A stem cell treatment for MS offers some patients hope. But is it hope that will last? – WHYY

The origins of HSCT as an MS treatment

The way HSCT came about at least as a treatment for MS was kind of an accident.

Years ago, researchers noticed that some patients with MS who had received bone marrow transplants for certain types of cancer experienced an incredible side effect.

Their MS reversed, said Mark Freedman, a professor of neurology at the University of Ottawa and director of the Multiple Sclerosis Research Unit at Ottawa Hospital. And people started wondering, Well, what about doing this like for real [for] their MS, not just for cancer?

In the late 1990s, Freedman was among the scientists who were keen to give HSCT a shot. At the time, he didnt think that the transplants could be used as a treatment for MS. But Freedman knew that bone marrow transplants could essentially reboot patients immune systems which gave him an idea. Maybe by watching patients immune systems reboot, they could figure out what was causing MS in the first place.

Freedman got the idea courtesy of his 90s-era desktop computer. Every day, hed switch it on, and watch all the little programs load before the main screen popped up.

When we see a patient with MS, its like the Windows screen is open, but we dont know how it got there, Freedman said.

At that time, it was widely believed that MS was a purely genetic disease, which meant that, as the immune system rebooted, patients would likely get MS all over again. But as their immune systems were coming back online, Freedman thought, maybe theyd be able to observe what exactly was going wrong.

We were fully convinced that, OK, maybe its not going to treat it, but this will be a reboot, he said. And now, rather than seeing the full Windows screen, lets see the little programs as they load, and [that] might unveil the trip the bad program that led to MS, because otherwise we had no idea what started the disease.

Freedman and his colleagues collected patients stem cells and purified them in the lab. They then used powerful chemotherapy drugs to wipe out their patients immune systems, and reimplanted the stem cells to build fresh immunity.

And then they watched and waited to see when and how that bad program would load, leading the MS to return. They waited and they waited and to their surprise, it never happened. The procedure didnt reveal the cause of MS but what it did was stop the MS from progressing.

From our standpoint, from the science standpoint, it was a failure, Freedman said. From the patients standpoint, however, obviously, they were quite pleased.

So they never figured out what exactly was causing the MS. But they did figure out a way to stop it from attacking.

I liken this to the person who goes out and buys a car, and the air conditioner keeps going on the fritz, Freedman said. And youve taken it back 10 times, and they cant repair it. And finally they just say, You know what? We dont know whats wrong with the conditioner. Were just going to give you a brand new one. And lo and behold, it works! And its something similar. We dont know what the defect is in the immune system to cause MS, and it may well not be the same defect in different people. Our success has been on the basis of being able to completely remove the old immune system.

Even with the incredible early results, Freedman remained skeptical. He couldnt help but believe that eventually the MS would return.

I kept thinking, well, its just a matter of time, its just a matter of time, he said. And after about five years, I went, Maybe it isnt a matter of time.

Thats when some of his old patients started coming in including one with extreme vision problems due to MS, the kind Freedman said hed never seen go away.

I used to have to get her a special eye chart because her eyes, if you looked at them, were bouncing all over the place and they never stopped, he said.

But as Freedman was moving to pull out the special eye chart, the patient stopped him, he said told him she didnt need it and started reading off the letters off of the regular chart. Freedman was shocked.

I went, Wait, hold it. What?! Are you actually reading that? How the hell? And I had to look very closely, Freedman said. And sure enough, her eyes werent bouncing anymore.

Another patient who participated in the study had initially come in barely able to walk.

She was really quite disabled, Freedman said. And I saw her also around month 18, and she strolls into the clinic on high heels. The patient told Freedman she was even going on ski trips.

Freedman and his colleagues published their results in The Lancet in 2016.

HSCT wasnt a cure, he emphasized: It couldnt reverse the damage that was already done. What it did was stop the disease in its tracks.

As they discovered, the rebooted immune system no longer recognized the patients myelin sheaths as an enemy. That stopped the inflammation, giving their bodies a chance to heal. Some patients gained functionality back. Others simply saw their disease progression stop.

More importantly, the study demonstrated that, when done properly, HSCT could produce long-lasting remission without patients needing to undergo further treatment. It also showed that it was possible to deliver this treatment without a major risk of mortality a risk that had previously stopped some researchers from considering stem cell transplants as a treatment for MS.

Freedman and his colleagues werent the only ones experimenting with HSCT as a treatment for MS. Over the past few years, other researchers have also conducted studies with headline-grabbing results.

Success stories have inspired MS patients around the world to seek out HSCT. The trouble is, its still hard to access, even in countries like Canada and the U.K., where its become an accepted treatment. In the U.S., its primarily available only through clinical trials that are extremely difficult to qualify for.

That has led scores of patients to travel in search of treatments including Jessie Flynn.

Flynn boarded a plane to Mexico City on April 3. From there, she took a bus to Puebla, a city a couple hours drive away.

In pictures, along with Flynns own Facebook Live videos documenting her trip, Clinica Ruiz looks like some kind of upscale summer camp for grownups. Just about everything was right there on site: the medical facilities; the apartment where Flynn would be staying for her month of treatment; a cafe; even a roof deck, where, in the Facebook Live videos, Flynn is shown hanging out with her fellow patients.

The whole group, we were all so excited, she said. Everyone was so nice, and obviously the doctors and medical staff were just amazing. I mean, you should have seen it; it was like a machine.

Flynn even had her own caregiver, who, shortly after she arrived, offered Flynn the lay of the land.

She had an entire calendar for me, she said. We sat together and mapped out the entire month.

The first few days were dedicated to testing, designed to ensure that patients were healthy enough to withstand the treatment.

After that came two days of initial chemotherapy designed to condition the immune system and begin to mobilize stem cells into the bloodstream. Then came several days of shots, Flynn said, to boost her stem cell action in preparation for the transplant.

After having her stem cells collected, Flynn received another couple days of high-dose chemotherapy to suppress her immune system.

Basically, they dock you down to nothing, Flynn said. We werent allowed to see anyone, talk to anyone, where we needed to be very isolated and careful because we didnt want to contract any infections because we had virtually no immune system.

Once her immune system was wiped out, they took Flynn in for her stem cell transplant. And after that, it was a waiting game to see whether and how the stem cells were able to grow a healthy new immune system.

On the whole, Flynn said, the treatment went smoothly except for one night, after having her immune system decimated, when she got seriously ill.

Im convinced that I got a bad case of Montezumas revenge, and I spiked a fever, Flynn said. It was horrible. But I had an entire medical crew in my room, and they were applying cold compresses, taking my temperature every half-hour. They had to give me a blood transfusion.

Despite that one very scary night, the rest of Flynns recovery went off without a hitch.

Im feeling better every single day, Flynn said a couple weeks after her return from Mexico. And Ive actually seen some improvements, so Im very, very excited.

There was nothing huge, but a lot of little things: more mobility, less stiffness, fewer leg spasms. Even her vision was better, something she didnt expect. The only downside, as far as Flynn was concerned, was that she had to stay hermited away for about six months until her immune system was back up and she was ready to receive all of her vaccinations (necessary since the treatment should have wiped out all of her old immunity).

Asked how the results had stacked up against her expectations, Flynn was positive.

I mean, I had realistic expectations I just wanted everything to stop, she said. That was my goal. So these are kind of like little bonuses, the improvements Im seeing. So its stacked up remarkably well.

Her husband, Bobby, said hed also noticed improvements. In fact, the other day while he was in a meeting, hed watched as Jessie walked to the bathroom and back with just the aid of her walker.

She hasnt done that in over a year, so its absolutely incredible, he said. We didnt have a choice, like we had to take this chance and do it, but it feels so good just seeing her get better.

In a phone call, Flynns physical therapist, Kami Palmer, confirmed her improvements.

I didnt see any significant difference until probably about a week or two after, Palmer said. I noticed that, especially on her right side, she was able to pick up her right leg a little bit more.

Flynns muscle spasticity wasnt as bad, which improved her postural stability, Palmer said. She was also walking better, and wasnt falling over when she sat down or stood up. She could do a lot more without assistance. Those improvements, Palmer said, are really big.

Its very big for fall risk at home, she said. Its very big for her husband. He reported not having to assist her into the showers like he used to. He would have to almost, like, carry her into the shower, where now she could actually step up because her leg could bend, which is huge.

Neither Flynn nor her husband had any doubts about what had caused her improvements. But neurologist Mark Freedman, whose Lancet study helped boost HSCT as a viable treatment for MS, was more skeptical.

He voiced his doubts after talking with Flynn about her medical history and her treatment in Mexico.

Its unfortunate that its the same story I hear all the time, he said. Its very unlikely that any objective change has occurred. But when you put 60K out of your pocket, youre going to look for every little possible benefit.

Freedman had several reasons for doubting Clinica Ruiz. For one thing, he said, based on descriptions of the protocol that the clinics director, Dr. Guillermo Jos Ruiz Argelles, had published, he didnt believe that what they were doing was true HSCT.

This is not your typical HSCT, Freedman said. This is low-level HSCT. Ruiz does it because people will come down there and pay for it. Hes not what I would consider to be one of the centers that I would ever recommend anyone going to. And the procedure that hes using is one that is least likely to produce major side effects.

That, Freedman said, is because Clinica Ruiz uses a lighter form of chemotherapy.

Theyre certainly not wiping out the old immune system, he said. Theyre not wiping out immunological memory.

And thats important, Freedman said, because the entire treatment depends on fully wiping out the existing immune system.

Dr. George Georges, a medical oncologist at the Fred Hutchinson Cancer Research Center who is helping to lead a major, National Institutes of Health-sponsored study on HSCT, agreed with Freedman.

It is not a dose of chemotherapy that completely wipes out your immune system, Georges said. It does not completely kill off your own hematopoietic stem cells.

What that means, Georges said, is that the next step the infusion of stem cells is rendered unnecessary.

You dont actually need the stem cell support or infusion to rescue patients from this dose of chemotherapy, he said. Transplanters do not consider this a real transplant.

Freedman had another reason for doubting the efficacy of Clinica Ruizs treatment. Based on what Flynn had told him about her medical history, he postulated that her MS had progressed too far for it to respond to HSCT.

Weve had zero success, and other people have had minimal success at treating later-stage secondary progressive MS, he said. I think if youve got early secondary progressive MS, meaning youre relapsing-remitting so much that youre creating an accumulation of damage, those patients do well, and that means their immune system replacement may well lead to either a stopping or reversal of disease. But late-stage progressive disease with no evidence of ongoing inflammation is simply not going to benefit from this procedure.

That, Freedman said, is why clinics like his along with clinical trials in the U.S. have extremely strict criteria for patients. They cant have been sick too long, or progressed too far. They cant be too old. They must have active inflammation, and worsening disabilities. In other words, they have to be just the right amount of sick which is why, Freedman said, lots of patients from around the world end up traveling to places like Clinica Ruiz.

The reason why theyre going there is because nobody wants to offer it to them in their center, he said, because theyre probably in this progressive stage that its unlikely that theyll benefit. So theyre going to be desperate. OK, well, fine. Im going to go do something else.

Yet if all of this were true, why was Flynn seeing improvements?

Freedman said his best guess was a combination of wishful thinking and a drug thats part of the clinics protocol rituximab.

They get benefit from rituximab, which is an effective medicine [for MS], Freedman said. I dont know that they would benefit beyond that.

Despite its efficacy at improving MS, rituximab isnt formally approved for that purpose by the Food and Drug Administration, which is why it isnt commonly used to treat MS in the United States. (Officially, its meant to treat certain kinds of cancer.)

Georges added that the chemotherapy could also be playing a role in why patients of Clinica Ruiz could be seeing improvements.

They dont need this stem cell to get the benefit from the treatment, Georges added. Its just the chemotherapy thats providing them the benefit. So thats whats a little bit of a sham.

Jessie Flynn was skeptical about what Freedman and Georges had to say.

[Freedman]s not in a place to diagnose what type of MS I have, she said. His saying that there was no hope for people with secondary progressive MS, thats false. There is less of a chance of reversal, I guess. And I have heard that, and Ive heard that even at Clinica Ruiz. All I know is my own case.

But Flynn also found some of their specific concerns worrying.

Its troubling I dont really know how to respond to that, she said. Obviously, theres a side of me thats kind of scared of what hes saying is true because were taught to trust doctors and you know, take everything they say as truth and its hard to hear things like that.

The director of Clinica Ruiz, Dr. Guillermo Jos Ruiz-Argelles, responded to questions about his clinics treatment over email.

Ruiz-Argelles confirmed that the chemotherapy and rituximab were indeed responsible for the improvements patients experienced but he said that was only because they were also responsible for a key step of HSCT, shutting down the immune system.

He acknowledged that the clinic uses less intensive chemotherapy, but said it was no less effective: Our published results clearly prove that this diminished intensity conditioning renders similar results to high-dose conditioning.

Ruiz-Argelles also acknowledged that the clinic lacks the kind of stringent patient criteria of other HSCT providers because, he said, we have shown and published that our method renders results in all types of MS.

But Paul Knoepfler, a professor of cell biology at the University of California, Davis whos written about HSCT, was skeptical of the studies that Ruiz-Argelles attached in his email response to the interview questions.

What stood out to me about the papers you attached is the lack of rigorous clinical trial design, Knoepfler said. I dont see inclusion of important features that are needed to make firm conclusions from trials about safety and efficacy. For instance, I dont see randomization, double-blinding, or the use of placebo control in their studies.

In response, Ruiz-Argelles wrote: We are not an institution supported by the government or insurance companies, so we cannot perform randomized trials as it will be unethical to offer a placebo to our patients. We are aiming to improve patients condition, not to show nice statistics.

In emails, Ruiz-Argelles boasted of his former patients outcomes, but HSCT experts Mark Freedman and George Georges complained that the follow-up contained in his studies was neither rigorous nor long-lasting enough to draw any conclusions about the efficacy of his clinics treatment.

One former patient who had a broader perspective than most Caroline Wyatt, a BBC reporter in London with MS, wrote a feature about her experience getting HSCT at Clinica Ruiz.

Wyatt was in her late 40s when she was diagnosed with MS by which time, she said, her symptoms were spiraling out of control.

I was in a really bad way, physically and mentally, she said in an interview. I had double vision, sometimes triple vision, and I couldnt speak very clearly. So I couldnt work.

She couldnt even focus her eyes enough to read or watch TV. She couldnt lift her arms. All she could do was lie in bed. Wyatt was desperate to get her life back, but nothing was working. She tried getting into an HSCT trial at a nearby hospital, but was turned away. Finally, she heard about Clinica Ruiz, though her doctor was against it.

My general practitioner immediately said, You know, there is a possibility you might die, and surely thats not worth it to try to halt the progression of your MS. And I said, Well, for me, actually, it is worth taking that risk if there is any chance at all that it will help me carry on working, carry on functioning.After lots of research, Wyatt decided to go to Clinica Ruiz anyway and, she said, her gamble paid off.

I was able in those first few months to walk 10 miles a day, which just felt incredible to be able to walk up hills and at a normal pace, she said. To get my balance back, to get my concentration and focus back so I could read again. I could follow stories. I could remember plots, I could remember names. It was amazing. And that was the most fabulous feeling.

In the interview, Wyatt was told about Freedman and Georges critiques of Clinica Ruiz that what is being done there isnt real HSCT.

Wyatt whos done extensive reporting on both HSCT and cutting-edge MS treatments responded that theres a whole debate over whether HSCT must fully destroy the immune system in order to work.

I think there is definitely a belief among some scientists that that is the way to go if you can, but then you would probably be excluding a lot more patients from that because of the need to be well enough and fit enough and healthy enough to have that done, she said.

In fact, Wyatt said, thats one of the reasons why she chose Clinica Ruiz. At her age, and with how fragile shed become, she wasnt sure shed be able to handle a treatment that completely wiped her immunity out.

As for the notion that only patients in certain stages of MS can benefit from HSCT?

It is still an emerging area of science, Wyatt said. I think the jury is still out as to exactly who is the ideal patient for which sort of HSCT.

Wyatt added one other shade of gray to the conversation: She said that the different stages of MS arent as definitive as you might think. Theres no one test that says whether a patient has remitting-relapsing MS or a progressive form of MS, which is important because patients diagnoses determine what treatment they receive or are even eligible for.

Its a disagreement among different neurologists, she said. And I bet you anything, if you ask 10 neurologists, you will get 10 different opinions on it.

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A stem cell treatment for MS offers some patients hope. But is it hope that will last? - WHYY