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

Abstract

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.Processing and Product Results (N=10)mean (median)rangeMMH marrow volume (ml)395 (396)377 – 409Harvest TNC content (x 109)6.65 ( 6.73)3.85 – 8.59Harvest CD34+ content (x 106)45.3 (50.2)16.9 – 86.7Harvest CD34+ % of TNC0.75% (0.72%)0.54% – 1.06%Selected CD34+ content (x 106)17.8 (16.5)8.4 – 28.9Selected % CD34+ recovery40.3% (41.9%)30.2 – 49.7Selected %CD34+ viability97.1% (98.0 %)96% – 99%Selected % CD34+ purity82.5% (84.%)70% – 91%Total processing time (hours)14.2 (14.0)11 – 17SDF-1 induced migration (% of CD34+ cells)20.2% (17.0%)9.5% – 35.4%CXCR-4 expression(% of CD34+ cells)*58.7% (52.0%)44% – 78%VEGF-2 expression (% of CD34+ cells)**0.82% (0.86%)0% – 2.39%*N=7 (technical loss of 3 samples);** N=9 (technical loss of 1 sample)