Safety and Efficacy of Allogeneic Immunosuppressive CAR-DC Targeting FAP in the Treatment of Acute Myocardial Infarction With Cardiogenic Shock
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- The proportion of subjects with Dose-limiting toxicity (DLT)
研究概览
简要总结
To study the safety and efficacy of fibroblast activation protein (FAP)-targeted allogeneic immunosuppressive chimeric antigen receptor-dendritic cell (CAR-DC) in the treatment of acute myocardial infarction with cardiogenic shock and provide a new method for the treatment of acute myocardial infarction with cardiogenic shock.
详细描述
Background: Cardiogenic shock following acute myocardial infarction (AMI) remains a major unresolved clinical challenge. Despite advances in urgent revascularization and mechanical circulatory support, short-term mortality remains unacceptably high, approaching 40% within 30 days. Few evidence-based therapies have demonstrated a meaningful survival benefit, highlighting the urgent need for novel, mechanism-driven interventions. Growing clinical and experimental evidence indicates that a dysregulated systemic inflammatory response-manifested by hyperthermia, leukocytosis, and elevated proinflammatory mediators-plays a central role in the pathophysiology and progression of cardiogenic shock. Excessive inflammation exacerbates myocardial dysfunction, promotes multiorgan injury, and impairs recovery, suggesting that targeted immunomodulation may represent a complementary therapeutic strategy in this high-risk population. Dendritic cells (DCs), as professional antigen-presenting cells, occupy a pivotal position at the interface of innate and adaptive immunity and are uniquely suited to orchestrate context-dependent immune responses. In particular, tolerogenic DCs exert potent immunosuppressive effects through regulatory cytokine production, expression of co-inhibitory ligands, antigen-specific suppression of effector T cells, and induction of regulatory T cells. Collectively, these properties render DCs an attractive yet underexplored cellular platform for resolving excessive inflammation and promoting tissue repair in cardiogenic shock with AMI.
Purpose: In this prospective clinical study, the investigators engineered a stable, immunosuppressive, and fibrotic lesion-targeted DC therapy, termed immunosuppressive DCs (iCDC). This study was designed to evaluate the safety and preliminary efficacy of allogeneic fibroblast activation protein (FAP)-targeted iCDC therapy in patients with AMI complicated by cardiogenic shock.
Study design: This single-center, prospective, concurrent non-randomized controlled clinical trial enrolls patients aged 18-80 years presenting with acute myocardial infarction complicated by cardiogenic shock. Eligible patients are treated with allogeneic FAP-targeted immunosuppressive iCDC therapy.
Outcome measure: The primary outcome is the safety of FAP-targeted immunosuppressive iCDC therapy in patients with AMI complicated by cardiogenic shock. Secondary outcomes include 30-day all-cause mortality; hemodynamic parameters following iCDC therapy (systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate); time to hemodynamic stabilization; dose and duration of vasopressor and inotropic support; arterial lactate levels; changes in biomarkers (BNP, CRP, creatinine, ALT, AST, and inflammatory mediators); need for and duration of mechanical ventilation; need for and duration of left ventricular assist device implantation; intensive care unit and total hospital length of stay; left ventricular ejection fraction assessed by echocardiography; SAPS II score; SCAI shock classification; heart failure symptom burden assessed by NYHA functional class and the Kansas City Cardiomyopathy Questionnaire; incidence of major adverse cardiovascular events (MACE), including cardiac death and heart failure hospitalization; and incidence of adverse events.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •（patients）:
- •Age ≥ 18 years and < 80 years.
- •Acute ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock, meeting all the following conditions:
- •Post-emergent revascularization (PCI or CABG)
- •Systolic blood pressure < 90 mmHg for >30 minutes, or requiring catecholamine support to maintain systolic blood pressure >90 mmHg
- •Signs of impaired organ perfusion, meeting at least one of the following criteria:
- •Altered mental status
- •Cold, clammy skin and extremities
- •Oliguria, with urine output <30 mL/h
- •Arterial lactate level >2 mmol/L
- •The patient or their legally authorized representative is capable of providing verbal confirmation of understanding the trial risks, benefits, and treatment alternatives associated with receiving immunosuppressive CAR-DC therapy, and provides written informed consent prior to participation in this clinical trial.
排除标准
- •（patients）:
- •Acute mechanical complications of infarction (e.g., ventricular septal rupture, acute mitral regurgitation).
- •Cardiac arrest.
- •Hypoxic-ischemic brain injury (cerebral injury with fixed and dilated pupils not attributable to medication).
- •Shock due to other causes (e.g., sepsis, hypovolemia).
- •Resuscitation duration >30 minutes.
- •Absence of spontaneous cardiac activity.
- •Persistent electrical instability.
- •Active bleeding or contraindications to heparin use.
- •Active autoimmune disease requiring immunosuppressive therapy.
- •History of malignancy.
- •Infection, including:
- •Active hepatitis B (HBV DNA >1000 copies/mL by PCR), hepatitis C, syphilis, or HIV infection at screening.
- •Uncontrolled systemic fungal, bacterial, viral, or other pathogen infections.
- •Pregnant women.
- •Contraindications to the investigational drug or study procedures.
- •Inclusion Criteria（donors）:
- •Age ≥ 18 years and ≤ 75 years.
- •Has provided written informed consent.
- •Hematocrit >30%, lymphocyte count >0.5 × 10^9/L, platelet count >60 × 10^9/L.
- •Pathogen screening results must be negative for HIV (antigen, core antibody, and RNA), HBV (surface antigen and core antibody), HCV, syphilis, CMV, and EBV.
- •Exclusion Criteria（donors）:
- •Active infection requiring treatment.
- •History of malignancy.
- •Active autoimmune disease requiring immunosuppressive therapy.
研究组 & 干预措施
Administration of allogeneic FAP iCDC
Administration of FAP immunosuppressive CAR-DC cell therapy in AMI CS. Patients are planned to be enrolled in the dose-escalation trial (1×10^5/kg、4×10^5/kg、and 8×10^5/kg) .The first dose group (4×10⁵/kg) initially enrolls 3 subjects to observe Dose-Limiting Toxicity (DLT) responses.
- If no DLT occurs and all 3 subjects demonstrate efficacy after 6 months of treatment, and this dose is determined as the safe and effective dose.
- If 1 subject experiences DLT, 3 additional subjects are enrolled. ·If 1/6 subjects develops DLT, and efficacy is not fully achieved in all 6 subjects, escalate to the next dose group (8×10^5/kg). ·If ≥2/6 subjects develop DLT, de-escalate to the previous dose group (1×10^5/kg).
- After identifying a safe and effective dose, enrollment will be expanded at this dose to bring the total sample size to 8-10 subjects, to further evaluate safety and efficacy.
干预措施: FAP allogeneic immunosuppressive CAR-DC (Biological)
Standard therapy
Patients in the control group do not receive cellular therapy intervention.
结局指标
主要结局
The proportion of subjects with Dose-limiting toxicity (DLT)
时间窗: in 14 days after injection
The proportion of participants with DLT as assessed by CTCAE v5.0
Incidence of treatment-emergent adverse events (TEAEs)
时间窗: in 14 days after injection
Incidence of iCDC treatment-emergent adverse events
次要结局
- All-cause mortality(30 days after injection)
- Systolic blood pressure(24 hours、48 hours、72 hours、7 days after injection)
- Diastolic blood pressure(24 hours、48 hours、72 hours、7 days after injection)
- Mean arterial pressure(24 hours、48 hours、72 hours、7 days after injection)
- Time to hemodynamic stability(From the end of the iCDC infusion to achievement of hemodynamic stability, assessed continuously until ICU discharge (up to 30 days).)
- Dose of vasopressors(24 hours、48 hours、72 hours、7 days after injection)
- Duration of vasopressor use(From enrollment to hospital discharge (up to 30 days).)
- Dose of inotropic drugs(24 hours、48 hours、72 hours、7 days after injection)
- Duration of inotropic drugs use(From enrollment to hospital discharge (up to 30 days).)
- Serum lactate level(The measurement frequency is once every 8 hours for a duration of 48 hours.)
- Change in B-type natriuretic peptide (BNP) level from baseline(7 days，14 days，30 days after injection.)
- Change in C-reactive protein (CRP) level from baseline(24 hours, 72 hours, 7 days，14 days after injection.)
- Change in serum creatinine level from baseline(24 hours, 72 hours, 7 days，14 days after injection.)
- Change in ALT (Alanine Aminotransferase) level from baseline(24 hours, 72 hours, 7 days，14 days after injection.)
- Change in AST (Aspartate Aminotransferase) level from baseline(24 hours, 72 hours, 7 days，14 days after injection.)
- Change in Interleukin-6 (IL-6) levels from baseline(24 hours, 72 hours, 7 days，14 days after injection.)
- Need for mechanical ventilation(From the end of the drug infusion until ICU discharge (up to 30 days).)
- Duration of mechanical ventilation(From the initiation of mechanical ventilation until ICU discharge (up to 30 days).)
- Requirement for left ventricular assist device implantation(From the end of iCDC infusion through study completion (up to 30 days).)
- Duration of left ventricular assist device use(From left ventricular assist device implantation through study completion (up to 30 days).)
- Simplified Acute Physiology Score II(Daily from ICU admission through ICU discharge (up to 30 days).)
- time to recovery from cardiogenic shock(From the end of iCDC infusion to recovery from cardiogenic shock, assessed continuously until ICU discharge (up to 30 days).)
- length of stay at the intensive care unit(From ICU admission until ICU discharge (up to 30 days).)
- Length of hospital stay;(From hospital admission until hospital discharge or death (up to 30 days).)
- Left ventricular ejection fraction (LVEF)(1 month after injection)
- SCAI Shock Classification(3 days、7 days、14 days after injection)
- assessment of heart failure symptom(1 month after injection)
- Incidence of major adverse cardiovascular events (MACE)(1 month after injection)
- incidence of adverse events(From the end of the drug infusion through study completion，up to 30 days.)