Colorado Blood Cancer Institute physician, Dr. Richard Nash talks about easing autoimmune disease symptoms with stem cells.
Interview conducted by Ivanhoe Broadcast News in 2022.
What is autoimmune disorder?
NASH: An auto-immune disorder is a disorder of the immune system, where the immune system generates a pathologic response to organ systems. And you can have auto-immune disorders that affect the brain, the lungs, the heart, the gastrointestinal tract, and many other organ systems, the skin, etc. So it’s a fairly common form of disease pathogenesis or disease mechanisms. And they can be very severe.
And the signs and symptoms of auto-immune disorders can be varying. Does that make it harder to diagnose and treat?
NASH: I don’t think that the way you frame the question is- I don’t think the kind of varying signs and symptoms, I think it’s the systems that are involved and the type of disorders which we’ve now characterized where we know some of these auto-immune disorders can be very severe and can be very debilitating. Some of the disorders can be very mild. But even within a disorder, say, for an auto-immune process, some of these auto-immune diseases can be mild and very- can be manageable and some can be very severe and then resistant to therapy.
What are some autoimmune diseases?
NASH: There are lots of different autoimmune diseases. Some of the ones that are probably better known are some of the rheumatologic autoimmune disorders. The disorder that- which we treat here at Colorado Blood Cancer Institute, which is a transplant program, is systemic sclerosis, which can be a life-threatening disorder. But also rheumatoid arthritis, systemic lupus erythematosus, SLE. And then there are various other types of rheumatologic auto-immune disorders like polymyositis, etc. So there are many different types for the gastrointestinal system, Crohn’s disease, ulcerative colitis. For the neurological system, multiple sclerosis. Despite what is more common ones, but there are other different types of auto-immune disorders, peripheral neuropathies, CIDP, stiff person syndrome, etc. So there’s quite a- there’s quite a selection of different types of auto-immune disorders.
Can we talk about what is myasthenia gravis?
NASH: So myasthenia gravis is an auto-immune disorder. And it’s at the neuromuscular junction, which is targeted by antibodies or by an immune process, and it prevents the signaling that occurs. So patients with myasthenia gravis, again, it can be mild and treatable. And then we have patients with myasthenia gravis who can be profoundly ill and disabled, who aren’t responding well to conventional treatments.
What are common treatments of auto-immune disorders?
NASH: The treatments for auto-immune disorders, the common treatments are treatments that are going to suppress the immune system so that when patients develop an auto-immune disorder, there’s activity of the immune system against that organ system or multiple organ systems. So what we try to do is suppress the immune response. And one of the ways of doing that is by administering various kinds of agents which may dampen down the immune response. And there are some agents that act against T-cells, which is one of the arms of the immune system, other agents that target B-cells which are part of the immune system. Some agents that are non-specific but are associated more with chemotherapy and really suppress the- all of the blood system as well as the T and B-cells. And then with transplantation, I mean, one of the things that we do is we give high dose therapy and follow that with autologous blood transplantation in an attempt to really reset the immune system.
When it comes to bone marrow transplant as a treatment, what is the idea behind that? When did bone marrow transplant become a treatment option?
NASH: So we started doing transplants probably about 20 years ago, maybe even longer than that. And there were a few centers that started doing this. I was at the Fred Hutchinson Cancer Research Center before coming here to the Colorado Blood Cancer Institute. And we started a pilot study to see if we- if there was going to be- if we could ascertain responses to the treatment and determine if it was a safe treatment to give to patients oftentimes who are very sick before the transplant. So we started out in this, studies have grown and we now have expanded. Since that time, we- there’s been a randomized clinical trial, which is one of the ways that we confirmed that a treatment may be effective for a disease. But there’s been now a number of randomized clinical trials showing that high-dose therapy and autologous hematopoietic cell transplantation for a disease called systemic sclerosis can be effective in improving survival as you follow patients long-term where patients who are on the conventional treatment arm did poorly or they had a higher mortality rate versus patients who are on the transplant arm. We’re also doing studies now in multiple sclerosis. And those studies, again, started a long time ago. There’s been a number of studies showing that the transplants for MS can be effective. There was a randomized clinical trial that showed that the transplants could be highly effective as well. There’s another randomized clinical trial ongoing, which is looking at more updated treatments- conventional treatments for MS versus transplant and that’s a study that we’re trying to accrue to right now in terms of a patient population. But what we see so far is that about 70 percent of patients- so patients have relapsing, remitting disease, relapse remitting MS, that about 70 percent of the patients can stay in remission long term about five years after their transplant. So that’s really a significantly- a significant improvement over what was sort of the conventional therapies for MS. So we’re transplanting patients now with MS. Again, the MS in this study is an important study that’s trying to confirm that the transplants may be better than conventional therapy with the more modern forms of conventional therapy and what was used previously on an earlier randomized clinical trial. And that’s a study that we’re supporting here as well.
Can you explain what bone marrow transplant for auto-immune disease, what the procedure looks like?
NASH: So when patients come in for transplantation, we evaluate the auto-immune disease to get a better idea of the activity of the auto-immune disease. And we evaluate the patient, do a medical status evaluation, evaluating organ systems to make sure that patients are reasonably, except for their auto-immune process, that they’re reasonably stable coming into the transplant. If patients are very, very sick coming into the transplant, we may not be able to proceed with transplant because the transplant may make the patient sicker. And there’s a possibility that if patients are sick coming into the transplant, the transplant may actually be associated with their death. So we do a thorough evaluation of the patients. Some patients after we’ve done the evaluation, we may not feel comfortable moving ahead. So we’ll step back and patients will go back on to conventional therapy. When we’ve determined that the patient can move on to transplant, we then mobilize the stem cells- the blood stem cells, which are then frozen and can be stored for- used for the transplant. When we mobilize the stem cells, this is when we give- there’s different ways of doing it. But when we mobilize stem cells, stem cells come from the marrow, we give some chemotherapy and an agent called G-CSF to mobilize those cells from the marrow into the peripheral blood and then we collect the cells in the peripheral blood and then they’re frozen. Weeks later when patients have recovered from the immobilization procedure, we move on to the transplant where patients receive high-dose chemotherapy, and that high-dose chemotherapy is going to ablate or basically eliminate the blood stem cells and the centering the patient at that time and also eliminate and reset the immune system that’s causing the auto-immune process. So we give the chemotherapy and then on day zero, after the chemotherapy is given, we administer it to the cells, and then we support the patient into recovery of counts and recovery of counts, as you’ve read about day 11, on average, after the transplant.
Is one transplant enough for life and is it a cure?
NASH: So the data we have right now from patients that we’ve transplanted and there’s going to be some variability, some patients where some diseases seem to be very responsive to transplants other diseases maybe less responsive to transplant but that’s something that we still have to sort out. The attempt now as to what we’re trying to say is whether patients- if the transplants are going to be effective for life and that really requires that we do long-term follow-up, some of the follow-ups we’ve done, say for relapsing, remitting MS patients that at about 10 years after the transplant- systemic sclerosis patients 10 years after the transplant show that a lot of patients are still remaining in remission with an MS, it’s 50-60% with systemic sclerosis it’s probably maybe as high as 70- 60, 70% of the patients are off therapy and in remission with some recovery of their disease, some recovery of the organ systems that were involved.
And the traditional treatments wouldn’t provide that level of emission?
NASH: So one of the reasons for doing a randomized clinical trial is to address that question, is doing the transplant more effective and produce better survivals or better long-term outcomes than conventional therapy? There are some patients on conventional therapy which may do well, but what we’re seeing is that we get better disease control with transplants at this time for both systemic sclerosis and multiple sclerosis, and potentially other auto-immune processes- for these other auto-immune processes, we still need to do more work, but we’re still seeing some very promising responses to treatment, high-dose therapy and transplants for these treatments. And then the other thing that we’re doing right now is we’re now exploring the possibility of doing allogeneic stem cell transplants because this is where we do a transplant from a donor where the overall outcomes of transplants from a donor has improved a lot. And we see this experience in patients who have transplanted right now from a donor for hematologic malignancies or for sickle-cell disease and thalassemia were the outcomes now we’re actually very good, so the question now is.
And we talked about which autoimmune diseases does this work for and what have been some of the outcomes you’ve noticed with myasthenia gravis in particular?
NASH: So there’s still very limited experience doing transplants for us. The group up at the University of Ottawa really had a major case series where they had done seven patients, I think the first patient was back about maybe 15 years ago, and again, seven patients. And what they saw was that there was good responses and that the patients did well for a long period of time and coming off their therapy. We had a case here of a patient who was referred to us from the East Coast, and this patient had a profound case, a very severe case of myasthenia gravis, and had been intubated three times before she came here, she had a feeding tube, was in a motorized wheelchair, could barely talk, I couldn’t understand her, her husband interpreted for me and we took her to transplant. And basically on day 4 after the transplant, I was on rounds and went into see her and she was actually starting to speak with a stronger voice and I could understand her and then she just continued to improve from there, and now two years- more than two years after the transplant the patients had a complete recovery and she’s off all of her therapy at this time. So we’re still continuing to follow her but I think that makes it a very strong case for the possibility of doing transplants for patients with MS and she’d failed essentially all of the therapies that have been given for myasthenia gravis the non-transplant therapies. So we’re actually planning and I’ve written up a clinical trial which will proceed from a number of centers across the country and then with a center in Canada, the University of Ottawa, where we’ll be doing transplants for patients who have failed therapy- conventional therapy, and then we’ll be doing transplants on those patients.
Why wouldn’t this be the standard of care?
NASH: That’s actually an excellent question. So the- right now, there is a risk associated with doing transplants, so we always have to weigh the potential benefits and the risks, so the- for patients, if they’re failing therapies and they’re doing poorly then the risk of transplant may be a reasonable thing to do. And I think in those cases, certainly for systemic sclerosis, that it is going to be a standard of care for those patients. There are patients with systemic sclerosis who rationally really do have mild to moderate disease and a reasonably stable, we’re not going to do transplants for those patients because of the potential risks of the transplant itself. We quote that the risks for transplant with the randomized clinical trial that we were in that was sponsored by the NIH, the treatment-related mortality was 3, 4%, which is still significant in terms of the potential risk of death associated with the treatment. And then for different types of auto-immune diseases where we are doing transplants right now, we still don’t have enough information to say that we know that the transplant is going to be effective for that disease because we’re still in the process of doing clinical trials and even though something might be promising, we still can’t consider that a standard of care at this time.
Are there certain types of autoimmune diseases that BMT would not be good for?
NASH: So I think that that is something that we’re still exploring. The mechanism of an autoimmune process and the reason why these patients have an autoimmune disorder, because we’re having such a profound effect on the immune system, one would suspect that the vast majority of cases are going to be effectively treated with a transplant, either from the patient’s own stem cells after high-dose therapy or transplanted from a donor. That may not be the case or we still have very limited experience for the vast majority of autoimmune diseases, I knew that there were studies done with rheumatoid arthritis early on where patients had a low-intensity treatment regimen with high-dose cyclophosphamide and then were transplanted and many of these patients were relapsing after the transplant. So that’s really where we’ve not taken many steps forward in investigating that disease but higher intensity doing allogeneic transplantation may be a much more effective way of managing patients with rheumatoid arthritis but again, there may be differences in the way different diseases respond to the transplant and that’s still something we have to learn.
END OF INTERVIEW
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