This time I talk to Prof. Dr. Roland Martin about the findings to date on autologous stem cell therapy (aHSCT) in MS patients and his experiences. As former head of the Section for Neuroimmunology and MS Research at the University Hospital Zurich, he played a key role in establishing this induction therapy in Switzerland and making it a health insurance benefit. But retirement is not on the cards. He is still affiliated with the University of Zurich and pursue research in the Institute of Experimental Immunology as an emeritus. Roland is also Chief Scientific Officer at Cellerys AG in Schlieren, Switzerland, and continues to be associated with the Department of Clinical Neurosciences at the Karolinska Institute in Stockholm, Sweden.
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Table of Contents
Introduction – Who is Dr. Roland Martin?
I am a neurologist and immunologist by training and have worked for 40 years both in research and clinical care for multiple sclerosis patients (MS) and also patients with other neuroinflammatory diseases. My wife, Dr. Mireia Sospedra, is also an immunologist, who works on disease mechanisms of MS and recently more and more on nutrition.
The development of new treatments for MS has been an important part of our work, and these reach from small molecules, natural compounds, biologicals such as monoclonal antibodies and cell therapies that aim at immune tolerance or – the topic of the interview – complete exchange and renewal of the immune system.
Mireia and I have a 16 year-old son, and from my first marriage, I have four more children, 2 girls and 2 boys, who are all married and work, three in the US, and one in Berlin.
Currently, I have 6 grandchildren. Besides our research, which has always been a hobby and vocation, I am an enthusiast photographer, love to walk and hike with Mireia.
Personal motivation for your career choice?
Despite the minimal space that the immune system occupied in my medical training, it has always fascinated me. I was originally most interested in pediatrics, but, since I did not find a position after a post-doctoral fellowship in immunology and virology directly after medical school, I started in my second choice, neurology – also an interesting and fascinating field.
Understanding Autologous Stem Cell Therapy (aHSCT)
Could you provide a brief overview of what autologous stem cell therapy is and how it's used in the treatment of multiple sclerosis?
Autologous hematopoietic stem cell transplantation or short aHSCT is a treatment that is commonly used in the treatment of certain cancers, for example, after very invasive chemotherapy for breast cancer to restore blood cells and immune function, but also for certain leukemias and lymphomas.
In autoimmune diseases and MS, aHSCT has been tried first in the 1990-ies with the idea that a misguided immune system that attacks a tissue and organ of the own body, the brain and spinal cord, should be eliminated by chemotherapeutic drugs or irradiation and then a new blood cell and immune system be built with the persons own blood stem cells (or hematopoietic stem cells as medical term).
The treatment, which now consists of mobilization of the stem cells from the bone marrow, harvesting them from the blood and storing them in a freezer, then a cycle of chemotherapy to destroy blood and immune cells, and last the re-infusion of the person’s own stem cells.
During the following days and weeks, these stem cells form all blood and immune cell populations again, and hence the immune system is renewed. The hope is that this new immune system will not attack the brain again and that the MS will stop – ideally forever.
In the meantime, it has been shown that this concept works. At the beginning, the side effects were high, and until approximately the year 2000, the likelihood of dying from the treatment (mortality) was around 7%. This number is almost as high as if one used allogeneic stem cells, that is stem cells from another donor.
In the following years, the procedure has been refined more and more, and now, the mortality is well below 1%. Regarding its efficacy, multiple smaller and larger studies and experiences with over 5,000 registered patients world-wide have shown that the efficacy of aHSCT is very good and that it represents the most effective treatment for patients with active or highly active MS.
Is the treatment approach tailored to the individual characteristics and needs of each patient or is it always the same depending on the clinic?
No. There are a few so-called aHSCT regimens, which differ slightly with respect to which chemotherapeutic drugs are used and which doses. The best examined and most effective are BEAM-ATG and Cy-ATG. The letters stand for the chemotherapeutic drugs that are used, and ATG means antithymocyte globulin. These are mixtures of antibodies from rabbits or horses, which destroy lymphocytes, i.e. the cells that are thought to play an important role in the disease mechanisms of MS.
It is important for patients to know that some clinics offer aHSCT regimens that are milder. While they are better tolerated, they do not meet the main criteria of the treatment, i.e. they do not completely eliminate immune cells, which explains why they are also less effective.
There is general agreement and consensus between the experienced centers, which transplant regimens are best and how they have to be given. Since aHSCT is commonly used treatment for hematologists and oncologists, the standards are very high, and the experiences are continuously reported to the associations that follow and improve stem cell transplantation.
In Europe, this is the European Blood and Marrow Transplantation Group (EBMT), which has a working party for autoimmune diseases. In North America, it is the Center for International Blood and Marrow Transplant Research (CIBMTR).
What specific criteria is considered when determining if a patient is suitable for autologous stem cell therapy?
The experiences in the last 20 years have led to several key observations regarding this question.
- aHSCT works best in younger patients with aggressive disease. Young means until 50 years of age and, depending on the state of the patients, sometimes a few years more. However, it is clear that the efficacy of immune system renewal and of aHSCT drops from 50 years of age onward – from reasons that are not understood right now.
- The treatment works better in patients with relapsing-remitting disease when compared to progressive forms.
- The patient’s disability grade and duration of the disease should not be higher than EDSS of 6 (in some cases, one can go higher; but this needs individual assessment by experts) and 10-15 years disease duration.
- The patient should not suffer from other diseases or problems that pose a problem, e.g. chronic lung disease….
- The activity of the disease, that is relapses and / or MRI lesions, as well as disability development, should be assessed carefully.
- Patients should have active disease and they should have received at least one highly effective therapy before.
- Patients in the progressive phase of the disease without any signs of relapse or new MRI activity are not suited for aHSCT.
Patient Experience and Outcomes
From the perspective of someone living with MS, what can they expect from autologous stem cell therapy in terms of long-term disease progression, symptom improvement and quality of life?
If aHSCT is applied to the right patient or patient group, its efficacy is very high, higher than any of the approved therapies. The majority of patients, that is more than 75% remain completely disease-free and for long periods of time or forever. It comes closer to a cure for MS than any other treatment. If patients have already entered the secondary progressive disease stage, it can be expected that the disability increase is less than before aHSCT. However, this cannot be promised or predicted.
How does autologous stem cell therapy compare to other available treatments for multiple sclerosis in terms of effectiveness?
As already mentioned, it is the most effective treatment for patients with aggressive MS. In trials, patients, who received aHSCT, had usually multiple prior treatments and more severe disease than in phase III trials of the most effective, approved drugs, and hence, remarkable efficacy has in most cases also been seen in these more difficult patients.
What are the potential risks associated with this therapy, and how do you balance these risks against the potential benefits?
The treatment is more invasive, i.e. has more early side effects, than conventional treatments. The main problems are infections of the intestinal tract, but potentially also bladder, lung, in the first three months, during the time when the new immune system is not fully developed yet. Patients routinely receive antibiotics, antiviral- and anti-fungal drugs, but infections – despite many improvements of the therapy – remain the main issue early on. Patients have to be re-vaccinated after transplantation, and it is advisable to give the attenuated varicelly zoster vaccination prior to aHSCT.
Another aspect that has to be discussed in detail particularly with women is the potential to become infertile. The infertility rate is in the range of 30% and becomes more with increasing age. Fertility-maintaining steps such as harvesting and cryopreserving eggs and sperm have to be discussed and performed if the patient wishes. With increasing duration after aHSCT, the rate of side effects steadily drops and beyond three months is more or less comparable to a healthy individual. The treatment is a one-time treatment, that is no follow-up MS treatment is needed.
There is a long-term risk of secondary autoimmune problems, particularly thyroid, but this is in the range of a few percent and can be treated well. It is much lower than for example after alemtuzumab, one of the approved treatments for MS, where secondary autoimmunity occurs in approximately 40% of patients.
From the above, it is clear that the treatment is not without side effects, and that the balance between side effect profile and expected benefit have to be weighted. In young patients with aggressive and therapy-refractory disease, it is clearly the best treatment option (in my opinion), but this may be different for other patients.
One other aspect that we underestimated when we began is that patients should be carefully assessed also by a psychiatrist to find out if any depression or other psychiatric issue exists. We had two patients with progressive disease who committed assisted suicide longer than one year after aHSCT despite objective measurements (walking etc.) that they did not develop new disability, that is they remained stable. Both had not told us that they had enrolled in an assisted suicide program, and in both cases, our interpretation was that their hopes for the effects of aHSCT were not met. We made sure in all patients not to raise any unjustified hopes and to describe the treatment procedure as well as what can be expected realistically.
How do you monitor patients’ post-treatment, and what kind of follow-up care is typically required?
Follow-up care is monthly for the first few months after leaving the hospital (depending on the center and routines there, the in-patient time ranges between 2-4 weeks), it involves antibiotics, antiviral, antifungals and later also re-vaccinations. From 6 months onward, another two threemonthly visits are recommended and then yearly controls. On the mid-term and long run, care and exams are less with this one time treatment.
System Support and Future Trends
Why is the Swiss healthcare system willing to cover the costs of autologous stem cell therapy for certain MS patients?
Getting a new drug/treatment approved for MS requires two phase III trials. These are large (in the range of a 1,000 patients per trial) and very expensive trials. Since the drugs that are used in aHSCT are not patented anymore and cheap, no pharma company is interested in performing phase III trials for aHSCT. On the other hands, foundations, patient associations and governmental funding agencies do not support trials that cost hundreds of millions. Hence, no large phase III trial has been conducted so far, and the ones that are ongoing are more phase IIb than phase III trials. They will, however provide important additional information.
Despite the above routine requirements from the regulatory side, the evidence about efficacy and safety is so strong now that the Swiss Health Authorities (the Bundesamt für Gesundheit or BAG) accepted this evidence as sufficient to approve aHSCT first only in one center, i.e. ours in Zurich together with the hematologists, who perform the aHSCT, and since July 2023 also for other centers in Switzerland.
They requested that we enter transplanted patients into a registry and follow them for 5 years, which is much longer than the follow-up that is routinely done by the transplanters and reported to the EBMT. Until summer 2023, 45 patients had been transplanted with results that are entirely consistent with those of the international community.
I think that another motivation for the Swiss Health Authorities to approve aHSCT was the fact that a substantial number of patients travelled to Moscow, Israel, Mexico to receive aHSCT at own cost, often at centers that are on the one side very experienced, but often do not participate in the systematic international efforts to improve this treatment as centers in Europe and North America do.
The treatment is substantially more expensive in Switzerland compared to for example Germany, Italy, Greece, France, and hence it is very good that the expenses of aHSCT are covered by the health providers now. Health economic analyses furthermore show that aHSCT already after a few years is overall less expensive than highly effective approved therapies.
Another relevant point – from my own experience after having worked in Germany, the US, Spain, and Switzerland – is that it is absolutely essential that both the MS experts/neurologists and the transplanters (usually hematologists and/or oncologists) at one site both need to be interested in this treatment for MS patients. It is crucial that these specialties work very closely together and that other specialists (fertility, psychiatry, infectious disease specialists) are also familiar with the aHSCT program for MS patients. This was (at my time in Germany) not the case for most academic sites. Either the MS experts were interested or the transplanters, but usually not both. This made it very difficult for patients to find a center in their vicinity where aHSCT might be an option for them.
What are the challenges of including autologous stem cell therapy into the healthcare system for defined MS patients in other countries, and how can these be addressed?
From a scientific point of view, there is no doubt that the evidence for the efficacy of aHSCT is very strong. Since it is a routinely applied treatment procedure in other indication areas and known to be very effective in MS, I can only emphasize that regulators in the respective health care systems of other countries should be open to this treatment. It is essentially like an off-label use of an approved treatment in another indication.
What do you see as the future trends in stem cell therapy for multiple sclerosis, and how might these impact patient care?
While significant improvements have been made regarding the aHSCT regimens and also the general care of patients receiving this treatment, the treatment has essentially remained the same or very similar over the last 25 years. Considering the progress in drug and treatment development during this period – particularly in the area of treatments targeting the immune system – I hope that combinations of so-called biologics, for example monoclonal antibodies against certain immune cells – with less side effects than chemotherapeutic drugs, will be developed that replace the current aHSCT regimens but achieve the same that is eliminate a mis-guided immune system and permit development of a new one from autologous (own) hematopoietic stem cells. There are multiple hurdles, however. Neurologists do not use drug combinations, and to develop these systematically is much more demanding than single drugs.
How do you ensure that patients are well-informed about the procedure, its potential outcomes, and any associated risks?
This is a key aspect of the treatment. Choosing the right patient, assessing their disease activity, evolution in the previous years as well as their treatment history, potential risks, wishes regarding fertility and numerous other aspects needs to be pursued in an interdisciplinary team of neurologists with strong MS expertise, hematologists and the abovementioned other medical specialties.
Informing the patient realistically about what the treatment can achieve, but particularly also what it means to go through this therapy, for example transiently loosing your hair and other aspects, as well as the mid-term and longer term potential risks is very important. This cannot be done at a single visit.
We followed an algorithm, in which the patient is first seen, a detailed history taken, examined, the MRI images reviewed, followed by an internal discussion in the MS team, if the patient is suited. If so, at the next visit the patient will be seen by the transplant team and other exams (fertility…) and discussions be organized, if the patient remains a good candidate. Only, when all this is concluded and the patient does not have concomitant risks, then the treatment will be scheduled.
Are there any ongoing research initiatives or technological advances that you believe will further improve the efficacy or long-term safety of this therapy?
I think much more can be learnt from this treatment, and research in this area should definitely continue or even be strengthened. To give a few examples. The evidence – including numerous studies from our group – for both the clinical efficacy and also the mechanism(s) of action with respect to renewing the immune system is very strong. However, there are still many aspects that we do not understand sufficiently well.
Atrophy of the brain, that is loss of brain tissue over time, is one area. MS patients show approximately 10 times more loss of brain tissue per year than the healthy population. Shortly after aHSCT, brain atrophy even increases for a few months, which is probably an effect of the toxic drugs that are used to destroy immune cells.
However, at approximately 1 year or earlier after aHSCT the brain atrophy rate normalizes, which means that MS patients after aHSCT do not show an increased loss of brain tissue anymore. This is difficult to explain purely by the effects of aHSCT on the immune system, but could have to do with so far unknown regenerative effects of the hematopoietic stem cells and cells that they give rise to or also regenerative/remyelinating effects of certain immune cell populations, for example so-called regulatory T cells. This is just one example.
Farewell
Can you recommend a certain website where people with MS can inform themselves if they belong to the group that would benefit and get more details about the procedure?
Good question. I am not aware of a specific website covering all this in an easy-to-understand way. It is probably best to „google“ for the name of prominent investigators in this area. I will name a few here:
- Riccardo Saccardi, Florence;
- Paolo Muraro, London;
- Joachim Burman, Uppsala;
- Gianluigi Mancardi, Genova;
- John Snowden, Sheffield;
- Richard Burt, Chicago
How and where can interested people follow your research activities?
As I may have said at the beginning, I have retired from my clinical position last year since the retirement age is interpreted very strictly in Switzerland, which is a pity for somebody who loves his work and works with the brain rather than with a hoe in a coal mine. I continue research in the field of MS at the University of Zurich and the Karolinska Institute in Stockholm and spend most of my time at a startup company that we founded to develop yet another very interesting cell therapy for MS, that is antigen-specific tolerance induction.
We have written many articles on aHSCT in MS, but also about other therapies, disease mechanisms, infectious triggers, and more. All this is easily accessible on the internet, but most of it is (unfortunately) rather scientific and sometimes to hard to understand for a lay person.
Many thanks to Roland Martin for this clear picture of the aHSCT as a whole. I learned a lot during the interview. I hope the same applies to you.
See you soon and try to make the best out of your life,
Nele
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