S6E6 Advanced cell therapy for progressive MS with Dr Stefano Pluchino

04:23 “It is becoming more complex between active and non-active types of primary and secondary progressive MS where activity is attributed to other episodes. Clinical episodes of disease or radiologically evident episodes of disease, which can be identified by the use of contrast agents at the time of the MRI. So, they are very complex very heterogenous types of disease, with or without activity, which inevitably undergo accumulation of neurological deficits.”

06:39 “What’s becoming very interesting is that [over the last] few years, there is a general worldwide consensus that progressive MS is becoming and has become a clinical unmet need. The old MS world is concentrating on financing, funding and efforts towards stopping MS through the development of a new generation of DMDs which will eventually target progression rather than relapses.”

19:10 “There is space for assessing whether a proportion of the injected cells [can] differentiate in vivo into new myelin-forming cells. There is a space to assess whether some of the cells [can] increase the survival of neurons in the brain. There is space to assess whether the transplanted cells [can] reduce the type of inflammation which characterises progressive MS, which is what we call a smouldering inflammation.

These highly diffuse homogeneous, low-level activations of microglia (immune cells of the central nervous system) and astrocytes (star-shaped cells that hold nerve cells in place) might be reduced by means of advanced cell therapy and the reason why I am specifically alluding to these three major biological mechanisms of disease, remyelination, reduction of inflammation and neuroprotection is because we have managed to identify each of these mechanisms in clinically relevant animal disease models in the last 25 years. So, there is [an] expectation that a clinical trial designed in a way that will allow us to establish the efficacy of the treatment will reveal what we have established already in one of these models.”

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Overcoming MS  00:00

Welcome to Living well with MS. This show comes to you from Overcoming MS, the world’s leading multiple sclerosis healthy lifestyle charity, which helps people live a full and healthy life through the Overcoming MS program. We interview a range of experts and people with multiple sclerosis. Please remember all opinions expressed are their own, Help others discover living well with MS. If you enjoy the show, please rate and review us wherever you listen to podcasts. And now let’s meet our guest.

Geoff Allix  00:36

Welcome to the latest edition of the Living Well with MS podcast. Joining me on this edition is Stefano Pluchino. Stefano received his MD and PhD degrees from the University of Siena in Italy, and has had additional training at Cambridge University in the UK. He is currently professor of regenerative neuro immunology and Honorary Consultant in neurology within the Department of Clinical Neurosciences at Cambridge University is here today to talk about this research in advanced cell therapy. So welcome, Stefano.

Stefano Pluchino  01:06

Thanks so much, Geoff, for the invitation.

Geoff Allix  01:09

I hope you’re enjoying weather in the UK.

Stefano Pluchino  01:11

It’s so windy

Geoff Allix  01:17

Interesting that you’ve moved from somewhere that I’d consider almost paradise to where we live anyway. So to start off with, could you introduce yourself and your work and your interest in MS?

Stefano Pluchino  01:31

Yeah, actually, you already pretty much introduced me but I can elaborate a little bit on on my background. I am clinically trained as a neurologist. But I’ve always had a very, very strong interest in experimental research and preclinical research. And I have spent, I would say, the great majority of my career trying to develop, trying to first identify and then to develop new therapies for MS. I started with my PhD in experimental neuroscience where we develop an experimental therapy made of brain stem cell for an animal model of MS in mice. And then we move to a larger nonhuman primate study. And as you can see from the most recent publication, which I think is one of the reasons why we are here today, we finally managed to complete the first in men phase one proof of concept human study, using the very same principles but of course, in humans using human brain stem cells for people with progressive MS. So that’s my background. That’s where I’m coming from, and that’s my interest.

Geoff Allix  02:37

So, if the trial was specifically for progressive MS, so, firstly, how would you define progressive MS. And how is it different from relapsing remitting MS?

Stefano Pluchino  02:52

There are multiple ways to define progressive MS. One, which is, which I think is very well understood to even to lay people is a type of the type of disease which is characterized by accumulation of neurological dysfunctions in the absence of clinically evident flares of disease. The definition, the neurological definition a little bit more complex than that, because we are using clinical and imaging readouts to identify what is progressing and what is not progressing. What we know, the more we understand about MS is that within the same nomenclature, there is a very heterogeneous type of disease, which might be different from patient to patient, but in general, just to be to be clear, whenever we identify progression, in the absence or in presence of clinical relapses, then we start discussing of progressive illness. There is a distinction between a disease which is characterized with by the accumulation of indolent progression for the very very beginning from the onset, which is what do we call primary progressive MS and the results of a disease which instead is an evolution of an initially relapsing remitting type of disease, which is called secondary progressive MS and then in the context of primary and secondary progressive MS, we can distinguish and it is becoming more complex between active and non active types of primary or secondary progressive MS where activity is attributed to other episodes, clinical episodes of disease or radiologically evident episodes of disease, which can be identified by the use of contrast agents at the time of the MRI. So they are very complex very to the genius type of disease, with or without activity, which inevitably undergo accumulation of any logical deficits

Geoff Allix  05:03

And most treatments are for relapsing remitting MS, aren’t they?

Stefano Pluchino  05:09

In the general in the general belief or in the general knowledge, we are very lucky we and patients are very lucky to be to be having the opportunity to be considered or offered for what we call disease modifying therapy. So basically, the pharmacology of MS has to distinguish between two main categories of drug treatments, the former of which is for symptoms, what we call symptomatic treatments, with minimal impact on the disease progression on the disease evolution, and then we would we call the DMTs. The DMTs is an acronym which stands for disease modifying therapies. So these are therapies, I would say, next generation biologics or advanced therapeutics, from which we expect a modification of the disease evolution, or what we call trajectory in the context of DMT that we have available on the NHS, which are under continuous development and discovery in clinical trials. The great majority of what we have available at the moment is for relapsing remitting MS. Because of the initial exercise to develop a disease modifying therapy for MS was targeting that type of inflammation which leads to clinical relapses, new hospitalization, increased costs on the NHS, but what’s becoming very interesting is that since a few years, there is a general worldwide to say consensus that progressive MS is becoming and has become a clinical unmet need. And the old MS world is concentrating money finances, funding and efforts towards stopping MS and stopping MS to the development of a new generation of DMDs which will eventually target progression rather than relapses.

Geoff Allix  07:16

And do you think ultimately, that could work for all forms of MS. Will there always be a sort of relapse remitting DMTs and progressive DMTs?

Stefano Pluchino  07:27

Whenever you have to develop, whenever you have to identify a potential drug, pharmacological target and develop a new therapeutic, you are inevitably bound to a good understanding of what is the mechanism of disease that you want to target? What is becoming more and more accepted is that mechanism of disease in progressive illness, both primary and secondary, are very similar to disease mechanisms in other classical neurodegenerative conditions, including, for example, Frontotemporal dementia, Alzheimer, Parkinson’s, and other chronic conditions of the brain. So there is expectation that this exercise of identifying new targets or repositioning FDA or fully approved medication from another neurodegenerative conditions to MS. My other good impact but in primary and secondary progressive MS because of the share mechanism of the disease. And so your trial, could you tell us a bit about the trial design and how you gathered the participants and select the participants who ultimately took part. The trial that you are alluding to is the one that we published back in December last year, which received lots of attention in the media and in scientific community and which is the beginning of the end actually, it is the end of 25 years of work preclinically and it is the beginning of another journey, which would be that of showing non ambiguously that there is space for advanced cell therapy for progressive MS. So it did take as much as 20 to 23 years from the initial first experiment in mice to complete a phase one first in man dose escalating proof of concept human study in people with progressive MS. The clinical trial design is very simple, because it is similar to many other phase one studies and to understand clinical trial design, we have to remind ourselves what is the remit of the phase one study? And the ambition of the phase one study the phase one study is the first human trial in the long journey leading to authorization and licensing of a new medication for clinical use. In the aim for the clinical trial are usually the feasibility of the study, the safety of the procedure and the administration of the drug and the tolerability. So everything but means of efficacy, there is no placebo control group, there is no, there is no control group whatsoever. But what is important is that we assess very rigorously whether we can produce a new medication for clinical application, whether that medication is not putting at risk, the health and the life of participants, and the medication is well tolerated. And I’m very, very proud and very happy to say that the trial that we completed, reached and met all these major aims, we were doable, it was safe, and it was very well tolerated.

Geoff Allix  10:58

I was gonna say the other thing, which you might be carrying on to then. Did you also test for what results you got? You know, whether so that mean, that’s the first thing, obviously, it needs to be safe, you know, but then, sort of leading up to further trials, did it also have an effect on the participants?

Stefano Pluchino  11:17

Yeah, that’s what conventionally we do, we do in phase one study. So we try to develop a little bit of biology or biomarkers in the trial, without emphasizing too much on the outcome, because the reasonable control group is a piece of evidence that we use to start putting together a phase two study, which is the inevitable follow up of a successful phase one study. And we did indeed a little bit of by much more than a little bit of biology in the phase one study by by collecting longitudinal biofluids from participants. So actually, we did two things, the first thing that we did was to escalate the number of injected cells, from a minimum of 5 million cells per patient to a maximum of 24 millions in order to identify that what we call maximum tolerated dose. And there were no adverse events whatsoever, regardless of the number of cells injected, so which means that even 24M cells we can escalate even further. And then we collected as I was saying biological fluids multiple times. Over 12 months of follow up from patients and the way we managed to do the sampling. I think it’s second to no other study, because thanks to the incredible support of those participants to the trial, we were able to collect seven longitudinal serum samples in 12 months, and five conduct longitudinal CSF samples. So these individuals, the participants to the study, underwent five consecutive lumbar puncture, from the beginning to the end. And then we subjected the CSF and the serum to what we call untargeted unbias profiling, looking for metabolites for proteins and lipids. In order to study the way the metabolism of the brain responded to the transplantation of the advanced cell therapy product. And that’s the biology that we started gathering. Because regardless of the intrinsic limitation of the study, one of which is the fact that we were for ethical reasons, we were bound to recruit people with very advanced disease, who were not eligible for any other treatment. So it is a very late stage disease with very high levels of disability with minimal hypothetical minimal response to a given treatment. Regardless of this, we found very interesting biological readouts in the CSF and plasma which are very, very important very promising when putting together a phase two study, and the type of responses we collected was that still, despite the very late stage disease type and the very advanced disease, the brain was responding to the treatment in a dose dependent and time sustained fashion, which means that the more cells injected the more response which was sustained over 12 months of follow up, which is which is very, very exciting biologically and moving forward.

Geoff Allix  14:35

And eventually the difference between primary and secondary progressive this was just for secondarythat right, Is there likely to be an expansion of the trials for people with Primary Progressive MS as well?

Stefano Pluchino  14:49

full honesty, there was another I don’t want to call it competing. It was a complimentary independent trial, which was conducted in in Italy, in Milano at San Raffaele Scientific Institute which enrolled people with primary and secondary progressive MS active and non active that goes much more into the heterogeneous in terms of patient selection, we decided to be more homogeneous and we recruited and selected people with active and non active secondary progressive MS only. But I think moving forward there is enough enough room to expand some of these preliminary early findings in human also towards Primary Progressive MS.

Geoff Allix  15:34

And so, you said stage one was successful. So, is a stage two trial planned, and how would you select participants for that trial if people who are listening are interested? How could they apply to be part of it?

Stefano Pluchino  15:50

There is no website yet available. There is no MS register yet in place where a patient can apply. We are working very very intensively towards an international consortium, which would imply would include representatives and key opinion leaders for from main European and non European countries, including the UK to establish phase two NSC transplantation consortium and by the time we will reach a stage of maturation of the project including some funding, we will make a press release and will make people aware of the direction the consortium is taking and the different possible means by which they can apply to be considered for the study to be screened for the study and then to be eventually enrolled into the study. Inevitably, a phase two study has to add some prerequisites which make it very different for from phase one. So, one of these requisites would be to slightly review the type of patients to consider for the diseases to be a little bit less advanced and there would be a placebo control group, because otherwise it would be equally very difficult to extrapolate any means of efficacy. We are planning to expand towards a higher dose of cells, so 24 million starting from 24 Million and considering also twice as much cells because there were no adverse events at 24 million of cells and there will be lots of imaging applied to the to the patient matrix, because by means of sophisticated imaging, we may infer whether the applied ACT advance cell therapy is impacting on the disease trajectory by which mechanism which can be the protection reduction of inflammation re myelination eventually, but we need imaging because otherwise it will be very difficult

Overcoming MS  18:03

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Geoff Allix  18:14

So there’s a potential because you just mentioned remeylination there, which I think is that sort of people who’ve had MS for a while that’s the kind of dream. Because you think well, okay, you can stop progression, but you know, there’s that dream of actually getting getting improvement. Is that a potential and have you found signs that there might be remeylination?

Stefano Pluchino  18:33

I think that potentially is there. I am I’m a great believer of multiple modes of actions, because one single mode of action I think is not enough to interfere meaningfully or or in a way which is clinically relevant with the complexity of MS. MS is not a simple disease it’s made of multiple mechanisms of disease, which are redundant in time and space. There is regional diversity and the results for temporal evolution of MS. There is space for assessing whether a proportion of the injected cells are able to differentiate in vivo into new myelin forming cells. There is a space to assess whether some of the cells are able to increase the survival of neurons in the brain. And there is space to assess whether the transplanted cells are able to to reduce the type of inflammation which characterize progressive MS, which is what we call now a smoldering inflammation. These highly diffuse homogeneous, low level activation of microglia and astrocytes which which might be reduced by means of ACT and the reason why I am specifically alluding to these three major biological mechanism of disease, remyelination, reduction of inflammation and neuroprotection is because we have managed to identify each of these mechanisms in clinical real relevant animal disease models in the last 25 years. So, there is expectation that a clinical trial designed in a way that it will be allowing us establishing the efficacy of the of the treatment will reveal what we have established already none of these models.

Geoff Allix  20:31

And so, when we say stem cell treatments and MS I think most people would, probably mostly thinking about HSCT or hematopoietic stem cell treatment or possibly autologous stem cell transplant. So, those are sort of traditional, if you like, but the stem cell treatmentd familiar and they use chemotherapy to effectively wipe out your immune system and rebuild it from stem cells. So, is this a similar sort of action or is it distinct from from those systems?

Stefano Pluchino  21:05

I think if if they are distinct, and the distinction is based on the different biology, the what do you call HSCT or hematopoietic stem cell transplantation or bone marrow transplantation is a procedure which was established for blood malignancies, back in the mid 60s. So, it is already kind of 50-60 years old, established technology, which has the ambition to reset the immune system of the individual receiving the transplantation without going into very much technical details of how autologous HST is done in people with MS. We We know now that unless there is disease activity, disease progression is not much affected by the transplantation about autologous hematopoietic stem cells, what we have developed is and advanced cell therapy, which is basically made of brain specific stem cells. So, these cells are extracted out of miscarriage human fetal material, they are fully characterized in the laboratory, and then they are expanded increasing number put on proliferation and application in in the presence of very complex recipe or recipes of chemically defined media, and then they are prepared for transplantation. So the idea is to put back in the brain stem cells of the brain for neuroprotection, reduction of inflammation and remyelination, the HSD go to the bone marrow. So the site where the transplantation of bone marrow stem cells and graft is the bone marrow, the site where the stem cells of the brain should be in grafting and surviving is the brain. So there are two complete different, completely different approaches.  So you’re not using chemotherapy? We are using a very, very low dose regime of immune suppression for precaution. Because the way the phase one study was done was to use a single miscarriage human fetus as a starting material and immunologically, that fetus is recognized by the immune system of the receiving patient as allogeneic. So we need to avoid the risk of rejecting the transplant itself. So it’s completely different from the intense chemotherapy that is given to people in preparation for the bone marrow stem cell transplantation. This is a very low dose combination of immune suppression to reduce the risk of rejecting.

Geoff Allix  24:04

And he mentioned some miscarried fetal donor, is it? Is it potentially possible that you could actually get the stem cells from the patient themselves in the future?

Stefano Pluchino  24:11

Yeah, there is two options actually, one is the one that you just mentioned. But we and other groups have data that would suggest that there is something wrong in the stem cells of the patient or at least there is something wrong in the body of the patient, which might predispose to those developing MS. So we have to be very careful when proposing autologous therapies. The other option which is very, very doable, because of the fantastic technology we have available is to use what we call cell reprogramming methodologies to generate brain specific stem cells from minimally invasive biopsies from the skin or from the blood, from the hair follicles others which we can make using again cell reprogramming technologies, unlimited numbers for tissue specific stem cells, including brain stem cells, you know what we call iPSC technology. This is a Nobel Prize in Physiology and Medicine 2012 to Shinya Yamanaka  and John Gurdon, which is now applied in the clinic to make pluripotent stem cells and to deny the tissue specific stem cells from these pluripotent stem cells, it is doable, and there is technology available.  That sounds like science fiction to me. So you’re literally taking them from any cells effectively. And they can build specific stem cells. So if assuming everything was was to go well, at phase two, then there’s normally a phase three trial before, actually, normal patients would be like, see the therapy. So how long would that typically take to go from where we are now at the end of phase one, up to actually a DMT going on the market? This is what everyone would like to know, including myself, I think will take less than 25 years, I think it will take less than how long it has taken to bring the initial the first experiment to the conclusion of phase one. Usually we can do clinical trials and make very elegant prediction of outcomes in the long run. But the key thing is that phase two and phase three clinical trials, especially for advanced cell therapies, or advanced therapies in general, are extremely expensive. So the academic work that we have done so far, because this is a fully academic, fully academic journey would be unlikely to be fully sustainable if there is no strategic partnership with either a funding body or a society or Pharma. Because that’s what becomes game changing in terms of speed of delivering the outcomes when moving to larger trials. So that setting, the key limit, limiting factor to things are the source of the cells. So we need to refine protocols and methodologies to make it fully sustainable and fully renewable. And then the funding because once you get to large studies, large human studies, we had lots of patients with hospitalization, MRIs, biomarkers, and the costs become insane.

Geoff Allix  27:39

And so you’re what you sort of, say 10 to 15 years would be typical?

Stefano Pluchino  27:43

I think is going to be less. If this the phase two trial is successful, then I think the interest will raise exponentially and with the interest might be also a raise of the available funding or the number of people interested to partner with the consortium.

Geoff Allix  28:06

And just to try and understand a little bit more about how it works. Could you explain how to go about reprogramming micro microglia and how to change the brain’s metabolism and Fatty Fatty Acids could halt disease progression?

Stefano Pluchino  28:22

And that’s another thing that we are doing in the lab, which does not apply directly to the to the ACT fire that’s a very, very elegant and innovative piece of mechanistic science that we’re doing in my my lab in Cambridge. We’ve been studying actually how cells behave in physiology and in disease and together with other groups, we have discovered that the initial if you like old fashioned understanding of cell types, you know, there is B cells, T cells in the bladder there are microglia astrocytes. So we believe there is a single cell type, it’s completely wrong. In each cell type there are multiple, what do we call cell states. So basically, a single cell is able to transmit between multiple different functional states from homeostasis to disease. And all this is regulated by their metabolism, the way they use, the food that we provide or the food that the organ provides or the blood provides. And by studying very, very molecular aspects of how metabolism works, we have identified a specific metabolic feature which is associated with a specific type of microglia that is responsible for disease progression in MS. And by targeting and by knocking that function down. We are able to stop progression in animal models and we are able to save neurons. So basically we have identified a potentially new pharmacological target, which is specific for microglia, which is accessible by brain penetrating small molecules, so it is pharmacologically druggable. And which plays a major role in the damage to neurons, which is responsible for disease progression. So this trial, are you at the start of the 25 years? This is not a trial, this is an experiment with very, very sophisticated genetic tools and small molecules and transgenic mice very, very sophisticated and single cell analysis, which is the beginning of another journey that we hope will be faster than the stem cell one leading hopefully to another trial with a molecule which will block microglia from becoming bad. And from becoming respondent to cause progression in MS.

Geoff Allix  30:58

So, I mean, I think the takeaway from that would be for me would be that, that’s going to take quite a long time. But there’s there’s constant research, though, isn’t there? It’s like, it’s, it’s not like, Okay, there’s one new drug, it’s like, there’s actually loads of trials happening. And then they’re here, we’re just talking about, I mean, it’s leading university, certainly, but a university in a country. And presumably, you mentioned Italy as well, but presumably around the world, there are many centers that are doing other research.

Stefano Pluchino  31:30

Correct. So there is other groups who are contributing to advancement of knowledge and develop a new understanding of mechanism of disease and identification of new drugs. So everyone is working to make it possible, and to allow everyone saying that we can stop MS soon.

Geoff Allix  31:55

And just as a final question, what would you hope your legacy is and the impact of your research?

Stefano Pluchino  32:04

The legacy the legacy that I envisage is students coming from to my lab and developing their career as independent scientists and traveling the world, and creating the network of individuals with enthusiasm and ambition and curiosity to identify why the MS brain goes wrong and how to fix it. And this is something which is happening already. There is people who have been trained in my lab and scientists who have been trained in my lab, we’ve been traveling all over the world, they are back in other university, they have been offered academic faculty positions, and they have established their own groups and this is already already ongoing.

Geoff Allix  32:52

Okay, so I think just to finish up, just to wrap up and say, if people are interested, as someone who’s been classified now a secondary progressive MS, I think, it’s absolutely fascinating, because you do feel a little bit left out in that there’s a huge choice of treatments for relapsing remitting MS and very few for the progressive types. So if people are interested, another thing to do would be really just to at the moment, keep an eye on information coming out about to future trials, it is unlikely to happen in the next year or so that that you would start to be talking about phase two trials.

Stefano Pluchino  33:38

There is lots of trials already ongoing. There are trials, mostly driven by pharma. One key example of a phase three trial which is currently ongoing in the world in people with progressive MS is the BTK inhibitors trials which have been run by multiple big pharmas at the same time, the results academic trials. I think we have in the UK the largest ever academic trial for progressive MS. The name of the trial is Octopus. It has received funding or at least been negotiating funding with UK MS Society, multi million pound it is currently recruiting. I think the impression of being left off out is understandable, but I would say it is temporary because of the number of efforts that the whole community is putting around progressive MS. We should remember everyone listening today that there is an initiative which was started few years back which is called Progressive MS Alliance. This is a worldwide Alliance uniting MS societies and scientists and companies to attack progression in MS. So we will get there. And I think it will take much less time than how much it did take to attack relapsing remitting MS. Don’t forget that what we see now in the NHS, all the DMTs were started being developed back in the 90s. And they were not available until the end or beginning of 2000. So it did take a while already that time. Now, relapses and inflammation is curable in MS. Progression is not curable yet. But everyone is committed to understand why progression happens and how to stop it. And it will happen.

Geoff Allix  35:47

And so if people are interested in trials, in my personal findings that actually my MS nurse, put me on to a research group, I live in the southwest of the UK to the Southwest Research Group. And they then gave me their contact details to the Octopus trial. So I would say and I think it’s probably worldwide if you speak to your healthcare professionals, they would typically have the connections to be able to set you up with with trials if you’re interested.

Stefano Pluchino  36:15

Yeah, I think the pathway is always the same: your healthcare professional, lead neurologist, MS nurse and then MS Society because you’ll find any information you’re looking for very much up to date in the MS Society website or MS Society chapter. Or MS Society branch or  working group that would say lead neuroligist, MS Nurse, MS Society.

Geoff Allix  36:39

Okay. And with that, I’d like to thank you firstly, very much for your research. And secondly, for joining us on the podcast.

Stefano Pluchino  36:45

Thanks, Geoff. It was very pleasant to speak with you today.

Overcoming MS  36:48

Thank you for listening to this episode of living well with MS. Please check out this episode’s show notes at overcoming ms.org/podcast you’ll find useful links and bonus information there. Don’t forget to subscribe to the podcast so you never miss an episode. And please rate and review the show to help others find us. This show is made possible by the Overcoming MS community. Our theme music is by Claire and Nev Dean, our host is Geoff Allix. Our videos are edited by Lorna Greenwood, and I’m the producer Regina Beech have questions or ideas to share. Email us at podcast at overcoming ms.org We’d love to hear from you. The Living Well with MS podcast is for private non commercial use and exists to educate and inspire our community of listeners. We do not offer medical advice or medical advice please contact your doctor or other licensed health care professional