Safety and Efficacy of Second Infusion of FAP iCDC in End-stage Dilated Cardiomyopathy

Heart failure is a life-threatening syndrome with high morbidity and mortality. Dilated cardiomyopathy (DCM) is a major cause of end-stage heart failure, and currently available treatments for advanced DCM remain limited.

Immune activation and myocardial fibrosis play key roles in the progression of heart failure. Targeting cardiac fibrosis through immune modulation has emerged as a potential therapeutic strategy. Our research group has developed a novel immunosuppressive chimeric antigen receptor-modified dendritic cell (CAR-DC) therapy targeting fibroblast activation protein (FAP), designed to reduce cardiac fibrosis and improve cardiac function.

Preclinical studies demonstrated that FAP-targeted immunosuppressive CAR-DC (iCDC) therapy significantly improved cardiac function and survival in animal models of heart failure, with a favorable safety profile. Based on these findings, an exploratory clinical study of single-dose iCDC infusion in patients with end-stage DCM has been conducted, and preliminary follow-up results up to three months have shown good safety and potential clinical benefit.

However, in clinical practice, patients with end-stage DCM may experience recurrent deterioration of cardiac function due to infections or other triggers. Whether a second administration of iCDC can restore or further improve cardiac function remains unknown.

Therefore, this study aims to evaluate the safety and preliminary efficacy of a second infusion of FAP-targeted immunosuppressive CAR-DC in patients with end-stage dilated cardiomyopathy who experience worsening heart function after initial treatment.

• FAP immunosuppressive CAR-DC (Biological): Each subject receive FAP immunosuppressive CAR-DC by intravenous infusion

Primary outcomes

• The proportion of subjects with Dose-limiting toxicity (DLT) [in 14 days after injection]: The proportion of participants with treatment-related adverse events as assessed by CTCAE v5.0
• Incidence of treatment-emergent adverse events (TEAEs) [in 14 days after injection]: Incidence of iCDC treatment-emergent adverse events

Secondary outcomes

• Left ventricular ejection fraction (LVEF) [1, 3, 6 months after injection]: The difference of LVEF from baseline. LVEF will be assessed by echocardiography.
• Left ventricular ejection fraction (LVEF) [6 months after injection]: The difference of LVEF from baseline. LVEF will be assessed by Cardiac Magnetic Resonance (CMR).
• Enhanced volume (volume%) [6 months after injection]: The difference of Enhanced volume (volume%) from baseline. Enhanced volume will be assessed by CMR.
• INTERMACS Profile [1, 3, 6 months after injection]: Profile 1. Critical cardiogenic shock; Profile 2. Progressive decline on inotropic support; Profile 3. Stable but inotrope dependent; Profile 4. Resting symptoms home on oral therapy; Profile 5. Exertion Intolerant; Profile 6. Exertion Limited; Profile 7. Advanced NYHA Class III symptoms
• Left ventricular internal diameter end systole (LVIDs) [1, 3, 6 months after injection]: The difference of LVIDs from baseline. LVIDs will be assessed by echocardiography.
• Left ventricular internal diameter end diastole (LVIDd) [1, 3, 6 months after injection]: The difference of LVIDd from baseline. LVIDd will be assessed by echocardiography.
• Left ventricular end-systolic volume (LVESV) [6 months after injection]: The difference of LVESV from baseline. LVESV will be assessed by CMR.
• Left ventricular end-diastolic volume (LVEDV) [6 months after injection]: The difference of LVEDV from baseline. LVEDV will be assessed by CMR.
• NT-proBNP [1, 3, 6 months after injection]: Analysis of differences of NT-proBNP serum level from baseline.
• 6 minutes walk test (6MWT) [1, 3, 6 months after injection]: The difference of 6MWT from baseline.
• Change in New York Heart Association (NYHA) Functional Classification [Baseline, 1 month, 3 months, and 6 months]: Assessment of heart failure symptom severity using the New York Heart Association (NYHA) functional classification. NYHA class ranges from I to IV, with higher classes indicating worse functional status.
• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score [Baseline, 1 month, 3 months, and 6 months]: Assessment of heart failure-related health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ). The KCCQ score ranges from 0 to 100, with higher scores indicating better health status and quality of life.
• Incidence of major adverse cardiovascular events (MACE) [1, 3, 6 months after injection]: Incidence of Cardiac death, readmission due to heart failure.
• incidence of adverse events [6 months after injection]: Incidence of adverse events of heart, nerve system, mental system, digestive system and immune system.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* ≥18 years and ≤75 years of age, with a confirmed diagnosis of dilated cardiomyopathy.
* Patients who previously received a single infusion of immunosuppressive CAR-DC (iCDC) therapy and, at 6 months after the first treatment, failed to maintain improvement in cardiac function, with cardiac function declining to baseline levels prior to treatment. These patients should have persistent heart failure symptoms that cannot be adequately improved, with left ventricular ejection fraction (LVEF) <35%, New York Heart Association (NYHA) functional class III-IV, and INTERMACS profile 3-6.
* Able to verbally confirm understanding of the risks, benefits, and alternative treatment options of the second administration of iCDC therapy, and willing to participate in the study. The participant or his/her legal representative must provide written informed consent prior to enrollment.
* Hematocrit >30%, lymphocyte count >0.5 × 10⁹/L, and platelet count >60 × 10⁹/L.

Exclusion Criteria:

* Severe renal failure or requirement for renal dialysis, or serum creatinine >2.5 mg/dL.
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 5.0 times the upper limit of normal (ULN), or total bilirubin >3 mg/dL.
* Presence of active infections at screening, including: Active hepatitis B infection with hepatitis B virus DNA >1000 copies/mL by PCR testing; Hepatitis C virus infection; Syphilis; Human immunodeficiency virus (HIV) infection; Uncontrolled systemic fungal, bacterial, viral, or other pathogenic infections.
* Severe hemodynamic instability (e.g., shock).
* Known contraindications to the investigational product or study-related procedures.

• Xinyang Hu, PhD, Principal investigator, Second Affiliated Hospital, School of Medicine, Zhejiang University, China