Cell therapies are different than typical pharmaceutical reagents where one batch is needed for every patient. So the decentralized model where you have one main manufacturing facility that provides for the world, it does not really function well for cell therapies. They benefit from local manufacturing. Accessibility to these therapies in other parts of the world has been much more challenging. And so we believe that we can transfer our technology to centers in different parts of the world that do not have access to cell therapy yet and basically be there for them every step of the way to hopefully make this therapy more available in their parts of the world. welcome back in part one chantal bernard shea from ctmc a joint venture between resilience and md anderson cancer center walked us through the science and complexity behind t-cell therapies and how ctmc builds processes that respect the biology rather than fighting it now we go further We'll talk about next-generation cell therapies, the realities of global technology transfer, and the manufacturing barriers that still stand between these treatments and the patients who need them. Let's pick up where we left off. Are you juggling the complexities of CMC development while trying to enjoy the beauty of biotech? Have you ever wondered if there's a way to simplify bioprocessing? Welcome to the Smart Biotech Scientist podcast, where we're diving headfirst into the very challenges you face. We're breaking it down, demystifying the jargon, and giving you the keys to unlock your full potential. I'm your host, David Brulman, and I get it. With 15 plus years in the biotech industry, I face the same challenges you do. There's a way to simplify and streamline so you can remove complexity, you can skip trials and errors, deliver without delay your groundbreaking therapy to clinics at market and still enjoy every single step. Do you want to learn how industry experts and I did it? Grab a cup of coffee and your favorite notebook and pen. Now is the time to take your bioprocessing game to the next level. Let's smarten up biotank. I'd like to zoom out now, Chantal, and look at the way you operate. You work in a particular setting. You are operating or you embrace a patient-adjonesome manufacturing model that is directly embedded within MD Anderson. Can you tell us how this changes the way you develop processes and also then how you are able to develop these processes faster and get into clinics faster. Yes. So I would say that our close collaboration with MD Anderson Cancer Center, we're physically in close proximity and we also have a very good collaboration with clinical teams over there and also with the regulatory interactions with FDA. Our regulatory team, actually, for first in human studies files the IND on behalf of MD Anderson in electronic format with FDA. So we have been able to have touch points with FDA on multiple products at this point, fighting pre-INDs, INDs, and IND amendments for multiple engineered and unengineered till different CAR-T modalities. So I think it's been useful for us to understand from a process perspective also the requirements of FDA that are phase appropriate when you move into clinical development. and also because of our background in T-cell therapy development at MD Anderson. And now, and actually I'm from MD Anderson, a lot of people from my group joined this new company. So we are just continuing the work that we've started at MD Anderson early on and we've built bridges, logistic workflows with MD Anderson in terms of acquiring affairs with products for tissues, tumor tissues, and sending the finished product back. We work very well with them, and we are able to accelerate the study activation time post-IND safety proceeds. So that is very well aligned with accelerating the development of the products. I would say on the process development perspective, we have accumulated experience with different platforms tailored to different products. So it's rather easy for us to assess the needs of a new product coming in and tweak platforms that we already have existing to accommodate the needs of a new product. So I think having touched many different patient population and cell therapy products, it becomes easier to navigate. But we also need to stay on top of the innovation with instruments and reagents side to really allow newer products to break new ground and take the manufacturing to the next step At CTMC we have a focus on what we call bioinnovation trying to see what are the new trends and what can help us to help our partners in our processes. For example, a lot of our products use retroviral transduction, which can be particularly interesting in terms of closing the process. For various reasons, retroviruses need proliferating cells to integrate and to get cells to be in a proliferative state. We need sometimes to activate them in a stronger fashion, stronger manner, which is difficult to then do in a closed system manner. But we now have worked with other innovative companies that have found solutions to these problems. And we're incorporating these new technologies in our new iterations of our platforms. So I think for me, it's been very interesting to see how we can work together with our technology partners and biopharma partners to improve on the quality of the package that we provide. What are the key success factors with this model? Is this the close proximity that allows you to develop faster? Is it the access to knowledge? Is it something else? It's a little bit of both. I would say that we have developed a model that's maybe unusual. It's not akin to a typical CDMO. It is collaboration-based. We like to really add value to the products. And so for that reason, we have collaborated more with smaller companies that may not have a fully defined process that we can help them work through their process challenges so they don't have to reinvent the wheel. We are very familiar with TIL and CAR-T processing. If a new TIL or CAR-T comes in and they want to add a gene or knock out a gene, we usually can incorporate this in a platform process and save them a lot of time going from a research process to a GMP room appropriate process. That's still phase appropriate for phase one, but I think we can accelerate there just because we have good experience with taking these type of products from research to clinical proof concepts. In addition to that, you're working on an alliance that aims to transfer cell therapy manufacturing knowledge globally. How does that work? Yes. This program probably stems from the realization that cell therapies are different than typical pharmaceutical reagents, where, as I talked about before, one batch is needed for every patient. So the decentralized model where you have one main manufacturing facility that provides for the world, it does not really function well for cell therapies. So they benefit from local manufacturing. Though in the U.S. there are multiple CAR-T products approved and now a TILT therapy product approved, accessibility to these therapies in other parts of the world has been much more challenging. And so we believe that we can tech transfer our technology, our platform processes for TILT, for example, to centers in different parts of the world that do not have access to TILT therapy yet. And we have a first partner in our alliance, which is in Brazil. and we intend to work very closely with them to see what they need. So these type of alliances will be definitely customized based on the needs of the different centers that wishes such an interaction. But we are equipped to transfer our procedures on the process side and the analytics as well. We can really understand where they're at and help them have even discussions with their regulatory bodies that may not be used to receive applications as used as the FDA to review cell therapy applications so we can help them formulate a regulatory strategy, engage with their regulatory authorities, and give them training, hands-on training on the process in analytics side, and basically be there for them every step of the way to hopefully make this therapy more available in their parts of the world. We've seen that people are welcoming this, so we hope that this model can be extended to multiple other centers. What are you seeing as you're working on this model? What are the biggest manufacturing and process barriers that currently limit patient access? Well, the Global Alliance Network model is really to extend the availability of these therapies to other centers. What we're seeing for cell therapy, particularly because it's newer in terms of being FDA approved, we see that centers see the benefits of cell therapy being reported and they want to be part of it, but they are unsure where to start. It is more involved manufacturing than CAR-T. As I mentioned, it's a longer time frame and it involves a larger number of cells. So people are unsure where to start and we can really help them get started make sure they have the critical reagents I mentioned that we developed ways to grow cells even from highly pretreated patients that took us years to sort of understand and readjust our processes to get there, but we can provide them with that process right away so they don't have to overcome that challenge when it presents to them. For a smart biotic scientist who is unsure where to start, what is one piece of advice you would give them? I think that for somebody starting out. First of all, in my team, I have the privilege of working with scientists who understand the realities of GMP manufacturing because they have that background. So I think that for a process development scientist, it is really useful to expose yourself to a GMP manufacturing environment and understand the constraints of that environment. Because sometimes what seems doable or easy in process development lab may not be adapted to GMP environments. I think it's important to keep that in mind at every step of the way when you develop a new process. Other than that, I think that challenges will occur, but it's about being patient but persistent because there's always a way to overcome. But we've sent quite a few processes in the clinic that at some point struggle, come back for more optimization, and then it's a back and forth. But I think every product is different. New technologies require new adaptation. Now on the CAR-T front, people are coming in with very innovative approaches, with logic-gated CAR-T attacking more than one antigen. I think these are tomorrow's successes probably in the clinic. The process development for each of these iterations needs to be adapted to the new reality. Speaking of the future, Chantal, how do you see the future of CAR-T? Because we hear now about second and third generation TILs and CAR-T approaches. What does that mean and where is the field going to? Yes. So I would say for CAR-T specifically, we've seen quite a few generations, as you remarked. The constructs were iterated on first with enhancing the signaling through the CAR-T molecules are the second generation, then adding other genes to the CAR-T to make them function in the tumor microenvironment. Right now, we see more of these approaches to try to widen the antigens that are targeted by CAR-T by having safety gates around them, meaning that I said at the beginning that it's difficult to find one antigen that is only expressed in tumors and not on normal cells that will not cause damage to normal cells if targeted. So now there are intelligent CAR-T molecules that can target several antigens, but only kill the target if the antigens are expressed on the tumor cell. For example, the link cell therapies that we are working with as a company developing a product that targets two antigens, the ENPV3 and CN9, that are normally co-expressed on tumor cells for renal cell carcinoma, but they can also be found on normal cells but never co-expressed. So this CAR construct can actually be only fully activated when a cell co-expresses the two antigens, which should be a tumor cell. So there are more next-generation designs that will potentially avoid toxicity on normal cells and focus the cytotoxicity on tumor cells and hopefully extend the patient population that can be benefiting from these CAR-T therapies. On the TIL side, the only FDA-approved version is unengineered yet, relies on the natural ability of the T-cell to recognize the tumor. What we see coming as next generation is engineered TIL, engineered in different ways. We have our longest interaction at CTMC with a company called Obsidian Therapeutics, who is developing a membrane-bound IL-15 engineered TIL product to remove the need to treat the patient with high-dose IL-2 concomitantly with the TIL. And that was historically done to favor engraftment and persistence of the TIL. Now, if they carry the cytokine directly on the T-cell, they will not need to supplement with ex vivo cytokine. and this will limit the toxicity profile of the TIL because a lot of the toxicity comes from the high-dose IL-2. So this is great. They're showing improved efficacy. We need to see more patients. Those are only a small number of patients that the outcome has been reported, but I think it's very encouraging. KSQ Therapeutics is also developing another TIL product in which critical genes impending the activity of the TIL are removed by CRISPR technologies. So they have a dual edited product that targets both SOX1 and Regnase 1 and to improve the function of the TIL. So the field is evolving to or improving the function of the infused T cells, both for CAR-T and TIL. I think this is where the future lies. For CAR I think the short manufacturing process preserving more of the fitness of the T cells is definitely something pursued and I think very promising But there also in vivo CAR which is basically removing the ex vivo manufacturing altogether. This is where patients are infused with the viral vector that will, in the body, target the T-cells to engineer them into CAR-T cells. But there's very limited data available on this therapy. It is promising, but it has the caveat that we cannot totally monitor. Well, with ex vivo expanded T cells, we can fully monitor the dose that we're giving, the number of viral integration in the product that is infused, and we can make sure this is uniquely a T cell product. These safety guardrails are not available for the in vivo CAR T. strategies are elaborated so that the virus will integrate only in T cells, but it still needs to be demonstrated that there are no other cells that are engineered or tumor cells that would be engineered. So I think that there's a long way to go before this becomes mainstream, but it is a very interesting approach, very promising approach, but we just don't know enough yet to understand how applicable it will be. Before we wrap up, Chantal, what burning question haven't I asked that you are eager to share with our biotech community? I think that CAR-C and TIL therapy are there to stay as a treatment modality. I'm very hopeful for the future. I think that we are seeing more and more effective therapies. So I think the future is bright. Being in this field for a while. I'm very excited to see it coming to fruition and having so much successes. I don't know what question to ask you. Excellent. This has been great, Chantal. We have covered a lot of ground today. If our listeners had to take away just one single thing, what would that be? I think the field currently has come a long way. We have now regulatory approval for both CAR-T and TIL. I think many hurdles have been overcome. I see a lot of interest to expand accessibility to these therapies in maybe other geographies. And I really hope that in the next few years, we see an acceleration of these in that patients just have more access globally to these therapies. Where can people connect with you and learn more about your work and hopefully also get inspiration from your novel model? We can connect on LinkedIn. I'm happy to chat about our model. We're happy to have anyone stop by in Houston at CTMC as well. Happy to connect and see how we can help you develop your product or just learn about our model. Because I think that the model that we are developing, which is really a comprehensive partnership with early cell therapy developers, is something that is needed in the field. I think the fee-for-service model has a lot of limitations, and our model can actually help these early cell therapy developers to avoid missteps and accelerate the development. And what I mean that is getting to testing new therapies faster and getting access to patients. There you have it, smart biotic scientists. Use this opportunity to reach out to Chantal, and you will find the links in the show notes. And thank you very much, Chantal, for being on the show today and sharing your passion about cell therapies and giving us a picture of where this field is going to. Thank you so much. My pleasure. Thanks for having me. From next generation cell therapy approaches to global manufacturing networks, Chantal Bernadze has given us a clear eyed view on where this field is heading and what it will take to get there. this conversation is packed with insights you'll want to bring back to your bench and if you found it valuable please leave a review on apple podcasts or wherever you listen it helps other scientists to find the show thank you for tuning in today and i'll see you next time all right smart scientists that's all for today on the smart biotech scientist podcast Thank you for tuning in and joining us on your journey to bioprocess mastery. If you enjoyed this episode, please leave a review on Apple Podcasts or your favorite podcast platform. By doing so, we can empower more scientists like you. For additional bioprocessing tips, visit us at smartbiotechscientist.com. Stay tuned for more inspiring biotech insights in our next episode. Until then, let's continue to smarten up biotech.
