POSEIDON: Allogeneic Stem Cells Are Safe in Chronic Ischemics

Reed Miller

November 05, 2012

LOS ANGELES — The POSEIDON trial results indicate that myocardial injections of allogeneic mesenchymal stem cells (MSC) are safe and may eventually be an "off-the-shelf" therapy for chronic ischemic MI [1].

"We come away from this [trial] with optimism and feel that we've helped to define the parameters around which cell therapy can and should be used for ischemic cardiomyopathy," lead investigator Dr Joshua Hare (University of Miami, FL) told heartwire . "Trying to address an unmet need, we've established important safety parameters around using these cells." Hare presented the trial results here today at the American Heart Association 2012 Scientific Sessions, which have also been simultaneously published online in the Journal of the American Medical Association.

"Mesenchymal stem cells [are] immunoprivileged and immunosuppressive, so as the field contemplated allogeneic therapy, it became obvious to consider mesenchymal stem cells the prototype," Hare explained. This is the first study to compare allogeneic mesenchymal cells from young healthy donors head-to-head with autologous cells from the patient. "The advantages of using a donor [is] that you can have the cells prepared in advance, so there's a convenience factor," he pointed out.

Assurance of safety and signal of benefit

POSEIDON twice randomized 31 patients with chronic ischemic left ventricular dysfunction secondary to MI. Patients' average ejection fraction was about 28%, although on average their most recent MI was 10 years ago. Patients were first randomized to three doses of MSC: 20 million, 100 million, or 200 million. Each dose group was then randomized to receive either autologous or allogeneic MSC.

At the 30-day postcatheterization follow-up, one patient in the autologous MSC group and one patient in the allogeneic MSC group were hospitalized for heart failure. At one year follow-up, there were no ventricular arrhythmias in the allogeneic MSC group and four in the autologous MSC group (p=0.10).

Importantly, the allogeneic MSC patients showed no significant alloimmune reaction, Hare stressed. "The big concern would be that, if the cells are not immunoprivileged, patients would develop antibodies against those cells. If that were to occur, then patients could reject the cells or, even if they didn't reject them, it could create a problem down the road for the patient if they wanted to have a heart transplant--or any kind of organ transplant--because you always worry about a patient who develops antibodies," he said. Only one patient in the study demonstrated an immunologic reaction, but it was a very weak reaction, so "the population, by-and-large, tolerated the donor cells very well," he said.

"We're very comfortable that the safety profile is the same between the two cell groups and also acceptable relative to prespecified criteria," Hare said.

Combined, both autologous and allogeneic MSC patients showed improvements in the average six-minute-walk duration at six and 12 months (p=0.009), but the improvement did not significantly differ between groups (p=0.87). There were no significant changes in peak VO2. Both the allogeneic and autologous MSC reduced mean early enhancement defect (infarct size shown by computed tomography) by about a third, but did not significantly improve LVEF.

Allogeneic, but not autologous, MSC patients showed a reduction in left-ventricular end-diastolic volume. End-systolic volume improved overall in the groups combined, but the difference was not significant in either group alone. Ventricular mass increased in all patients, suggesting myocardial regeneration.

The dose–response was inverse for ejection fraction, left ventricular end-diastolic volume, and early enhancement defect improvements, with a significantly greater effect with 20 million than 200 million cells.

In an accompanying editorial [2], Drs Eduardo Marban and Konstantinos Malliaras (Cedars-Sinai Heart Institute, Los Angeles, CA) write: "On balance, the results of POSEIDON are encouraging, particularly with regard to the safety of allogeneic MSC, but the small sample size, the open-label design, and the lack of a control group should prompt some caution regarding claims of efficacy."

The editorialists agree with Hare that the allogeneic cells offer practical advantages over autologous cells. "Allogeneic cells are highly attractive" because patients are spared the risks and discomfort of the cell-harvesting procedures. The source tissue can be selected and validated to maximize potency and safety and then turned into a readily available "off-the-shelf" product, they explained.

Hare's group has secured funding from the National Institutes of Health for the Autologous Cardioblasts for Reverse Remodeling in Ischemic Dilated Cardiomyopathy (AIRMID) trial of a mixture of MSC with cardiac stem cells. "We believe that will enhance the efficacy of the cell approach," he said.

Hare reports receiving research support from BioCardia and has modest ownership interests in Vestion.