The faltering progress of cell therapies in cardiovascular disease has gained a little momentum. While so many experiments have failed to show efficacy, data disclosed at the American Heart Association scientific meetings this week reveal that researchers have a better idea of where stem cells might be able to benefit sick patients in need of regenerated cardiac tissue.
Researchers have focused on use of stem cells in advanced heart failure and peripheral arterial disease, two conditions in which patients have few options and could benefit from rejuvenated cells and tissue. The data were mixed, but they were encouraging enough to prompt discussion of advanced tests that will add to the body of evidence that is starting to build with a big European phase III trial in myocardial infarction.
Sicker patients benefit
The most hopeful news came from work in heart failure patients, a very sick group with few therapeutic options. In many cases, a left ventricular assist device (LVAD) is used to improve cardiac function until a transplant heart comes available.
Researchers from the University of Miami released data from the 65-patient phase I/II TACT-HFT trial, a test of mesenchymal stem cells and mononuclear bone marrow cells against placebo in patients with ischaemic cardiomyopathy. Both types of therapy, which were infused into 10 left ventricular sites, significantly improved quality of life scores as measured by the Minnesota living with heart failure scale, and the mesenchymal cells also significantly reduced the size of dead heart tissue, and improved patients’ performance on a six-minute walk test.
Joshua Hare, director of the university’s Interdisciplinary Stem Cell Institute (ISCI), said an analysis of the data showed a correlation between reduction in dead cardiovascular tissue and the improvements in the quality of life scale.
Commenting on the TACT-HFT results, Stefan Janssens, a cardiology professor at the University of Leuven in Belgium, said that although the improvements in quality of life and walk test were significant they did not achieve the 10-point and 50-metre increases that clinicians view as meaningful. Meanwhile, Dr Janssens called the correlation between the growth in cardiovascular tissue and improvements in walking distance “intriguing”, but cautioned that there could be other explanations.
“It could also be that the cells would have a significant change in peripheral vascular function and skeletal muscle function,” Dr Jannsens said. Measuring changes in maximum oxygen consumption would help clarify how the therapy improves function, he said.
Off target but still working?
Indeed, whether the cells are hitting their intended targets – whether cell therapies actually regenerate tissue directly or stimulate other biological pathways that result in new growth – is a question that has not been resolved from research so far.
“What seems to be happening is the cells get into the heart and secrete cytokines and other factors which we may have not yet clearly identified that then promote the endogenous repair mechanisms,” said Gerald Dorn, a professor at Washington University in St. Louis. “If this is true one wonders whether or not the cells are essential.”
Other work in heart failure was less conclusive. A study of Mesoblast’s mesenchymal cells in patients on LVAD – with the ultimate hope of being able to wean patients otherwise expected to use the devices permanently – showed glimmers of hope. At 90 days 50% of patients treated with the mesenchymal cells could tolerate a temporary wean, compared with 20% of control patients; at 12 months there was no statistical difference, with 30% of intervention patients and 40% of control patients able to tolerate a reduction in LVAD activity.
Still, with the early signs of efficacy the Mesoblast cells will no doubt still be considered a potential experimental treatment for heart failure.
Myocardial infarction still a big ask
Less promise has been shown for cell-based therapies as a treatment after myocardial infarction. The National Institutes of Health-sponsored Time study of bone-marrow-derived cells announced 12-month follow-up results that were no more promising than the six-month data released a year ago (AHA – Distant promise of stem cells draws nearer, November 8, 2012).
A newer approach is the use of colony stimulating factors, which induce proliferation of hemopoietic stem cells. A larger study of Januvia and a granulocyte colony stimulating factors (GCSF) in patients who have experienced a myocardial infarction failed to improve patients’ heart function. At 340 patients, this is the largest stem cell trial ever in the cardiovascular stem cell space.
However, a separate study of Sanofi’s granulocyte macrophage colony stimulating factor (GM-CSF) Leukine in patients with peripheral arterial disease and intermittent leg pains managed to improve patients’ ability to walk, but only when measured in a per-protocol analysis.
The fact that the largest trial so far has included just 340 patients – and that much of the research is confined to academia – has many welcoming a move towards larger studies. Thomas Povsic, an assistant professor at the Duke University cardiology division, said a meta analysis revealed that 50 trials in cardiovascular cell therapy have been undertaken, including 36 randomised controlled trials, but these had a median size of just 39 patients.
The European Society of Cardiology’s 3,000-patient BAMI trial launched last year will seek to settle the question of whether an infusion of bone marrow cells in myocardial infarction patients can reduce mortality when it reads out in 2016.
“This field has had a huge amount of replication of effort,” Dr Povsic said. “People have struggled with how best to design phase II studies that have multiple goals, including establishing mechanism of action, as well as looking for evidence of clinical efficacy.”