Baseline in Daily Prednisone-Equivalent Corticosteroid Dose(Baseline through Week 96 after CAR-T cell infusion)
- Incidence of Serious Adverse Events and Long-Term Safety Events(From informed consent through Week 96 after CAR-T cell infusion)
研究者
Jinbo Chen
Deputy Director of Dermatology, Principal Investigator, Clinical Professor
Wuhan Integrated Traditional Chinese and Western Medicine Hospital