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OUSTON — 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.

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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.

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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.

UT Health Medical School
Machines isolate stem cells used in an experimental traumatic brain injury treatment. Michael Starghill Jr for STAT

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.”

UT Health Medical School
The trial is being led by Dr. Charles Cox (left) and Dr. Billy Gill. Michael Starghill Jr for STAT

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.”

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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?”

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  • My husband has brain damage due to a heart attack. He lost some oxygen/blood to his brain. Has shown very good inprovement but then he regressed, showing more progress again lately. Lives at home, needs lots of care, but understands and reacts a lot of the time, talks at times. His heart has healed and his health is good. Has stayed under doctor’s care. Does not have Alzheimer’s, has had a scan. On and off different medicines, none seemed to help. PT, OT and ST off and on, some kind of therapy ever since this happened. We have been told over and over “it will take time, we don’t know a lot about the brain”. Spends his time in a wheelchair, feeds his self, can stand with help. Let me know if there may be some new help……please

  • I lost my wife because of a traumatic brain injury last August. (On our 35th anniversary) We were lucky to have discovered, and subsequently repaired, three brain anurisims ten years earlier in October of 2007. I well understand the pain of seeing your loved one in a vegetative state and trying to make the best decisions. I think I understand double blind trials but if the patient is comatose, why give placebo? From the article; “(Some patients receive a sham injection as the placebo control.)”
    Unless you think they are having an out of body experience? I’ve heard all kinds of strange things happening, even from doctors, nurses, and especially stories from the O/R. I guess I’ll always be second guessing myself.

  • To add on the to the first post. They said that my son Gemiah went 15-20 minutes without oxygen while he was in the cath lab were they took him to place his pacemaker.

  • I have a son name Gemiah. He is 20 years of age. Suffers from an anoxic brain injury. On Sept.27 2017 my son faint at work but regain conscious quick as he approach the ground. He call for me to pic him up. As I was on my way to get him, the job called and said that the parametric were checking him out and said that they had to go to the emergency room. Heart rate and blood preasure was to low. I at the time said ok and ask for what hospital. I was like since he is an athlete his blood pressure and heart attends to run low. Got to the emergency room and met up with my son who was looking fine to me. He was in no pain, laughing and talking on the phone. He did explain that he have been having shortness of breath and a headache for some days. An Ekg tech came out and explain that it showed that he might of had a small heart attack recently. I was like he had something a couple of days ago but I thought it was an anxiety attack. They gave him some medicine but his BP did not come up. Some they decided that they were going to place a temporary pacemake and put him in ICU for three days to see what was going on with the heart. I said by to my son who said by to me and wave. Later a doctor came to the waiting room and explain that one side of my son heart muscles were very weak and this critical. I made my way to the ICU waiting room only to be approach by another doctor a couple minutes later tell me my son heart stop and they have been doing everything they can do to get it back beating. Of course my heart was torn I ran out the waiting room. I return to the message that my son heart was beating slowly and the pacemaker was on, he would be moved to his room were they will do they hypothermia threarment to cool his body. That my son would need a heart transplant if he comes back alert and comprehensive. He came back with severe damage done to the brain. He was then sent to UT Southwestern Medical center of Dallas cardiology ICU. Were they were not happy with the pacemaker used and also the placement of the pacemaker which was placed in his groin ( private area). They remove the pacemaker and put one of theirs. Did a biopsy of the heart and found myocardist of the heart. Their pacemake lasted less then a day as they said the heart has healed it self. Currently my son is in a Ltac facility in a vegitated state with myclonic jerk and temor. Need 24 hr trache care. He breath room air, awaiting a nursing facility that will take him. Most can’t because of he age. They say he is considered pediatric and by state law require education. My son was in his second year of college majoring in computer science and minoring in religion. Work as a manager at the YMCA and love to play soccer. Very proactive in his siblings life and mines. He was my oldest and as a single parent you utilizes the oldest alot. He never complained. He help with their needs and school clothes. Please if their is any way that he can be place in one of the stem cell treatments it would mean the world to my family and I.

  • I’m writing you this for any type of help that you can give me please! On July 4th my 57 year old husband (Kevin) had a heart attack and coded 13 times….11 codes in 1 day! He was rushed to a cath lab upon this procedure both stents occluded which therefore followed a 22.30 anoxic brain injury. My husband was in the hospital for a hundred days got a feeding tube removed on December 19th, he’s in intensive PT, OT, speech therapies. As I was reading your article I know that they have to be in a coma ….i think i understood that…but what I am begging you if there’s any way on the stem cell research that I can get my husband there due to his occipital lobe which is damaged he has blindness , he also has short term memory loss he also has mobility issues …all four areas of the brain were affected. I’m reaching out … desperate… I am really thinking about going across the border for stem cell replacement because I do not know what else to do!!! Again if there’s anything you can do for my husband…please connect me with someone that can make this happen or possibly at least review my husband’s medical records and see if he’s a candidate… if not for this research then another research somewhere? I have been very blessed in my life l, this eonderful man is my high school and college sweetheart we’ve been married 34 years and he is a wonderful husband and father. He is 6′ 2 , 205 lb, non smoker, very active fishing, hunting, golfing, basketball, I can go on and on he was very physically fit… and now this very strong man can barely walk he’s a weak version of himself and no matter how much physical therapies …he has a lot of the areas in the brain which shows gray matter. I have all of the current EEG, MRIs, CT scan the last MRI was March 2018! We need some new stem cell research, We need a miracle please…. again if you could help me in any way…I would appreciate it with my whole heart! My # 405 206 2527…Thank you! Margaret Craft.

  • God bless this work, the patients and all involved! May this bring help and hope to the many suffering. Perhaps something will also be learned abt the affects on the lungs as well for the many of us affected.

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