Safety and Efficacy of FAP-Targeted Immunosuppressive CAR-DC in the Treatment of Ischemic Cardiomyopathy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Incidence of Dose-Limiting Toxicities (DLT)
研究概览
简要总结
This study aims to evaluate the safety and efficacy of fibroblast activation protein (FAP)-targeted autologous immunosuppressive chimeric antigen receptor dendritic cell (iCDC) therapy in patients with ischemic cardiomyopathy, and to explore its potential as a novel therapeutic strategy for this disease.
详细描述
Ischemic heart disease (IHD) is becoming an increasingly serious global public health challenge due to its rising prevalence and the continuous increase in human life expectancy. Despite substantial advances in reperfusion therapy, pharmacological treatment, and risk factor management in recent decades, clinical prognosis remains poor. Many patients continue to experience adverse cardiac remodeling after the initial ischemic injury and eventually progress to heart failure. This persistent residual risk suggests that current therapeutic strategies do not fully address key pathogenic mechanisms underlying disease progression. Inflammation plays a central role in linking acute myocardial injury to chronic cardiac remodeling.
Dendritic cells (DCs), as professional antigen-presenting cells, function at the interface between innate and adaptive immunity and play a critical role in coordinating immune responses within the tissue microenvironment. Recent advances in the study of tolerogenic dendritic cells (tolerogenic DCs) have provided new insights into their potential application in cardiovascular diseases. Unlike conventional immunostimulatory DCs, tolerogenic DCs can induce antigen-specific immune tolerance through multiple mechanisms, including secretion of regulatory cytokines, expression of co-inhibitory ligands, suppression of effector T-cell responses, and induction of regulatory T cells. These properties make DCs a promising but underexplored platform for immune modulation.
This study evaluates a novel therapeutic strategy using fibroblast activation protein (FAP)-targeted autologous immunosuppressive chimeric antigen receptor dendritic cell (CAR-DC) therapy, also referred to as iCDC therapy, in patients with ischemic cardiomyopathy. This approach is designed to direct engineered dendritic cells to sites of cardiac injury and fibrosis, with the goal of modulating the balance between injurious and reparative immune responses. By targeting local immune regulation at the site of injury, this strategy may help attenuate adverse cardiac remodeling while potentially avoiding the systemic immunosuppression associated with conventional therapies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years and ≤75 years.
- •Diagnosis of ischemic cardiomyopathy, with at least 3 months of optimized guideline-directed medical therapy (GDMT) at maximally tolerated doses; left ventricular ejection fraction (LVEF) <35%; New York Heart Association (NYHA) functional class III-IV.
- •Ability to understand the risks, benefits, and treatment alternatives of immunoregulatory CAR-DC therapy, and willingness to participate in the study; the patient or his/her legally authorized representative must provide written informed consent prior to study enrollment.
- •Adequate hematologic function defined as: hematocrit >30%, lymphocyte count >0.5 × 10⁹/L, and platelet count >60 × 10⁹/L.
排除标准
- •Life expectancy <1 year due to non-cardiac conditions.
- •Cardiac resynchronization therapy (CRT) implantation within 3 months prior to enrollment or planned CRT implantation.
- •Percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 3 months prior to enrollment OR plan to PCI.
- •Presence of non-ischemic cardiomyopathy, including but not limited to dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic cardiomyopathy, peripartum cardiomyopathy, inflammatory or immune-mediated cardiomyopathy, metabolic or genetic cardiomyopathy, or cardiomyopathy secondary to moderate-to-severe valvular heart disease, congenital heart disease, or other non-ischemic etiologies.
- •Persistent hemodynamic instability.
- •End-stage renal disease (eGFR <25 mL/min/1.73 m²) requiring or receiving renal replacement therapy (hemodialysis or peritoneal dialysis).
- •Active autoimmune disease requiring immunosuppressive therapy.
- •History of malignancy.
- •Active infection, including but not limited to active hepatitis B (HBV DNA >1000 copies/mL by PCR), hepatitis C, syphilis, or human immunodeficiency virus (HIV) infection, or uncontrolled systemic fungal, bacterial, viral, or other infections.
- •Pregnant women.
- •Known contraindications to the investigational product or study-related procedures.
结局指标
主要结局
Incidence of Dose-Limiting Toxicities (DLT)
时间窗: Within 14 days after treatment
Incidence of dose-limiting toxicities (DLT) within 14 days after administration of FAP-targeted immunoregulatory CAR-DC therapy
Incidence of Treatment-Emergent Adverse Events (TEAE)
时间窗: Within 6 months after treatment
Incidence of treatment-emergent adverse events (TEAE) occurring within 6 months after treatment in patients with ischemic cardiomyopathy.
次要结局
- Change in Left Ventricular Ejection Fraction (LVEF) by Echocardiography(Baseline, 3 months, 6 months)
- Change in left ventricular end-systolic volume (LVESV) as assessed by Echocardiography(Baseline, 3 months, and 6 months)
- Change in left ventricular end-diastolic volume (LVEDV) by Echocardiography(Baseline, 3 months, and 6 months)
- Change in global longitudinal strain (GLS) measured by Echocardiography(Baseline, 3 months, 6 months)
- Change in wall motion score index (WMSI) measured by Echocardiography(Baseline, 3 months, 6 months)
- Change in left ventricular ejection fraction (LVEF) by Cardiac Magnetic Resonance Imaging(Baseline, 6 months)
- Change in left ventricular end-systolic volume (LVESV) by Cardiac Magnetic Resonance Imaging(Baseline and 6 months)
- Change in left ventricular end-diastolic volume (LVEDV) by Cardiac Magnetic Resonance Imaging(Baseline, 6 months)
- Change in stroke volume (SV) by Cardiac Magnetic Resonance Imaging(Baseline and 6 months)
- Change in Myocardial Late Gadolinium Enhancement Volume by Cardiac Magnetic Resonance Imaging(Baseline and 6 months)
- Change in Extracellular Volume Fraction in Remote Myocardium by Cardiac Magnetic Resonance Imaging(Baseline and 6 months)
- Change in Myocardial Scar Transmurality by Cardiac Magnetic Resonance Imaging(Baseline and 6 months)
- Change in Serum B-type Natriuretic Peptide (BNP) Level(Baseline, 3 months, and 6 months)
- Change in Six-Minute Walk Test Distance(Baseline, 3 months, and 6 months)
- Change in Heart Failure Symptom Assessments--NYHA(Baseline, 3 months, and 6 months)
- Change in Heart Failure Symptom Assessments--INTERMACS(Baseline, 3 months, and 6 months)
- Change in Heart Functional Status Assessments-KCCQ(Baseline, 3 months, and 6 months)
- Change in Cardiac 18F-FAPI Uptake by PET/CT(Baseline and 6 months)
- Incidence of Major Adverse Cardiovascular Events(Up to 6 months)
- Incidence of Adverse Events(Up to 6 months)