Latest / BioSpace / From MSCs to iPSCs: building the cell therapy future
Transcript
- speaker-0: My name is Jennifer Smith-Parker, Director of Insights at Biospace, and you're listening to The Natured. In this episode, you'll be hearing from Miguel Forte, President of the International Society for Cell and Gene Therapy, and John Ellis, CEO and co-founder of Trench and Bio. We dive into mesenchymal stem cells and induced pluripotent stem cells, exploring the science behind them, the manufacturing challenges, and the potential for scalable, engineered next-generation therapies. Hi Miguel and hi John. Thank you so much for joining this episode of Denatured where we'll be discussing mesenchymal stem cells as well as induced pluripotent stem cells. So for shorthand MSCs and iPSCs. So I think to start off, if you can introduce yourselves, that would be great. Miguel, why don't we start with you? speaker-1: Thanks, Jennifer. Thanks for the opportunity to chat about something that is dear to my heart, which is obviously MSC's, but myself, I'm an MD, PhD by training. I've done multiple things, academic, clinical, regulatory, and I've been in cell and gene therapy now for quite a while. I'm also currently a president of the Interactual Society of Cell and Gene Therapy. So passionate about cell and gene and the value that cell and gene can bring to patients. and MSEs are in the cornerstone of that and we'll come back to that point in a minute. speaker-0: Thank you so much, John. speaker-2: Yep. So I'm John Ellis. I've been playing in a sale, I've been out for 23 years. think time applies to be having fun for the last 10 or 12 years. Also, I've been working with new technologies and then really now the trenchant trying to bring a new platform to light, which is going to completely transform the way cell therapies are made. speaker-0: That's a great introduction for the audience. And I think let's just start off to set the scene. Can we just explain, basic 101, what are MSCs and IPSCs? speaker-1: I'll kick it off that discussion and enjoy and can compliment. So mesenchymal stem cells are cells that are widely distributed in the body and have a potential to differentiate further and become other cells and regenerate and control, drive the body to equilibrium or mystasis as we say in a clinical or technical term. Those cells are relatively easy to collect. easy to produce have been the first entry cells into cell therapy. The opportunity that they have shown already to control things like immune response, regenerate bone, regenerate cartilage has given them a place in the armamentarium of cell and gene therapy. We will see how we can optimize that and go to the next stage. But they were, as I said, the first entry. And there is a resurgence now. because the data has been recognized, they have been approved in the U S they are being used in Europe. They've been approved in China and we can talk about all of that. Now these cells, if we can go one step before and go for even less differentiated cells with a broader potential of differentiation, it's what we call induced pluripotent stem cells, IPSCs cells that we've induced to become able to go into different cells. MSCs, also NK cells, T cells and other cells. So MSCs have been the cornerstone. And IPSC are the promise of going forward to generate any kind of cell that we want, that we can then transform into a therapeutic tool. speaker-0: That's a really good introduction for the audience. John, you want to go ahead and chip in here too? speaker-2: So I can't add too much better terminology definition, but certainly on the manufacturing of these therapies, because that needs to be done at scale. think that's the new challenge is, these MSC and IPLC derived therapies have tremendous potential. speaker-0: fantastic. I think if we step back here where MSCs were once seen as overhyped, so what's driving their current resurgence and how much of that is linked to their recent clinical data like Mesoblast? And maybe we can all very quickly just talk about what's happened with Mesoblast 2 for those who aren't familiar. speaker-1: Sure. I'll start with what happened to Mesoblast. So Mesoblast, which is the follow on of one of the initial companies in cell engine therapy and the first ones entering MSC therapy has been able to take MSCs into the market by documenting and having been accepted by the FTA as being able to control graft versus host disease. Just for the audience, if you do a bone marrow transplant, that bone marrow can actually recognize the body that goes into as foreign and can attack that body. MSCs can control that reaction and really make the patients accept the transplant or the transplant accept the patient, if I can put it this way. And the fact that the MSCs have been documented there to work and the FDA recognized is a cornerstone now of the next set of MSCs. Now MSCs have also been used for GVHD in Europe for a while. under the hospital exemption context and also ⁓ widely used in Germany, in Spain and in other countries. And they've also been approved in China for the same indication and they had been already approved in South Korea for several indications. So they have been around for quite a while. They have kind of penetrated to certain extent, but having been approved by the major regulatory bodies, the FDA, gave them that notoriety, that stamp of approval that brings them to the next level. I think we need to talk down the road, how can we optimize this first step? This is a step that you use cells that you collect from a donor, that you expand to become a product, that you then use clinically and document the effect. How can we along this chain from manufacturing to the clinical to the potentiation of the therapeutic effect, can we bring this to the next level? And I think that's exactly where we are. Go from a recognized benefit to a potentially optimized benefit. speaker-0: think it's important point of the optimized benefit and so much of optimization is also tying into scale up and commercialization, if I understand correctly, John. So maybe you can talk more about that and some of the hurdles or the challenges for these particular class of products. speaker-2: Yeah, absolutely. Clinical benefits, one thing, but most of the patients can receive them. And the data I've seen recently looks spectacular in the GVHD setting, which is wonderful, particularly in the pediatric patients who really suffer. So it's how can we actually realize that at scale? So MSCs, as Miguel said, are pretty simple to isolate, culture expand, turn to a product, at least with highly trained people at small scale. How can you do it to make a product that could be manufactured at scale? That's definitely much more, much more challenging. All that we can use to really help with the production of these therapies, but they're um, they're not always the easiest to play with. They're quite challenging. Um, I think that's where now we need to understand what, what the commercial landscape, what's the, what's the price point of this service going to be? Um, how are they going to be distributed and then figure out how we're going to make them adapt because right now there are tools out there in the market that can do this, but I think it's also turning that into a real streamlined production setting. So that's what I'm looking forward to next is what does commercialization really mean. speaker-0: Flipping back to the science, Miguel, so we've often described MSCs as immunomodulatory, but that is a quite a broad definition, is it not? So how has our understanding of the mechanism of action become more precise in recent years? speaker-1: When I speak about MSC, it's a bit like you have a plumbing issue. One of your tubes of water in your house bursts and you need to get it repaired. And you go to your neighbor who is a kind of an amateur, but efficient plumber. He comes in and he actually repairs it. So MSC's are a bit like that. They are. very broadly able to do multiple functions. They kind of go around existing the body and they say, well, if there's an immune response, they control it. If there is a tissue that needs, sorry, a tissue that needs regeneration, they're able to go and reconstruct. So they are good doers that once they see a challenge, they go up to the challenge and they are able to repair it. What we've done, and that's what most of the companies have done is, taking those cells, expand them, as John said, and then you get large number of them that you can then bring. And so it's a large number of amateurs that do a great job. And the fact that we've seen sufficient benefit to be regulatory approved makes them a self therapy currently. What we would like to do then is to educate these cells to do their function even better. And so we've documented that the cells have a regenerative capacity so they can go and transform for instance, to cartilage, they can transform into bone. That's one of the mechanisms of action. They also secrete a series of factors like IL-10 and other factors that control the immune response. And in that way, they can kind of control the graft versus disease. They can be used in inflammatory bowel disease. They can be used in other autoimmune conditions where they're immunomodulatory factors that they secrete upon seeing the inflammation is able to control the disease. But they need, in my belief, and that's what the evidence is showing, to go one step further. It's kind of teaching your plumber how to do it and making him professional. And that's what we do at Kitchi. We have the ability to transduce, i.e. insert into the cell genes that will increase the quantity of the factors they produce. So in a way we're not doing something different, we're just potentiating what the cell does by augmenting the quantity of those factors and making them more effective, more professional, but still doing their initial ability, potentiated by that gene editing. That's what I call the professionalization. That's also the element of the, the optimization of the quantity of the cells and the consistency. You can also consider how do you can generate large numbers of these cells from an IPSC. which is an additional option that gives us consistency, eye level and potentially lower cost. And I'll come down to one point is we need to develop these products in a cost effective, therapeutically potentiated way so that we're able to compete from the scientific to the clinical to the cost with the existing products so that we can bring value to patients. speaker-0: That's a great point. John, go ahead as you're going to just pick up. speaker-2: No, I totally agree. think that's the key is particularly having scalable solutions so that you can work on the bench side initially. You go to your clinical trials and have a commercial manufacture or on-maps. And that's particularly important when working with APS-Cs and MSCs to make a consistent product at the end of it. And particularly if you looking at T cells, NK cells and what can come from APS-Cs, you want to make sure you've got nice pure cell populations that can be produced at scale. so certainly having that The key is having the tools to go from bench side to early clinical studies, students to commercial without having to change the core technology because that's where everything can fall apart if you're not careful. And so that I think again is that then as challenges, how can we have those tools to take full advantage of IPFCs. I love and get us a point as well about effectively supercharging MSCs, getting more therapeutic potential. I think that's key. Either have a greater clinical benefit or alternative use of USLs. There has to be something which I'll make about it. speaker-0: I'm just curious here with so much potential, but there's challenges, it definitely sounds like, to getting to this point. So I'm curious, how competitive are MSCs and IPSs today from a manufacturing and a scalability standpoint? Do you have a number of players that can get to this hopeful point that we're talking about, or is it still inherently challenging within the manufacturing space to get there? speaker-2: Definitely challenging, that's for sure. are relatively few companies who are trying to produce iPSC-derived immunotherapies at scale. There are challenges, no question. It's it's groundbreaking work. I guess we're still at the point where we're trying to derive these first effective therapies produced in this way. And I don't think anyone yet knows what optimal looks like. And so I think the real key now is to get rich data to understand how... manufacturing works, how do the clinical effects look like and then how can we then go back to drawing board, how can we make better therapies drive this way and once you know that, how can we scale it up to be commercial. I think the analytics to make sure we really understand what it is we're working with and again that's sort of the challenge with the new therapy because you don't quite know what you're looking for half the time and so particular MSCs and IPSCs are having strong analytics again rich data early on to the development stage so you've really got good control over what you're doing. That's still the big piece of it, I think. speaker-1: If I can add to that, I think the biggest difference between let's say, previous cell therapy, like MSC's and current cell therapy with IPSC going forward is that you take from the donor and you're very dependent on that source, but then you will homogenize that through the manufacturing while on the IPSC you go all the way to the initial cell line. so consequently you just expand always the same thing. Now. There's significant challenge to get this as John pointed out, and we're still at the beginning of that. Just to put it in perspective, only two products and two companies have IPSC sells in the market and that's unconditional approval in Japan. So it's re actually that's where the IPSC technology really started. So we have two there, but we also have several companies that are developing IPSC derived products in clinical stage, NK cells, T cells, MSC cells. And so there's a lot of clinical trials going on. So we're really at the beginning, but IPSCs and ISCT was involved in a major IPSC meeting just a few, a few weeks ago in Kobe, Japan, together with the Japanese society of protective medicine, JSRM. And we've agreed that IPSC is a mainstay now in cell therapy. So we will have every year, either in Japan with JSRM or at our annual meeting at ISCT, a dedicated full-day discussion on IPSC, recognizing that it is a going forward, ⁓ very useful source of cells that you can differentiate to a specific cell type. that you can potentiate gene editing them to a therapeutic optimization, really then delivering an ideal cell and gene therapy product. I'm also involved in a company that is developing NKs from IPSC and doing six edits. other words, inserting six different functions to the cell to make it a potentiated NK cell starting from IPSC. We're really talking about bioengineering and really using the cell as an educated vehicle of a therapeutic function. speaker-0: Yeah, that's fascinating to see, especially the potential, as you mentioned here. So, see, in this gene editing concept. I'm just curious, how do you position MSCs relative to iPSC-derived therapies? From what I'm understanding, it sounds like we're starting with MSCs, but we're leaning more into the iPSC arena, so we're going in that trajectory. So, will MSCs essentially be left behind and iPSCs be the new front forward, or we still have... room for both of them to be in parallel. speaker-1: That's a very trusting concept. And if I can put it this perspective is we're using MSCs, but those MSCs come from the IPSCs. So IPSCs is kind of a raw material. We use them to create the cell because IPSCs as such don't have the functionality that we want to have the therapeutic effect. I mean, an NK cell kills tumor cells. An IPSC cell. does not kill tumor cells but can become an NK cell that kills tumor cells. An MSC can do what everything that we talked about and we can make it even better by engineering. ⁓ It's different from an IPSC. An IPSC won't be able to do that but we can transform that IPSC into the MSC. speaker-0: I think also when it comes to, you mentioned the geographic areas, and from the development of IPSCs, now MSCs, but also from the manufacturing perspective, is, you mentioned, Japan, is there a reason that they're, been ahead of us over this or have more interest in it? Are there also more manufacturing capabilities, John, over there versus over here? speaker-1: I mean, science is translational science that we're talking about is where the initial research happens. And when you then take it into the clinic and into work, Kamenaka was actually where this started. I mean, he developed the IPSC concept. And again, without going into technology is you have any cell and you change that cell genome to make the cell fully able to differentiate into anything. That's why it becomes a pluripotent cell and we induce them. So that inducing capability was developed by Yamanaka in Japan. So that's why they have the technology, they have the scientific leadership and consequently they were able to take into the clinic and the regulatory environment in Japan is also conducive to early entry into the market. So they've got two products into the market and that's also JSRM and us are talking about that. But we see that happening in the US. This is Australian company that is... developing IPSC derived MSCs into the clinic. it's broadening and it's spreading. So it just followed where the science appeared and now follows where clinical development is being done. speaker-2: Yeah, that's a fair point. think just historically because of the Apple and Apple's work in Japan too, they're very strong in IPSCs. But there is, as my girls say, fair amount of work in the US as well. Companies looking to really leverage that and take advantage of that and make therapies. I don't think there's a technology advantage in one drug for another. think it was still yet pretty early on in the IPSC frontier. So there aren't really tools out there that are specifically designed for IPSCs. I think it's leveraging what is mostly existed already and weakening it. to work with IPSEs, but as we get more more data, more understanding, sure, our forms are bespoke for this particular application. And we'll see where that goes. speaker-0: Thank you so much, Miguel, and thank you so much, John, for joining me in this episode of DeNatured to talk about MSCs and IPSCs. We have a really brave new world ahead of us, and it's really exciting to hear about. And if you'd like to listen to more episodes of DeNatured, please turn into biospace.com. Thank you.