Varying Cell Therapy Techniques Demonstrate Safety, Mixed Efficacy at AHA 2013

DALLAS, TX—A wide array of studies portray the potential benefits and problems of different cell therapy techniques in patients with myocardial ischemia undergoing coronary revascularization, according to results presented November 18, 2013, at the American Heart Association Scientific Sessions.

Stem Cell Injection During LVAD Placement Safe, Feasible

April Stempien-Otero, MD, of the University of Washington (Seattle, WA), and colleagues tested the safety and feasibility of bone marrow-derived cell injection at the time of LVAD placement in a small, pilot trial. They screened 26 patients with ischemic cardiomyopathy and excluded 13 from therapy (controls) because of need for IABP, conversion to destination therapy LVAD, or logistical issues. Six patients (83.3% male) were injected intra-operatively with 3 different cell fractions, CD34+, CD34-, and bone marrow mononuclear cells, as well as saline, in separate areas of ischemic myocardium.

Within 7 days, there was no difference in occurrence of ventricular arrhythmias between the study patients and the controls (66.7% vs. 61.5%; P = NS). The primary endpoint was endothelial density as a marker of vascular genesis, and “surprisingly, the CD34+ stem cell faction had the fewest endothelial cells of the groups,” Dr. Stempien-Otero said. There were statistically fewer endothelial cells in the CD34+ injected cell areas in comparison with the saline injected areas (P = 0.02), and there was a trend toward similar improvement in both CD34- and bone marrow mononuclear cells.

There was no difference in inflammation among any of the injected cell groups. However, there was a decrease in activated fibroblasts in the CD34+ and CD34- factions (P = 0.02 for both).

“Injection of CD34+ stem cells does not increase vascularity in unloaded ischemic myocardium,” Dr. Stempien-Otero said. “Injection of cells may induce cellular changes via paracrine effects that are independent of the origin of the cell therapeutic delivered.”

TACtile Results

The TAC-HFT trial, led by Joshua M. Hare, MD, of the University of Miami Miller School of Medicine (Miami, FL), demonstrated the safety of transendocardial injection of autologous mesenchymal stem cells and bone marrow mononuclear cells in patients with LV dysfunction due to ischemic cardiomyopathy. Sixty-five patients were randomized in a 2:1 fashion to therapy with each cell type in 2 comparisons; mesenchymal cells (n = 19) vs. placebo (n = 11) and bone marrow mononuclear cells (n = 19) vs. placebo (n = 10). Cells were delivered into 10 LV sites.

No patient had a treatment-emergent serious adverse event at 30 days. The 1-year incidence of serious adverse events was 31.6% for mesenchymal stem cells, 31.6% for bone marrow mononuclear cells, and 38.1% for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with both mesenchymal stem cells (-6.3; P = 0.02) and bone marrow mononuclear cells (-8.2; P = 0.005) but not with placebo (0.4; P = 0.38). The 6-minute walk distance increased with mesenchymal stem cells only (P = 0.03). Infarct size as a percentage of LV mass was only reduced by mesenchymal stem cells (-18.9%; P = 0.004). LV chamber volume and LVEF did not change.

“The safety profile and the findings of scar reduction, improved quality of life, and functional capacity provide the basis for larger studies to provide definitive assessment of safety and efficacy of this new therapeutic approach,” Dr. Hare said.

LVADS Offer ‘Unique Clinical Laboratory’

In another study looking at LVAD recipients, Deborah D. Ascheim, MD, of Mount Sinai School of Medicine (New York, NY), and colleagues tested the safety and feasibility of adjunctive myocardial transplantation of allogeneic mesenchymal precursor cells. The researchers randomized 30 patients in a 2:1 fashion to receive 25 million study cells or cryoprotective medium alone at 11 US centers.

No primary safety events occurred at 90 days. Donor-specific human leukocyte antigen sensitization developed in 10% of the study arm and 30% of controls, but all donor-specific antibodies were resolved by 12 months. Half of patients in the study arm tolerated temporary wean at 90 days, while this only occurred in 20% of controls. Mean LVEF following successful wean was 24.0% in the study arm and 22.5% in controls.

At 90 days, there were 3 deaths, all in the control group. Also, the rate of serious adverse events was similar between groups.

“LVADS offer a unique ‘clinical laboratory’ for evaluation of adjunctive assessments underway,” Dr. Ascheim observed. “The [mesenchymal precursor cells] used in this trial have many potential advantages including off-the-shelf availability and potential for immunologic privilege.”

It’s Not So Much in the Timing

There appears to be little difference in early vs. late cell therapy administration after STEMI, with neither strategy achieving much benefit. For the TIME trial, Jay H. Traverse, MD, of the Minneapolis Heart Institute (Minneapolis, MN), and colleagues gave autologous bone marrow stem cells (150 x 106 cells) or placebo via intracoronary infusion to 120 patients with a first anterior MI treated by primary PCI with stenting. The patients were divided into 2 groups, each of which received therapy either 3 or 7 days after MI.

Six-month results were initially presented November 6, 2012, at the American Heart Association Scientific Sessions, showing that the timing of treatment had no effect on regional LV functional recovery, with major adverse events being rare among all treatment groups.

At 1 year, significant increases in LVEF and decreases in infarct size and LV mass were observed in both treatment groups. Between day 3 and 1 year, there was a nonsignificant increase in LVEDVI (75-88 ml/m2) and LVESVI (41-46 ml/m2) in the bone marrow stem cell group that was similar in the placebo group. No deaths or major adverse events occurred between 6 months and 1 year in either group.

“The recovery of LV function following STEMI is not enhanced by [bone marrow stem cells] at any time-point,” Dr. Traverse said. “The improvement in global and regional function is nearly complete by 6 months.”


Sources:

  1. Stempien-Otero A. Mechanisms of bone marrow derived cell therapy in ischemic cardiomyopathy with left ventricular assist device (LVAD) bridge to transplant. Presented at: American Heart Association Scientific Sessions; November 18, 2013; Dallas, TX.
  2. Heldman AW, DiFede DL, Fishman JE, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: The TAC-HFT randomized trial. JAMA. 2013;Epub ahead of print.
  3. Ascheim DD. Intramyocardial injection of allogeneic mesenchymal precursor cells in left ventricular assist device patients. Presented at: American Heart Association Scientific Sessions; November 18, 2013; Dallas, TX.
  4. Traverse JH. The NHLBI TIME trial: One-year results. Presented at: American Heart Association Scientific Sessions; November 18, 2013; Dallas, TX.

Disclosures:

  • Drs. Stempien-Otero and Traverse report no relevant conflicts of interest.
  • Dr. Hare reports having ownership interest in Vestion.
  • Dr. Ascheim reports serving as a consultant to BackBeat Medical and Velomedix.

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