CD34+CXCR4+ Cell Therapy (AMR-001) for Myocardial Infarction: Preliminary Processing and Product Results of a Phase I Dose Escalation Study.

Background: Approximately 20% of patients suffering a ST segment elevated acute myocardial infarction (AMI) have progressive peri-infarct zone myocardial cell death causing ventricular remodeling and poor cardiac outcomes in spite of large vessel revascularization and medical management. Neo-angiogenesis occurs when VEGF levels peak and endothelial precursors are mobilized and recruited to the infarct site. Stromal cell derived factor-1 (SDF-1), the ligand for the CXCR4 receptor, is expressed by CD34⁺ cells and plays a role in cell homing to areas of ischemic damage. CD34⁺ CXCR4⁺ cells home to areas of ischemia, rich in SDF-1, including infarcted myocardium and are capable of inducing neo-angiogenesis. Natural neoangiogenesis is present but insufficient following AMI, suggesting that direct administration of CD34⁺ CXCR4⁺ progenitors could mitigate peri-infarct zone myocardial cell death and improve ventricular function.

Methods: In this phase I study, patients with an ST segment (AMI) are enrolled in cohorts of 5 to receive one of four doses (5, 10, 15, 20 x 10⁶ of bone marrow derived CD34⁺ cells. Cells are harvested using a mini-bone marrow harvest (MMH) technique, acquired by Isolex selection and administered by infusion via the infarct related artery 5 to 10 day following successful coronary artery stenting post AMI. The first 10 subjects accrued as subjects on this phase 1 study included 9 males and 1 female, with a median age of 52 years (range 36–70).

Results: The first ten patients (of 20 planned) underwent a MMH under conscious sedation without incident. Adequate numbers of viable, enriched CD34⁺ cells were obtained following Isolex selection for treatment of subjects enrolled at the first two dose cohorts (5 x 10⁶ and 10 x 10⁶ CD34⁺ cells). The mean fraction of cells expressing CD34 in the marrow product was 0.75%, with a mean recovery of 40% following Isolex selection (Table).

Conclusions: Our study demonstrates the feasibility of collecting up to 409 ml of bone marrow using a MMH technique in the immediate post AMI setting, with yields up to 86 x 10⁶ CD34⁺ cells. All patient cells expressed CXCR4 and had in vitro migratory capacity. However the lower than expected percentage of TNC expressing CD34 (compared with 9 healthy age matched individuals (1.49% vs. 0.75%) and a low % recovery following Isolex selection may limit successful upper (>10 x 10⁶) cohort treatments. VEGf-2 expression on enriched CD34⁺ cells was variable.