A few months after the American Chemical Society won its lawsuit against the pirate site, the game of virtual whack-a-mole continues.
As researchers conduct the most rigorous human trials of cardiac cell therapies yet attempted, a clear picture of whether these treatments actually work is imminent.
May 1, 2015|
© DAN SAELINGER/CORBIS
For the better part of an hour, the catheterization lab at Cedars-Sinai Medical Center in Beverly Hills bustles like a restaurant kitchen on a Friday night. Nurses pivot carefully around a table laden with sterile instruments while a trio of physicians fusses over a catheter inserted into the groin of cardiac patient Ken Anderson. On a large screen next to his bed, the video feed from a tiny camera at the tip of the catheter shows the tube passing through Anderson’s vasculature into a coronary artery. Amidst the hubbub, only the patient is still, occasionally answering questions from a nurse about his level of comfort.
All at once, everything stops. The nurses stand still; the doctors stop chatting; all eyes turn to the image of Anderson’s beating heart.
Michelle Domingo, the study coordinator for the experimental cell therapy Anderson is about to receive, counts down from five, then shouts: “Inject!” For the next five minutes a doctor very, very slowly presses the plunger on a syringe hooked up to the catheter, sending 10 mL of solution and millions of stem cells into Anderson’s heart.
The cells, called cardiosphere-derived cells, originated from an organ donor whose heart was not suitable for transplant. Anderson, who had refused a heart transplant, flew to Los Angeles from Missouri to take part in this experimental treatment, hoping it would help his damaged heart become more effective at pumping blood. “I’m an old guy,” says the 69-year-old, speaking a few weeks later from his office at the surgical supply company he continues to run, despite his impaired cardiac function. “There are people in their thirties and forties who need hearts. . . . Why should they put a heart in me?”
Some anticipate that the results of ongoing Phase 3 trials will finally provide definitive evidence supporting the efficacy of cell therapies for the heart. On the other hand, negative results could spell the end of the approach altogether.
Anderson is one of thousands of patients who have had cells injected into their hearts over the past 10 years. (See “Trial of the Heart,” The Scientist, October 2006.) Like any new branch of medicine, cardiac cell therapy has progressed in fits and starts. Despite dozens of clinical trials, there’s no slam-dunk treatment for improving the cardiac function of heart failure patients, but marginal, statistically significant improvements observed in some of the studies are propelling the cell-based therapies to ever larger, more expensive, and more rigorous trials. Most cardiologists remain underimpressed, says Anthony Mathur, the director of cardiology at Barts Health NHS Trust and the head of an ongoing Phase 3 trial in Europe that involves injecting bone marrow cells into heart attack patients. “If [the trial] is positive, that’s great, but I still think we’ll have quite a challenge to convince people,” he says. “If it’s negative, then you get most of the cardiac community saying, ‘Yep, we expected that.’?”
Now, it’s make or break. Some anticipate that the results of Mathur’s trial and two other ongoing Phase 3s will finally provide definitive evidence supporting the efficacy of cell therapies for the heart—evidence that has so far been lacking. On the other hand, negative results could spell the end of the approach altogether. “If our Phase 3 doesn’t work, I think there’s little likelihood any program could succeed in this indication,” says Christian Homsy, the CEO of Cardio3 Biosciences, a Belgium-based firm sponsoring a clinical trial involving bone marrow–derived cells. “In the event they don’t work [this time], I think it will be the end.”
The cardiac-derived progenitor cells Anderson received are in the earliest phases of human testing. But the cells used in the therapies that are now moving into Phase 3 trials all originate in the bone marrow, and include mesenchymal stem cells as well as other cell types. (See illustration.) The idea to pluck cells from a person’s bone marrow and shoot them into the heart took root in 2001, when Piero Anversa’s group, then at New York Medical College, showed that doing so in mice could help regenerate damaged heart tissue.1 Within just a few months, patients in Germany were undergoing the procedure. “It was an example of very, very rapid translation of something that was an animal finding into clinical trials,” says Jalees Rehman, a regeneration researcher at the University of Illinois at Chicago College of Medicine.
Yet no one knew how the cells worked. At the time, the prevailing thought was that stem cells took up residence in the heart and proliferated to produce new tissue. But this idea has since become a matter of debate. While some researchers claim the cells can form new cardiac muscle, others assert that the cells only very rarely differentiate into cardiomyocytes and instead support cardiac regeneration by other means. Some studies have found, for example, that “any trace of the cells is gone after four weeks,” says Eduardo Marbán, the lead scientist at Cedars-Sinai who developed the heart-derived cell therapy that Anderson received. “We had to consider the possibility that the cells were not acting in the way we thought they were.”
Many scientists now believe that the introduced cells perform a paracrine function, signaling the activation of reparative pathways via growth factors or other secreted messengers. On its own, the heart regenerates about one percent of its tissue per year via the division of cardiomyocytes; perhaps cell therapies simply boost that normal behavior. “The mechanism is still unclear,” says cardiologist Roberto Bolli of the University of Louisville.
The absence of a concrete mechanism of action has been one of the main criticisms of the field. “I would like to be sure I understand the mechanism before I jump ahead to big trials,” says Rehman. “Just because it works is not good enough.”
We have more trials than we have meaningful basic science papers.—Richard Lee,
Harvard Medical School
On the other hand, most patients don’t care how a treatment works, just that it does. And with no cure for heart damage yet available, patients like Anderson are willing to try experimental treatments. “We have more trials than we have meaningful basic science papers,” says Richard Lee, a regenerative medicine researcher and cardiologist at Harvard Medical School. “You’d like it to be the other way round. But I understand why there was an explosion [of clinical trials]—because there is such a need.”
And many researchers disagree that a known mechanism is required for advancing the therapy. “Nothing moves a field forward like actual clinical trials,” says Joshua Hare, a University of Miami cardiologist who has conducted human studies using mesenchymal stem cells. While mechanisms are important—knowing them can help optimize treatments, for instance—“you can’t slow things down because the mechanism of action isn’t agreed upon by everybody.”
The three ongoing Phase 3 trials involve cells extracted from bone marrow—each treatment comprising its own particular cellular concoction. In the “BAMI” study, currently recruiting subjects in Europe, patients who have suffered a heart attack will receive an autologous mixture of various bone marrow cells, called mononuclear cells. Congestive heart failure patients enrolling in the congestive heart failure cardiopoietic regenerative therapy (CHART)-1 study in Europe and Israel will receive mesenchymal stem cells derived from their bone marrow. And in another congestive heart failure study in the U.S. and Canada, patients will receive mesenchymal precursor cells derived from the bone marrow of donors. These studies are the most scientifically rigorous human experiments to date in the field of cardiac cell therapy.
The BAMI trial is the simplest of the three, with mononuclear cells extracted from the bone marrow delivered directly into the heart with no manipulation. Investigators will measure whether patients randomly assigned to receive the cell therapy have a reduced chance of dying over the next two years than patients receiving a placebo. “We have a high bar” for judging success, says Mathur, one that’s designed to put an end to questions about whether or not the therapy works.
One of the criticisms of the BAMI approach is that the cellular mixture administered to patients contains very few stem cells and a slew of other cell types, including lymphocytes and monocytes. In the CHART-1 trial, based on the work of Andre Terzic at the Mayo Clinic in Rochester, Minnesota, mesenchymal stem cells are isolated from the patient’s bone marrow cell mixture, then bathed in a cocktail of growth factors and cytokines to “preemptively upgrade the regenerative capacity” of the cells, says Terzic. The final batch of cells that are administered back into the patients “express certain markers of cardiac differentiation,” says Homsy of Cardio3 Biosciences. The trial will track several outcomes, including exercise capacity and subsequent heart events, in addition to survival.
© LAURIE O'KEEFEThe third trial, sponsored by Teva Pharmaceutical Industries, also involves selecting a subset of cells from the bone marrow: mesenchymal precursor cells, called CEP-41750 cells, which are thought to aid in tissue repair and stimulate blood vessel growth. In this trial, the researchers are using cells collected from donated bone marrow, rather than from the patients themselves, paving the way to creating an off-the-shelf product.
Results from each of these trials are expected in the next one to two years. In the meantime, researchers are concocting even more refined versions of cardiac cell therapies, including the cells Anderson received, which are derived from donor hearts. Having yielded positive results in animal models and early-stage human trials, so-called “second-generation” cell therapies, employing other cardiac progenitor cells or select bone marrow cells, could replenish the field with fresh cell therapy approaches even if current Phase 3 studies fail. (See “Waiting in the Wings.”) But which cell type or combination of cells will prove the most effective in treating heart damage remains to be seen. “I’ve gotten away from the notion there’s an optimal cell type. We believe we can enhance the [regenerative] effect through cell mixtures,” says Hare, who is launching a clinical trial to test a therapy that comprises both mesenchymal stem cells and cells taken from the heart.
While early-stage research continues to hammer out which type of cell is optimal for repairing heart damage, a bigger question faces the field: Do cardiac cell therapies even work? Studies have found a range of results, from no benefit to substantial therapeutic effects, and research in the field has been plagued by a couple of high-profile scandals surrounding studies that made the biggest claims about heart regeneration. Chief among them has been the work of Bodo-Eckehard Strauer, a now-retired cardiologist from the University Hospital of Düsseldorf in Germany.
In 2001, just four months after Anversa’s group published its success with administering bone marrow-derived cells to mice with damaged hearts, Strauer and his colleagues were the first to try the method on a human patient who had recently suffered a heart attack. Within a few months, they claimed, the patient’s heart damage was reduced and his cardiac function improved. For a number of subsequent trials, Strauer continued to report positive results, but the claims were questioned by researchers who noted problems with data reporting, and upon investigating Strauer’s work, the University of Düsseldorf concluded that there was evidence of scientific misconduct. Although none of Strauer’s studies have been retracted, the field has largely turned its back on his work. Authors of recent meta-analyses of cardiac cell therapies, for instance, have opted not to include Strauer’s reports.
More recently, the work of Anversa, now at Harvard, has come under scrutiny. Beginning last year, his lab has been the subject of an institutional investigation into potential scientific misconduct. One of his papers, describing the regenerative capacity of the human heart, has been retracted,2 while another has received an Expression of Concern from journal editors at The Lancet, where it was published in 2011.3
The Lancet study included the positive results of a Phase 1 clinical trial called SCIPIO that delivered heart-derived cells known as c-kit+ cardiac stem cells to patients with ischemic heart failure. The editors expressed concern regarding two supplemental figures, which Bolli—who ran the clinical trial at the University of Louisville’s School of Medicine—claims had nothing to do with the reported improvements in patient outcomes. According to Bolli, Anversa’s team prepared the cells for delivery into patients and sent them to Bolli for the infusions. “There was a clear division of labor,” he says, and the supplemental figures in question have to do with the cell characterization, not patient outcomes. (Anversa declined to comment.)
It has been a very long journey of one disappointment after another, where the clinical trial results have been less than overwhelmingly positive.—Linda Marbán,
The future of clinical trials on c-kit+ cells is unclear, with no immediate plans to start a Phase 2 study, Bolli says. In addition to the concern surrounding the Phase 1 trial, c-kit+ cells are at the center of the debate over the mechanism of action of cardiac cell therapies. While Anversa has published work that he claims illustrates these cells’ ability to generate substantial amounts of new cardiac muscle, a number of researchers have produced evidence disputing this.
Bolli says it will be unfortunate if the controversy over c-kit+ cells spells their demise, because he believes the treatment is promising. He says the scandals in the field have given cardiac cell therapy a bad rap. “One or two bad apples make the whole field look bad,” he says. “The best answer . . . is to look at the totality of the data.”
But even studies that haven’t drawn accusations of outright misconduct are riddled with problems, according to a recent review by Darrel Francis, a cardiology professor at the National Heart and Lung Institute at Imperial College London. Combing through 49 clinical trials of cardiac cell therapies, Francis and his colleagues exposed some 600 inconsistencies and reporting errors, including conflicts between figures and raw data, and impossible time lines—such as dead patients continuing to produce clinical data.4 Later, Francis’s team published a detailed list of problems with the report on Terzic’s clinical trial of a mesenchymal stem cell therapy, resulting in multiple corrections.
Interestingly, the number of discrepancies Francis found in a clinical trial correlated with the reported benefit of the treatment: those that showed the greatest effect of the cells had the most problems, while the trials with the best reporting found little therapeutic benefit. Francis says that poring over the cardiac cell therapy studies has soured him on the approach, and he expects that none of the therapies currently being studied will pan out.
Several other meta-analyses have also yielded cautionary results. A study published by Marbán and colleagues this year, for example, examined the results of 12 trials (not including Strauer’s) that injected cells—mostly extracted from the bone marrow, with one study infusing cardiosphere-derived cells—into the hearts of patients following heart attack, finding no overall benefit.5 But another meta-analysis of 31 clinical trials, from Mathur and colleagues, found a lower risk of dying or returning to the hospital for heart problems among heart-failure patients who received a bone marrow-derived cell treatment.6 Mathur and his coauthors point out, however, that the studies they analyzed carry a high risk of bias—some were not blinded, for instance, and others didn’t fully report patient outcomes.
Despite the concerns, many researchers believe it’s important to continue with the Phase 3 studies, which may be the only way to get a solid answer out of a muddy mess of data. “I think BAMI will either be the end of bone marrow trials or the vindication of bone marrow trials,” says Marbán. Even Francis, perhaps the most skeptical among cardiac cell therapy critics, agrees there’s a learning opportunity to be had from the efficacy studies. “Maybe these carefully conducted Phase 3 trials will be positive, which will be excellent news for patients and a surprise to me. But if they are negative, then I think we are failing as a clinical scientific community if we do not thoroughly explore how it is that we got our entire clinical research field into this colossally expensive dead end.”
WAITING IN THE WINGS
“It has been a very long journey of one disappointment after another . . . where the [clinical trial] results have been less than overwhelmingly positive,” says Linda Marbán, Capricor CEO and wife of Cedars-Sinai’s Eduardo Marbán. The reasons, she says, are that “the trials were not well powered, the endpoints were not well adjudicated, and . . . those particular cells may not be the right cells.”
While researchers test the efficacy of bone marrow–derived cells in ongoing Phase 3 studies, waiting in the wings are alternative approaches that have shown promise in preclinical models or early-stage human testing. The cardiosphere-derived cells that Linda Marbán’s team is studying, for example, are shed by cardiac tissue when a sample is put in culture (the cells form spherical clusters, hence the name). When infused into 17 heart attack patients in a Phase 1 study, the cells caused a reduction in scarring and regrowth of heart muscle. “Conceptually, it put the wind in our sails,” says Eduardo Marbán. Although the treatment did not improve patients’ cardiac function, Capricor is moving ahead with two other cell therapy trials, both using allogeneic cardiosphere-derived cells.
Another cell type derived from cardiac tissue, known as c-kit+ cells, has also shown promise in an early-stage trial. Like cardiosphere-derived cells, c-kit+ cells exhibit regenerative power when administered to the hearts of laboratory animals. And even further along in human studies are CD34+ endothelial progenitor cells isolated from bone marrow. Researchers showed that these stem cells can reduce chest pain and increase patients’ exercise capacity, and a Phase 3 study is planned.
Preclinically, other cell types are stirring up excitement. Charles Murry’s lab at the University of Washington, for instance, made a splash last year after using human embryonic stem cells to successfully regenerate cardiac tissue in the damaged hearts of monkeys (Nature, 510:273-77, 2014). In this case, no one disputes the regenerative capacity of embryonic stem cells, but some have cautioned that their safety has not yet been sufficiently vetted to try them out in humans. Jalees Rehman at the University of Illinois at Chicago says cell therapy patches lined with regenerative cells such as induced pluripotent stem cells or embryonic stem cells are another possible route to cardiac regeneration.
If it turns out that the cells in clinical development aren’t differentiating into new heart tissue, but instead are providing the support needed for existing cardiac cells to ramp up repair—as many now believe—there is the possibility that acellular approaches could effect regrowth and repair, without dragging along unnecessary cellular baggage. To this end, Eduardo Marbán is testing out the utility of exosomes—little membrane-bound bubbles filled with proteins and RNA—in the lab. Other teams are looking to introduce growth factors, cytokines, or genes to induce the heart to fix itself.
“As the field evolves, maybe we will not need the cell itself,” says Andre Terzic of the Mayo Clinic. “That would be the ultimate product.”
Correction: In the original version of this article we stated that BAMI is a double-blind study. It is actually an open label clinical trial. The Scientist regrets the error.
May 9, 2015
The last time I checked, Cedars-SInai Medical Center was located in Los Angeles, not Beverly Hills.