In the ongoing, taxpayer-funded trial, cardiac stem cells are injected into the hearts of people with heart failure, in the hopes that those cells — alone or in combination with others — will improve patients’ heart function.
The regenerative effects of those cells were first reported by an influential but controversial scientist, Piero Anversa, whose work has been thrown into doubt. Harvard disclosed a years-long investigation had identified “falsified and/or fabricated data” in 31 papers from his laboratory, without specifying which publications were affected. Last year, the Harvard-affiliated Brigham and Women’s Hospital, where Anversa worked until 2015, reached a $10 million settlement with the Justice Department to resolve allegations that fraudulent data had been used by Anversa’s laboratory in grant applications for federal funding.
On Wednesday, the New England Journal of Medicine retracted one paper and flagged two others with an “expression of concern” intended “to indicate that the data presented in the articles named above may not be reliable.” The journal said it is waiting for more information on the two papers.
New York Medical College, where Anversa previously worked, released a statement saying that “serious concerns” have been raised about a 17-year-old study. It said an investigation has been initiated.
Anversa is not directly involved in the heart failure trial, which is being run by a national clinical trial network supported by $63 million in federal funds. But given the turmoil and uncertainty over the work that helped lay the foundation of the trial, outside researchers called for a pause and careful examination of whether it should proceed. The trial carries inherent risks, because it requires an invasive biopsy that can cause serious complications.
One patient died after their heart was perforated during a biopsy.
“I think that the trial should be halted, and they should have an external review,” said Darryl Davis, a cardiologist at the University of Ottawa Heart Institute studying how to regenerate heart tissue. “The Anversa data comprised part of the rationale for that trial, and I think we have to understand better what these cells actually can do before we subject the patients to the risk of having an invasive procedure.”
Anversa’s laboratory did the foundational work in this field and provided cells for a previous clinical trial that is cited as part of the supporting evidence for the current trial. However, the National Heart, Lung and Blood Institute does not consider the trial to be based on Anversa’s work, according to Denis Buxton, director of the Basic and Early Translational Research program at the institute. Buxton said that the trial is instead based on an idea that grew out of Anversa’s original work — that the cells secrete various molecules that help regenerate muscle tissue, although he said it was “not a well-characterized effect at the moment.”
“Multiple preclinical studies have demonstrated improvement in cardiac function, and advanced heart failure patients really have no treatment options and have poor survival,” Buxton said. There is “compelling need for new therapies that can improve quality of life in these patients. I think the feeling is this trial has the potential to provide such an option.”
He said that a b oard that monitors patient safety in clinical trials would now be tasked with evaluating the information related to the 31 retractions requested by Harvard, and that patients would be informed of the board’s recommendations.
Anversa’s lawyer said his client stands by the scientific findings in his papers and that Anversa only learned from the Harvard investigation that a longtime colleague who left his lab in 2013 had improperly altered images. Anversa says that, in many cases, those images can be replaced with correct images, and the results will still stand, his lawyer said.
“There is nothing wrong with c-kit positive cardiac stem cells, and the trial will answer the questions concerning their efficacy in patients,” Anversa said in an email.
Anversa’s work rose to prominence amid broad enthusiasm about stem cells in the early 2000s. Anversa and colleagues found a type of heart cells called c-kit cells were capable of giving rise to heart muscle, opening up new possibilities for helping heal patients after heart attacks or for reversing heart failure.
The discovery quickly led to clinical trials. The current trial, called CONCERT-HF is based in part on an earlier clinical trial in which Anversa’s lab created c-kit cells to be infused into patients’ hearts. The report of results from that trial is now overshadowed by questions about the integrity of images of the stem cells that were created and characterized in Anvers’s laboratory in Boston and then shipped to Louisville, where they were put into patients.
Roberto Bolli, the University of Louisville cardiologist who led the trial, told The Washington Post that the work his team did had nothing to do with the cell manufacturing in Boston. He said he doesn’t yet have enough information about the problems in Anversa’s lab to know whether they affected the cells provided to patients.
“This is obviously a major concern, and we are trying to clarify this important issue,” Bolli said.
The National Heart, Lung and Blood Institute said CONCERT was based not on Anversa’s explanation for how c-kit cells work but on an alternative mechanism that gained traction as other researchers, who were not affiliated with Anversa’s lab, found the cells were not turning into heart muscle, and instead were dying or fusing with other cells. To explain the effects the cells had on heart function in animal studies, some researchers now say the c-kit cells themselves don’t regenerate, but secrete various substances, exerting what are called “paracrine effects.”
Anversa told the Post that the CONCERT trial is based on his work and said in a phone interview, “I’m not sure I really understand why the trial should be stopped.”
In the CONCERT trial, cells are harvested from the heart and bone marrow of patients. Two types of stem cells are manufactured from those cells and then injected back into the patients’ bodies — with patients randomly assigned to four different groups that either receive c-kit cells, bone marrow-derived cells, both types or a placebo. The patient death occurred after a biopsy of the person’s heart cells and before the stem cells were implanted.
“I do think it’s time to pause and evaluate things like the CONCERT trial,” said Deepak Srivastava, president of the Gladstone Institutes and president-elect of the International Society for Stem Cell Research. “And if there’s not a foundation for that, I think in most fields, most such trials would be halted.”
Elizabeth McNally, a cardiologist and director of the Center for Genetic Medicine at Northwestern University’s Feinberg School of Medicine, said that, years ago, she was excited by the findings from Anversa’s lab, but then had trouble replicating them herself. She described a “religious fervor” that took hold among those who believed that c-kit cells were regenerating the heart that has continued as researchers have sought to find factors that could be responsible for what she described as “tiny to nonexistent” effects.
“It’s disappointing that it took so many years for this to come out,” McNally said. “It’s one question whether the trial should even continue, and I think at the highest level the individuals supporting the trial should really review that.”
Charles Murry, director of the Institute for Stem Cell and Regenerative Medicine at the University of Washington expressed concern about the safety of the patients in the trial.
“Given that the scientific premise of this trial is no longer valid, there do not seem to be potential benefits that justify the risk,” Murry said. “If I were leading this trial, I think I would stop it based on these recent developments.”