Cardiac Stem Cell Therapy Safe, May Regenerate Heart Tissue

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Patients who have experienced myocardial infarction (MI) can safely undergo treatment with autologous stem cells derived from endomyocardial biopsy, according to a proof-of-concept study published online February 13, 2012, ahead of print in the Lancet. But more strikingly, the researchers say, the therapy imparts “unprecedented increases” in viable myocardium that suggest regeneration is taking place.

For the 2-center CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial, Eduardo Marbán, MD, PhD, of the Cedars-Sinai Heart Institute (Los Angeles, CA), and colleagues enrolled 25 patients at 2 to 4 weeks post-MI. All had LVEF ranging from 25% to 45% (mean 39%); LV dysfunction was moderate but generally presymptomatic. Subjects were randomized in a 2:1 ratio to receive cardiosphere-derived cell treatment (n = 17) or standard care (n = 8). All underwent baseline magnetic resonance imaging (MRI).

Patients allocated to cell therapy underwent endomyocardial biopsy, which yielded an average starting tissue mass of 276 mg. At a mean of 65 days after MI, the tissue samples had been used to manufacture sufficient doses of cardiac stem cells for treatment (4 patients received 12.5 million cells, 1 received 17.3 million, and 12 received 25 million). Cells were infused through an over-the-wire angioplasty catheter, with the balloon inflated at the stented segment of the infarct-related artery.

Signs of Efficacy

No complications were reported within 24 hours of biopsy or cell infusion. Serious adverse events were observed in 5 patients (1 cell therapy and 1 control; P = 1.00) by 6 months and in 2 additional cell therapy patients by 12 months. Among them, only 1 was regarded as possibly related to treatment: a non-Q wave MI that occurred 7 months after a patient received 25 million stem cells. There were no deaths, cardiac tumors, or major adverse cardiac events (defined as the composite of death and hospital admission for heart failure or for nonfatal recurrent MI) at 6-month follow-up.

MRI analysis showed that patients who received stem cells had greater reduction in scar size (defined as scar mass normalized by total LV mass) than did controls at both 6 and 12 months (table 1).

Table 1. MRI Analysis: Changes in Scar Size from Baseline

Compared with controls, stem cell patients saw larger decreases in scar mass (P = 0.001), increases in viable heart mass (P = 0.01) and regional contractility (P = 0.02), and improvements in regional systolic wall thickening (P = 0.015) from baseline to 6 months. In particular, mean scar mass was reduced by 28% at 6 months and by 42% at 12 months in the cell therapy group.

Functional measures including end-diastolic volume, end-systolic volume, and LVEF did not differ between the 2 groups. However, patients treated with stem cells saw an 11.4-meter increase in 6-minute walk test at 6 months and a 33.0-meter increase at 12 months, while controls improved by 13.1 meters and declined by 9.6 meters at 6 and 12 months, respectively. Peak oxygen consumption increased by 2.6 mL/kg/min for the cell therapy group at 6 months but held steady in controls.

CADUCEUS vs. SCIPIO

In a telephone interview, coauthor Raj R. Makkar, MD, of Cedars-Sinai Heart Institute, explained that while CADUCEUS and another recent trial, SCIPIO (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy), both employ cardiac cells, their methodology differs. In SCIPIO, tissue specimens were obtained during CABG, while in CADUCEUS, biopsies were obtained using a catheter under local anesthesia.

“The procedure takes about 15 minutes,” Dr. Makkar told TCTMD. “The patients could literally go home within 2 to 3 hours.”

SCIPIO, published in the Lancet in November 2011, found that intracoronary infusion of autologous cardiac stem cells safely improves LV systolic function and reduces infarct size in patients with heart failure after MI.

In an editorial accompanying the CADUCEUS paper, Chung-Wah Siu, MD, and Hung-Fat Tse, MD, PhD, both of the University of Hong Kong (Hong Kong, China), also drew parallels between the 2 studies.

“In CADUCEUS, detailed assessment of cardiac structure by MRI provided striking evidence of cardiac regeneration after cardiosphere-derived cell therapy,” they write, adding, “Along with data from the SCIPIO trial, which used c-Kit-positive cells, results from CADUCEUS show that a different population of cardiac progenitor cells derived from adult human heart (cardiosphere-derived cells) can reduce infarct scar in patients with recent myocardial infarction.

“Although direct comparisons cannot be made between the relative therapeutic efficacy of c-Kit-positive cells and cardiosphere-derived cells because of the differences in study design and patient populations,” they continue, “the magnitude of reduction in relative infarct size shown in the 2 trials is not dissimilar and seems to improve with increased follow-up.”

Manufacturing Sufficient Doses

Warren Sherman, MD, of Columbia University Medical Center (New York, NY), told TCTMD that CADUCEUS offers “important proof that cells can be generated from biopsies and [used] safely in an acute population.”

However, he stressed that the method could be hindered by the time required to generate sufficient cell doses.

“The ability to expand the total number of cells is not as high as other autologous preparations, at least the more common ones, and certainly can’t compare to [allogeneic] cells,” he noted, adding, “In this technique, since it started with such a small piece of tissue, the criticism has been and probably still will be that you just can’t scale up quickly enough, especially in the acute injury model where it’s believed, at least with other populations of cells, that sooner . . . is optimal.”

Dr. Makkar reported that the researchers are now exploring not only a phase II/III trial of the autologous cells but also the idea of an allogeneic alternative. “This [preparation] could truly be off the shelf,” he said. “It could eliminate some of the possibility of manufacturing and logistical failures, and could be a viable alternative to autologous [cardiosphere-derived cells].”

According to ClinicalTrials.gov, the company Capricor is sponsoring ALLSTAR, a phase II trial that will randomly assign patients within 12 weeks of MI to receive allogeneic cardiosphere-derived cells or placebo.

Even in its current form, Dr. Sherman said, the therapy could prove useful to a substantial patient population, namely, “People who get their PCIs and then 2 or 4 weeks later start showing signs of [trouble].”

 

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Sources:
1. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): A prospective, randomised phase 1 trial. Lancet. 2012;Epub ahead of print.

2. Siu C-W, Tse H-F. Cardiac regeneration: Messages from CADUCEUS [comment]. Lancet. 2012;Epub ahead of print.

 

 

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