Two New Studies Report Cell Therapy Success

Posted by Sam Maddox in Research News on May 12, 2016

Two papers were published in the medical literature within the last few weeks. Both report positive effects of cellular transplants in human trials for chronic spinal cord injury. Missed the fanfare? Don’t expect much. One paper is from a questionable source; the other fleshes out trial detail presented several years ago, but might be headed somewhere if cause and effect can be sorted out.

The first one comes from Geeta Schroff, a physician/experimenter trained as an Ob/Gyn who runs a lucrative stem cell tourism clinic, Nutech Mediworld, in India. She’s been disparaged for the last 10 or 15 years for making all sorts of claims about how well her embryonic stem cell treatments work for every sort of malady, but she never followed her patients and never published any results. In the last few months, Schroff has cranked out several papers about her single line of proprietary embryonic stem cells to treat SCI, Crohn’s disease, cerebral palsy, muscular dystrophy, emphysema, and Lyme disease.

Schroff apparently didn’t take many notes during her stem cell tourism heyday; she didn’t have to. Now though, there’s more regulation and more scrutiny. I’m hoping people are actually paying attention to such get-the-facts sites as http://www.closerlookatstemcells.org. For Schroff, having her work published in a peer-reviewed journal may appear to legitimize her. It does not.

The second paper is from a group led by Wise Young, a widely known U.S. physician/neuroscientist based at Rutgers in New Jersey who developed a clinical trial group in China, ChinaSCINet. His paper is based on umbilical cord blood stem cell transplant experiments at two centers, in Hong Kong and Kunming; the results – 75 percent of patients including some with ASIA A (complete) injuries, were able to ‘walk’ – have been so widely discussed that there is little to report that was not revealed over the years by Young, speaking to visitors to his Spinal Cord Injury Project at Rutgers, on archived internet discussions curated by Young at Care/Cure, and from press releases from ChinaSCINet.

Young was aware of the risk of sharing results ahead of publication, per these 2012 remarks:

Most clinical trials do not release data until the trials have ended. As a service to the community, we are releasing interim analyses of data when they become available. ... In general, it is all right to present unpublished results at scientific meetings for discussion but it is not acceptable to present detailed data or analyses on internet. Some journals may consider this to be prepublication. So, we have to be careful.

Young submitted the paper several times before it was picked up, which of course is not unusual in scientific publishing. He was turned down by the New England Journal of Medicine, and Nature – top tier journals which sent the manuscript back without comment. It went to a couple of other publishers before being accepted by an open access journal, Cell Transplantation.

In 2014 Young told an interviewer for the Dana Foundation he was somewhat conflicted about merchandising his research.

One of the most difficult parts of what we do as scientists is getting into the business of selling ourselves and selling our science to the public. We need to be very careful about the distinction between hope and hype. When I was starting in this field in the 1980s, we were the very first to hold a press conference on the result of a clinical trial, and neurosurgeons were really miffed at the thought that they had to read about a scientific discovery in the Wall Street Journal as opposed to a scientific journal. In 25 years, the field has completely reversed its attitudes. You find that a huge number of studies are “press released” immediately upon publication by public relations people who are paid to hype a story because it means money or donations to a university.

Press-releasing trial data, it seems, is more than raising money to pay the bills. This, from Young, Care/Cure, 2010:

Yes, positive results will help raise money. Success is the most powerful of incentives. Everybody loves winners. Once we have had our first success, funding for more clinical trials will be easier to get. ... I am under constant pressure to show "positive" results not only to potential donors, supporters, and spectators but also to doctors, nurses, and subjects who are working their hearts out in these trials.... They all need incentives.

Geeta

In the early days of stem cell tourism, Schroff saw plenty of incentives in Young’s large and international cure community. Enthusiastic patient testimonials made their way to the Care/Cure message boards, luring customers to India from the U.S. and abroad, at $30k per visit. Without C/C we may never have heard about Nutech Mediworld; clearly some in the community made the trek to New Delhi, three or four times, and described their experiences.

Young’s early response to rogue stem cell therapies leaned toward a free market approach. People, he said, are going to do what they’re going to do. They are eager for treatments and won’t listen to facts. “Some people may call it desperation but I call it being very tired of spinal cord injury and needing to do something about it,” he said. “Over time, the spinal cord injury overcomes the patience of the most saintly and rational person.” Young later cautioned more forcefully about unregulated stem cell clinics. In 2008, Tim Gilmer, editor of New Mobility, asked Young directly about Schroff.

She’s also a scam. She has no background in stem cells, has never done anything in stem cells, never published anything in stem cells, and all of a sudden she comes out with something that she claims are human embryonic stem cells. They’ve not allowed anyone to look at these things, they’ve provided no evidence that these are human embryonic stem cells. And what is also not being published is there are multiple lawsuits against her by people who claim that she has done nothing, and there are a number of investigations. Geeta Shroff herself would take patients and tell them that she’s going to cure them — even before she sees them and examines them.

The Schroff paper

Human Embryonic Stem Cell Therapy in Chronic Spinal Cord Injury: A Retrospective Study was published this month in Clinical and Translational Science. This paper looks at 216 patient records from stem cell treatment in New Delhi between May 2005 to August 2012. (I can’t help it, I did the math. If each patient went for three treatments, that’s a net of $19.4 million.)

Results from each treatment (T) sequence:

At the end of T1, 45 percent of the patients improved by at least one ASIA grade. At the end of T2, 58 percent of the patients improved by at least one ASIA grade, and at the end of T3, 70 percent of the patients improved by at least one ASIA grade.

What that means is that better than two-thirds of her patients showed better motor or sensory scores after three regimen of embryonic stem cells. Looking at the data, it appears that 57 patients (37 percent) who were ASIA A (complete motor and sensory injuries) improved to ASIA C (some motor, some sensory).

Study design. Three treatment phases of eight weeks duration for paras and 12 weeks for quads, separated by four-to-eight month gaps “so that the hESCs [human embryonic stem cells] could grow, repair, and regenerate the affected part.” The first dose was 4 million cells given as a shot twice daily, via intramuscular injection. This, says the paper, is to “prime” the body so it won’t reject the stem cells. Each patient also got an IV injection of 16 million cells every 10 days, this so the cells could “home in” to the required area. T2 and T3 were the same dosage.

There is no evidence cited that Schroff’s embryonic stem cell line primes, homes in, or even survives, when injected to muscle or into the bloodstream of her patients. There was no immunosuppression. All patients got physical therapy.

The ChinaSCINet paper

Bottom line first: There was a good amount of recovery reported in patients with long-term spinal cord injuries after treatment with umbilical cord cells, lithium and intensive physical therapy. Safety was not an issue. More clinical trials are necessary to know what’s working and what’s not.

The title of the paper is “Phase I-II Clinical Trial Assessing Safety and Efficacy of Umbilical Cord Blood Mononuclear Cell Transplant Therapy of Chronic Complete Spinal Cord Injury.” Six million or two million umbilical cord blood (UCB) mononuclear cell transplants were given to a total of 28 patients. Some also got the drug lithium, believed to encourage stem cells survival. Most got a large dose of the steroid methylprednisolone. Each got surgery to de-tether their spinal cords, and most got very intensive physical therapy, six hours a day, six days a week, for six weeks; if the person was improving, he or she got even more PT.

In Hong Kong, none of eight patients got locomotor training (here they mean ambulation with a walker, not treadmill training). A functional measure of self-care, bathing dressing, respiration, transfers and mobility called Spinal Cord Independence Measure (SCIM), did not change significantly for this group. Those in Kunming who got the heavy PT, though, showed significant improvement in SCIM, especially in bladder, bowel, and toilet subscores. (Note: SCIM scores “toilet” in this way: zero points for needing total assistance with toileting, 1 point for needing partial assistance, does not clean self, 2 points for partial assistance, cleans self, 4 points for being independent but requires adaptive device, 5 points for being independent without adaptive devices.)

At the onset of the trial, two participants were independent for bladder and bowel care but 12 (60 percent) became independent by 41 weeks. Fifty percent were catheter-free at week 41, and 60 percent did not require assistance for bowel management.

Patients were monitored using diffusion tensor imaging and MRI. All had “white matter” gaps at the injury site; two patients, at six to 18 months post injections, had “progressive fiber growth crossing the gap” and narrower gaps. This suggests growth or perhaps replacement of nerve tissue, or white matter.

Walk this way, from the paper:

Walking recovery is rare in patients with chronic complete SCI. The finding that 15 of 20 participants (75 percent) with chronic complete SCI could walk 10m and seven (35 percent) walked 10m without manual assistance a year after treatment is unprecedented.

Seven walked with a rolling walker “without assistance,” six needed an assistant, and the other two used parallel bars. There was no reported voluntary motor function. How then is walking possible? Young et al suggest the cord cells, or perhaps the intensive training, fired up latent circuits in the spinal cord, the so-called pattern generators that activate programmed functions. The patterns for walking, bladder, and bowel activity are in the cord itself.

Of course, there are important questions ahead. Maybe the cells aren’t needed, just the heavy PT. From the paper:

Our trials left several critical questions unanswered. First, can intensive locomotor training alone improve locomotor function in people with chronic complete SCI?

Second, does untethering surgery improve the effects of intensive locomotor training? In our trials, all patients that received transplants also received untethering surgery.

Third, does lithium improve locomotor recovery when combined with UCBMNC and intensive locomotor training? We have previously observed that a 6-week course of lithium does not improve motor or sensory function in patients with chronic complete SCI but these patients did not receive any locomotor training. If lithium does not improve function when combined with UCBMNC and locomotor training, we should exclude it from future phase III trials.

We have proposed further phase II trials to answer these questions. The first trial will ascertain whether locomotor training alone or untethering surgery plus locomotor training restore walking in people with chronic complete SCI.

So, coming up, this one perhaps in the U.S., and maybe by 2017, a Phase IIb trial, which will consist of three groups of nine, ASIA A, C5-T10. The first group will get umbilical cord blood stem cell injections plus six weeks of oral lithium plus intensive rehab. The second group will get umbilical cord blood stem cells plus intensive rehab. Group three will get intensive rehab only. Once this data is released, one way or another, we’ll know more about the potential of this experimental strategy.