√ Taming An Unruly Immune System: A Risky Stem Cell Transplant That Changed Fate Of Some Canadian Ms Patients

By Hamideh Emrani (@HamidehEmrani)

This year, Dr. Harold Atkins was honored with the Till & McCulloch Award. He and Dr. Mark Freedman led a clinical trial that used stem cells to reset the immune system as a treatment strategy for Multiple Sclerosis (MS) and a few other neurodegenerative diseases, such as stiff person syndrome.

Dr. Harry Atkins; Image credit Signals Blog

You can read how this trial has affected patient Jennifer Molson here.

This trial was a hypothesis-driven interventional clinical trial. The researchers hypothesized that through chemotherapy they could completely obliterate the autoimmune active cells (immune cells that attack a patient’s own body) and, with the help of purified hematopoietic stem cells (HSCs: blood stem cells isolated from the bone marrow), completely reset the immune system so that it would become self-tolerant again. In order to avoid complications from transplant rejection, they would use the patient’s own stem cells.

For this study, they first collected and cryopreserved the patient’s own bone marrow. Then they put the patient through multiple regimens of chemotherapy to eliminate the patient’s immune system. HSCs constitute 3-5% of the bone marrow, and the mixture was thawed and purified (by selection for HSCs) and 48 hours after the last dose of chemotherapy, transplanted into the patient. The patient was then nursed through the period of side effects and the process of immune-reconstitution and monitored to evaluate the MS disease status.

As briefly described in another post I wrote, MS has different stages. During the relapsing remitting stage, an attack by the immune system on the central nervous system, (CNS: brain, optic nerve and spinal cord), results in damage. The CNS has repair mechanisms that go into motion during the remission stage and try to repair the damage. But with each attack, this repair process is slowed down. After multiple attacks, the patient goes into the neurodegenerative phase of the disease, where the body cannot repair the damage anymore.

Before the transplant, many of the patients in the trial had multiple disabilities. After the transplant, 70% of the patients had improved. The 30% that continued with the same disability had already entered the neurodegenerative stage of the disease. However, there was a profound suppression of relapses in all patients.

Relapsing attacks of the immune system appear as lesions detected through positive scans on the MRI machine. While many patients had positive MRI scans before the transplant, there were no new lesions after the transplants. In fact, 70% of the patients have been stable with no relapse activity for over 14 years of follow up.

The purpose of the trial was to stop the progression of disability due to MS. But surprisingly, for 40% of the patients, not only did disability stop but there was also recovery. Even when there was no improvement in mobility, there were improvements in cognitive ability, memory and bowel and bladder function. It seems that once the inflammatory attack of the immune system stops, the brain has the ability to heal.

This trial is not without consequences though. One of the patients died due to toxicity effect of the chemotherapy regimen, which is a common side effect from transplants. But as the researchers have refined the protocol, they have been able to keep the toxicity under control. There were additional side effects such as shingles, thyroid disease and premature menopause and, in one case, secondary leukemia.

Overall, the researchers were able to change the natural history of the disease and, unexpectedly, reduce the burden of disability in a fraction of the patients. As seen in Jennifer’s story, the impact for the patients has been beyond the disability score; some were able to go back to work, back to school, to form relationships, even have children. They are much more independent.

Drs. Atkins and Freedman have used this technique for other autoimmune diseases. They have done a total of 94 transplants at The Ottawa Hospital, half for MS patients. The other half have been patients with myasthenia gravis, stiff person syndrome(SPS), CIPD and NMO. Although some are still at early stages of the trial, 95% of the patients have seen improvements. Last year I shared Tina Ceroni’s story. She underwent the same procedure for stiff person syndrome and has been in remission ever since.

I sat down with Dr. Atkins after he gave the Till & McCulloch Award lecture and asked him a few additional questions.

What criteria determine whether an MS patient would be eligible for the stem cell transplant?

We chose the patients based on their level of disability, measured through a scaling system called the expanded disability status scale (EDSS), the pattern of the disease, ongoing disease activity and progression despite receiving immunomodulatory, and immunosuppressive treatments (medicinal strategies to manage and control the immune system). You can read more about the inclusion criteria in the original publication.

Do you know whether the repair, which was seen in the patients who received the treatment and had significant functional improvements, was also due to the stem cells?

This is not easy to answer, since the whole mechanism is still unknown. What we think might have happened is that taking away the inflammation, caused by the immune system attack, allowed the central nervous system’s intrinsic repair mechanisms to work and the healing to happen. In order to know what exactly happens we will need to be able to generate appropriate imaging data. We are not there yet.

Have you studied effects of female hormones on both the relevance of the disease and the outcome of treatment regimens? Do you know if any group is studying this? I am curious since there is a higher prevalence of MS among females.

The role of female hormones has not been studied. Both male and female seem to respond equally well to this treatment. I cannot comment on other treatments or relevance to the disease.

How can patients be actively involved in their treatments? Other than “going” to the Internet?  

The Internet can be a good source of information if credible sites are used. The trouble is finding the appropriate information by knowledgeable and reputable sources. In addition, patients can rely on their physicians, other MS clinic health care providers and the MS societies to learn about their disease and treatments.

Is this treatment available now, and how can patients enroll?

For the right patient, yes. This treatment is available and we receive a lot of requests to be considered for this treatment at The Ottawa Hospital. However, MS has many different variations among patients and there are many treatment options that are far less risky, with fewer side effects, available these days. (Compared to the start of the trial, 15 years ago.) For each patient the best strategy is to listen to their care team and neurologist to see whether they would benefit from such a treatment.

Make sure to also read a more personal interview with Dr. Harold Atkins here.

Shared with permission from Signals Blog.

About the author: Hamideh Emrani is a scientific communicator and the founder of Emrani Communications, serving clients in Toronto (University of Toronto) and California (Stanford University). She earned her B.Sc. in Cell and Molecular Biology at UC Berkeley and finished her M.Sc. at the University of Toronto (U of T). She was an intern at the Carnegie Institute at Stanford University, honours research student at UC Berkeley and has won awards for best podium and best poster presentations at the Faculty of Dentistry and IBBME at U of T. She is passionate about science and loves to talk and write about it. You can follow Hamideh on Twitter at @HamidehEmrani.

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√ Patient’S Powerful Story On Multiple Sclerosis And Getting Experimental Stem Cells

Caroline Wyatt, BBC, photo from Twitter

Multiple sclerosis (MS) can be an extremely debilitating disease that ultimately is fatal in some patients and reduces life expectancy and quality overall substantially. An MS patient named Caroline Wyatt, who works at the BBC, had the courage to open up in full detail on the BBC about having MS, her experience getting an experimental treatment of stem cells in Mexico, and how she is doing now. It’s a powerful new piece that brings home the complexities of having MS and of getting this hopeful, but risky stem cell therapy.

While some patients’ forms of MS are manageable, Wyatt’s MS was extreme. It was severely affecting her health as well as her life overall and currently available approaches such as the standard of care drugs did not help. It’s understandable then that she was considering various other options including things that aren’t yet approved such as stem cells. I’ve written extensively about stem cells for MS in the past on this blog.

There’s a lot of hope and hype out there on stem cells for MS. It’s a complicated mixture to navigate to have a clear sense of weighing risks versus benefits. Wyatt did some research and was interested in a new approach to MS with stem cells whereby chemotherapy is used to eliminate the autoreactive immune system and in a sense “reboot” the immune system with putting back in earlier harvested hematopoietic stem cells (HSC).

She wasn’t eligible for participation in formal clinical trials of this new approach in the US or UK, but a place in Mexico is doing what seems to be very much the same kind of clinical experiment, apparently with different inclusion/exclusion criteria. Wyatt was able to get this HSC transplant (HSCT) at a place called Clinica Ruiz in Puebla, Mexico.

(Note, that while Wyatt did not have any bad experiences in Mexico with the HSCT procedure itself, getting an unproven stem cell treatment outside of one’s home country more generally is often likely to be a high-risk thing to do for various conditions. One patient who got a stem cell treatment in Mexico as well as in a couple other international locales ended up with a tumor on his spine. Getting unproven stem cells in the U.S. can also be risky and patients have been hurt including a number who were blinded)

Getting back to the HSCT for MS specifically, it is a very difficult thing to go through for patients with multiple rounds of chemo, stem cell isolation, stem cell infusion, and recovery from the procedure itself. I recommend reading her whole article as it is very interesting and informative about the process. Wyatt is also so open about her experiences with MS as well as what she went through in the process and since.

Wyatt says that she’s not sure if she’s had a net benefit or not from getting the HSCT. It is clear that there are long-lasting side effects and challenges from her HSCT, but there is also hope. For instance, she wrote that her latest brain scan shows no further progression of the disease. Other patients have self-reported a range of experiences after this kind of HSCT for MS. Some patients fared worse (a few have died) and others reported more positive outcomes than Wyatt.

Wyatt described where she’s at post-transplant this way:

“Today, I quite often feel worse than I did before HSCT.

I still need to rest frequently during the day, and when I use my energy for work, I have none left for anything else at all.

But there are sunnier days when I feel a little better than I did immediately before the treatment, and then my hopes soar.”

And looking to the future:

“But I am an optimist, and shall remain so while my immune system finishes reconstituting itself fully by the end of this year, some two years after I started treatment.”

I wish Wyatt all the best. You can follow her on Twitter here:@CarolineWyatt.

At this point for HSCT for MS overall, the jury is still out on whether this kind of new approach will definitely be safe enough and effective beyond the standard of care. A recent report from a meeting brings new hope and we can anticipate a published, peer-reviewed paper on the trial perhaps later this year or in 2019. At that point we’ll have a much better understanding of the big picture.

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√ Upbeat Burt Team Pub On Stem Cells For Ms Comes With Uneasy Back Story

Types of Multiple Sclerosis and their impact on disability over time. Unmodified Wikimedia open source image by Osmosis.

Stem cells for MS? How promising is that? A new paper gives stronger reason for hope, but unfortunately this story is more complex than it seems on first glance.

New Paper

The idea of using a stem cell-related approach to treat multiple sclerosis (MS) has been around for a long time holding major promise, but there hasn’t been much in the way of high-quality trial data out there in the published literature. A paper this week from the Richard Burt team at Northwestern (NW) and conducted in part at other international sites provides a fresh boost of excitement in this area.

This cross-over study was larger than past published work. It was focused on highly active relapsing-remitting multiple sclerosis. You can see a helpful graphic about the different types of MS and their impact on disability over time at right.

Recipients of hematopoietic stem cell transplants (HSCT) with partial immune ablation fared significantly better in this study, published in JAMA, than recipients of immunosuppression alone. Also, the very large reported differences between those getting HSCT versus standard care suggest a real, meaningful effect.

The short take-home is good news for patients but with some big wrinkles to iron out as discussed below.

Complicated back story including big patient payments

Over the years, I’ve had some concerns about the NW work on HSCT for autoimmune disorders like MS. Some of these issues remain on my mind. For instance, many patients apparently had to pay to enroll. These payments, depending on insurance coverage, could sometimes be very large. It seems unusual to me that some patients would have to pay maybe $100K or more to be enrolled in a trial. That kind of practice could impact the end results of the study too.

What happens to those who cannot pay?

In addition, I don’t see an acknowledgement of patient financial contributions to the HSCT MS study in the new paper itself. Probably JAMA wouldn’t require that (maybe in part because so few studies would require major payments by trial participants). However, in my view, why not give a likely much appreciated hat tip to all the patients who not only took risks to be trial participants, but also financially contributed to the study’s funding?

Patients contributing in big ways to the financials of a study could also impact the results.

Other concerns: portrayal of ongoing trial as curative & off-study experiments on patients

In my opinion there was also a reasonable question as to whether the HSCT trials were being pitched already as curative years ago while they were still ongoing. There was buzz from patients about this as already known to work while the trial was ongoing too. This kind of thing could alter trial outcomes.

Some patients indicated that NW would give certain patients the experimental treatment in an “off-study” fashion, which was concerning to me as well and if confirmed, this would be something I’m still concerned about today. Presumably the off-study patients would still have to find large sums of money to pay toward the trial. Furthermore, the resulting paper(s) wouldn’t include their data. I don’t know if off-study severe adverse events or even deaths would have to be reported to the FDA.

FDA warning to team: any connection to this study?

It’s also a big deal that this team received an FDA warning letter a few years back for a variety of issues including failure to promptly report patient deaths. Unfortunately, we don’t know from the letter whether the deaths mentioned were amongst MS patients who were part of the group reported on in the new paper or were other patients in a different study. The new HSCT-MS paper did not mention the warning letter and it reported no patient deaths.

Numerous other issues were cited by the FDA in the warning letter too and we don’t know if any of those applied to the MS work either. Maybe not, but hard to say. Do JAMA or other journals that publish clinical trials have policies on whether papers in any way connected to warning letters must mention the warnings?

Importantly, the FDA indicated later that the team had addressed the issues in the warning so that’s encouraging.

Older immunosuppressants could have amplified apparent benefit of HSCT

The new study has at least one key limitation in that older immunosuppressant drugs were the focus, while newer drugs in this class work a whole lot better. The big difference in outcomes between HSCT + immunosuppression vs. immunosuppression alone would likely have been smaller in the context of new drugs. The use of older drugs in the study is attributable to the fact that this study simply began a long time ago.

Patient perspectives

Patients including some self-identifying as involved in this or similar studies at NW have had many useful perspectives in their comments on my 3 posts here on The Niche on the NW work (here’s the first post from which you can click on to the second and third). The patients also often let me have it for a variety of things in my posts. They are almost without exception big fans of Dr. Burt.

Take home: good news, but still big questions

In the long run, the bottom line is that the data here are very good news, but there were bumps in the road to get here and open questions remain. I hope Dr. Burt and NW can clear things up within the public domain quickly.

A number of other groups are studying HSCT for MS too and there have been preliminary results that seem promising. Looking ahead, could HSCT-related therapies become the standard of care for certain patients with specific kinds of MS? Despite its high cost, could it even become cost-effective when compared to expensive, toxic long-term drug therapies alone? I hope so as this would help thousands of patients.

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