In a bid to promote stem cell therapies, health officials open a new door for promising contenders

HOUSTON — When someone experiences a severe head injury, it’s not just the initial blow that batters the brain. The body’s immune response can go haywire, overwhelming and sometimes continuing to damage the brain for months.

Surgeons at Houston’s Memorial Hermann Hospital believe they might have a novel way to prevent that ongoing harm: by drawing bone marrow cells, including stem cells, from patients and infusing them back into their bodies.

The approach may sound unconventional — the cells aren’t even delivered directly to the site of the injury. But the Food and Drug Administration has granted a new designation to the clinical trial, one that signals that the agency sees as least some promise in the experimental treatment and that opens up the possibility of a speedier approval for the therapy, if it is shown to work.

At a time when there’s significant hype around stem cell therapies — and often not much clinical data — the idea behind such designations is to promote therapies in regenerative medicine that show the greatest potential. Since introducing the new pathway in November, the FDA has granted 18 products, including other cell- and tissue-based therapies, a so-called “regenerative medicine advanced therapy” (RMAT) designation.

“They want to speed up the ones that they see as good citizens,” Paul Knoepfler, a stem cell scientist at the University of California, Davis, said of the FDA.

In the stem cell field, there are plenty of bad citizens, including clinics that offer expensive, unproven, and, in some cases, dangerous interventions, regulators and experts say. So while warning of crackdowns on the worst of those actors, the agency has also been trying to foster clinical research that plays by the rules, in hopes of guiding new therapies to approval.

So far, for all the enthusiasm over stem cell therapies, there are only a few that have been validated — including bone marrow transplants to treat certain blood cancers — and those that have been around for years. Everything else remains experimental.

Definitive studies on “the safety and efficacy of such procedures … have been lacking,” as FDA Commissioner Scott Gottlieb and Dr. Peter Marks, the director of the FDA’s Center for Biologics Evaluation and Research, wrote in the New England Journal of Medicine last month.

“There’s a lot of preclinical work with a lot of potential. There are new stem cell types being defined. But it takes a long time,” said Sally Temple, the scientific director of the Neural Stem Cell Institute and past president of the International Society for Stem Cell Research. “We have to be reasonable in thinking about how long it takes.”

Here at Memorial Hermann, the therapy that has received an RMAT designation is aimed at the inflammation that accompanies a traumatic brain injury. When the injury occurs, immune cells called microglia flood the area. The problem is that the inflammation persists after the initial trauma, and the microglia continue to swarm, killing off more neurons and leading to a greater loss of brain matter over months, researchers say.

The cells being tested in the trial are intended to both promote anti-inflammatory reactions and tamp down the microglia, ideally halting the ongoing loss of brain volume soon after the injury occurs.

“We would rather that not be the way the brain responds,” said Dr. Billy Gill, a surgeon at the hospital and associate professor at McGovern Medical School at UT Health, Houston, who is helping run the clinical trials.

For their Phase 2 trials, the researchers have so far enrolled 14 of 55 patients for an adult trial, and 38 of 50 patients for a pediatric trial. (To be enrolled in the trial, patients have to have such severe injuries that they are comatose; family members provide consent for them.)

To deliver the therapy, clinicians draw a group of cells called bone marrow mononuclear cells from patients’ hips. The cells, which include types of stem cells, are then isolated and administered intravenously at a dose depending on the patients’ weight, either 6 million or 10 million cells per kilogram. (Some patients receive a sham injection as the placebo control.)

The cells don’t have to be delivered to the site of the injury, the researchers say, because when they accumulate in other organs, including the spleen and the lungs, they set off a cascade of anti-inflammatory responses that affect the brain and can still mitigate the activity of the microglia.

The researchers are upfront that, as with with any clinical trial, theirs faces a real likelihood of failure. To see if their therapy can minimize the loss of brain volume, they will scan and measure patients’ brains for several months after the injury.

“We think it’s mostly a numbers game,” said Dr. Charles Cox, a pediatric surgeon at Memorial Hermann and professor at the medical school. “We mechanically harvest [the cells] out of your bone marrow and then deliver them, and that large number of cells landing in the lung and spleen is what changes the signal transduction in terms of the immune response. What is it about these cells in particular? I think it’s a pure supercharging, augmenting the natural immune response with this number of cells showing up.”

The Department of Defense is funding the adult trial of the therapy, while the National Institutes of Health is paying for the pediatric trial. A company called Cellvation, which is a subsidiary of Fortress Biotech, has licensed the technology; Cox is a scientific founder of the company.

In order to obtain an RMAT designation, researchers or companies have to submit some “preliminary clinical evidence [that] indicates that the therapy addresses unmet medical needs,” as Gottlieb and Marks wrote last month in NEJM. The researchers in Houston, for example, had data from earlier trials.

But some experts have questioned whether the criteria the FDA has outlined for the RMAT designation is too vague and doesn’t set a high enough bar for “preliminary clinical evidence.” Phase 1 studies, for example, evaluate the safety of a therapy and are not meant to gauge efficacy.

“If we’re really going to push effective things ahead, then we should be basing our decisions on not just safety — there should be a rationale that distinguishes it,” Temple said. “We all feel this sense of urgency, and we want to get into the clinic and help patients. But if we push ahead too quickly without real rationale and efficacy data, we could end up with a lot of trials with a high failure rate, and we have limited resources.”

Leigh Turner, a bioethicist at the University of Minnesota, said: “Flexibility seems like a word that has positive associations, but is the bar not where it ought to be?”

Experts have also raised concerns that unregulated stem cell clinics might try to score RMATs. If they could claim they had this new designation from the FDA, would they then be seen as more credible?

So far, that hasn’t happened, and the FDA does seem to be scrutinizing applications with some rigor. While 18 RMAT designations have been granted, the agency has reviewed 49 applications. (It has received a total of 55 applications so far, said agency spokeswoman Tara Rabin.)

Knoepfler, the stem cell expert who has been tracking RMATs, said the FDA seems to be “blunter” about making distinctions between different types of sponsors.

“The big thing will be, in the long run, do any of these actually become a proven safe and effective therapy that we can say, because of RMAT, [they] got to patients three years faster?”