The Simple BioTech Podcast
The Simple BioTech Podcast
#11 - Catherine Stehman-Breen: Innovating an "On" and "Off" Switch for Cell and Gene Therapy
Imagine if you could turn the characteristics of a cell on and off… or up and down like a volume trigger… constantly tuning things until everything is working just right. It might sound impossible, but that’s exactly what Obsidian therapeutics is working on.
I’ll admit, it was tough for me to wrap my mind around this one at first, but my guest today did a fantastic job of explaining things. So without further ado, chief development officer of Obsidian therapeutics, Catherine Stehman-Breen.
Podcast notes and transcript available here: https://simplebiotechpodcast.com/catherine-stehman-breen-obsidian-therapeutics
-James Ruhle, SimpleBioTechPodcast.com
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As I've learned more and more about the current biotech landscape, I've grown, particularly excited about cell therapy. There's many companies working on cell therapy, but obsidian therapeutics is approaching things differently. Imagine if you could turn the characteristics of a cell on and off or up and down like a volume trigger, constantly tuning things until everything is working just right. It might sound impossible, but that's exactly what obsidian therapeutics is working on. Al admit. It was tough for me to wrap my mind around this one at first, but my guest today did a fantastic job of explaining things. So without further ado, chief development, officer of obsidian therapeutics, Catherine STEM and brain, the human experience is changing. And it's going to happen a lot faster than you think the world is going to be a vastly different place in the next 10 to 20 years because of what's happening in the biotech industry right now. Welcome to the simple biotech podcast. My name is James rule and I'm your host. The goal of the simple biotech podcast is to interview the researchers, founders, and investors that are working directly in the industry and to translate what they're working on into simple and easy to understand language. If that sounds like something you're interested in, let's get started. Hi, Katherine, how are you doing today? I'm well, how are you? I'm doing great. I want to start off. I always like to get to know my guests a little bit more before we dive into the awesome stuff that they're working on. I want to start off. I want to just get to know you a little bit. How did you get into this industry? How did you find obsidian or obsidian found you? What was your kind of path to get to where you are now?
Speaker 2:Well, I'm a physician I trained at university of Washington. I became a nephrologist and which is a kidney specialist and was on the faculty at university of Washington for quite a long time, doing research, primarily epidemiologic research. But about 20 years ago, I was approached about a position at a biotech company called Amgen. That was making was, it was really actually a pioneer and making monoclonal antibodies, which is a type of platform therapy to treat very serious diseases. And I became intrigued with the opportunity of being able to be part of making and developing life-changing therapies and in doing so effecting a wide range of patients in an incredibly meaningful way. And so I spent, uh, quite a long time at Amgen before eventually making my way up to Boston. I was very intrigued by the Boston biotech community. It's an incredibly exciting time to be in drug development right now. There's been an exponential increase in the number and breadth of new ways of treating serious diseases. And the ecosystem in Boston is, is hard to describe to people that are outside of that, that ecosystem. There's just an amazing array of innovation and brilliant science that, uh, is being developed to change the way that medicine is, uh, administered to change the lives of patients that are afflicted with serious illnesses that affect their lives and, uh, the lives of those people that know them and care about them. So to be part of that incredible innovation was really exciting for me. So a few years ago, I took a position at a small biotech company making innovative therapies for rare disease and in doing so, I, I ended up actually becoming, getting connected with Atlas venture. Uh, one of the venture capital companies that starts, uh, many of these really exciting innovative companies. And through that experience, I became exposed to obsidian, which was originally started by Atlas venture was really intrigued by the platform that obsidian was developing, which there is intended to provide drug-like properties to cell therapy. I mean, by that is the way cell therapy is administered. Currently. There isn't a lot of control over the dose for a number of reasons. And the technology that obsidian has and is developing allows physicians to be able to control the administration of the cell therapy. So I, uh, I, I joined obsidian a little over a year ago and have been excited to be part of what I think is an opportunity to unlock cell therapy for a much wider range of patients.
Speaker 1:That's really awesome. And yeah, I've had some calls with some of their companies working in cell therapy and it's such an exciting industry to be a part of before we go too far into what obsidian is actually, you know, what problem you guys are solving? I think I want to talk about car T cell therapy really quick to just kind of give an overview of what the problem might be. And if I'm wrong here, please correct me. But this is the very dumbed down understanding of car T cell therapy that I've kind of taught myself over the past few days. So the way that I see it is that T cells are the immune systems cop cells in a way, and they're walking around, they're patrolling, they're looking for abnormal cells that are up to no good. And we can call these cells. You know, the criminal cells, normally the cop cells have no, they can get rid of them. It's not a big deal, but every now and then they come across a certain type of cell, like a cancer cell is very good at avoiding them and avoiding being terminated through a variety of different ways. So we can call these cancer cells like supervillains right. So what scientists have done to kind of fight one method of trying to fight and capture destroy. These supervillain cells is they've taken out these T cells, these cops cells from their patients. They introduce them with a coach cell, like a virus that teaches them how to be stronger, how to become superheroes in a way. So these T-cells, these cops cells become super strong, super good at their job, and they get re-injected into the patient where now the superheroes can defeat these supervillains without issues. And this seems to be pretty effective, but it does come with some side effects. And I think if I'm understanding correctly, that's where obsidian comes in. How am I doing so far?
Speaker 2:That's pretty good. I like your analogy. The cells are engineered to have a, what we call a receptor on the outside of the cell that is very good at honing to and hunting down those cancer cells that are evading the immune system. And so, uh, they almost have a sort of a missile on them, uh, honing missile that will hone to the cancer cells. They're less likely to be floating around in the, uh, in the, in the blood they're honing directly to the cancer cells and are specific to those cancer cells so that they're attacking the cancer cell and less likely to attack other cells in the body. Right.
Speaker 1:And so when you have a bunch of these, um, engineered cop cells as ER superhero cells, it does cause some issues. And one of the ones that I've heard repeated quite a bit is a cytokine storm. What is the cytokine storm? What comes along with that? And why does it have
Speaker 2:So a cytokine storm, or it's also called cytokine release syndrome is caused when there's a large and significant and very fast release of something called these cytokines into the blood from the immune cells that have been affected by the heart team immune therapy that are attacking the tumor. And so cytokines are proteins in the immune system that activate other immune systems, stimulating them to produce more cytokines. And there's normally, there's a feedback loop that's kept in check, but in sometimes that feedback loop becomes uncontrolled and too many of the immune cells are activated. The body starts essentially to attack its own cells. And you get a, a range of symptoms that include kind of flu like symptoms like fever, nausea, headache, your heart can start beating rapidly. Your blood pressure can drop. You can have trouble breathing. And these symptoms can range from being mild to being life-threatening.
Speaker 1:It can potentially be lethal the cytokine. It can,
Speaker 2:It can be quite serious.
Speaker 1:What I mean, does this go away over time? Is this something that people who have car T cell therapy, you're just going to have to deal with forever before obsidian came along, how was this dealt with?
Speaker 2:So it's dealt with in a number of ways you can stop whatever the offending therapy is. So there's, there's a number of different things that can, other than car T cells that can cause cytokine release syndrome. But that's of course hard with cell therapy because you've administered the cell therapy and you can't decrease the dose. Like you could a, a regular, uh, antibody or, or a, a pill that you, you might take. There's a number of approaches that have been taken. One is you can treat with an antibody to[inaudible] six, which is a, another cytokine, and that's proven to be effective in treating the cytokine release syndrome. You can treat sometimes with steroids or sometimes companies will engineer the car T cells with something called a suicide switch that you can activate that will eliminate the offending car T cells. But of course, this isn't really a very good option because you are eliminating the cells that you have just infused into the patient to treat the disease. And for many patients, cell therapy is their last option for therapies. So it's really a last resort by activating a suicide switch. For example, the cytokine storm or cytokine release syndrome in many cases will resolve on its own, but sometimes it sort of feeds on itself and can become worse and worse and fatal. It's not something that you would live with for the rest of your life. It's self-limited either because it resolves or unfortunately, because in some instances, the patient ultimately doesn't survive.
Speaker 1:The city in therapeutics has a platform technology called cyto drive. So how does that fit into car T cell therapy? What are you guys, how are you guys involved with it?
Speaker 2:So what we do is we, um, when we engineer the cells, we engineer the cells to make a protein, for example. And when we engineer the cells to make a protein, that protein will, uh, help the body to fight the cancer, but in, in doing so, we essentially fuse another protein to the protein. That's the therapeutic. And when we fuse that additional protein to it, that protein, we can engage or not engage with a pill that we had administered to a patient or the patient will take like you would take aspirin. For example, when the patient takes this pill, it makes the protein of interest active. If the patient is not taking the pill, then the body recognizes the protein that we're making to treat the cancer. That's essentially garbage and should be two died the cell and, and degraded. And so what we call the off state when you're not taking this pill, the protein of interest is, is not produced, is not expressed by the cell. And therefore isn't acting in the absence or went in while you're taking the pill. Then this protein becomes active and is therefore therapeutic is therefore treating the disease. And so what this allows you to do is to provide what we call drug-like properties or the properties of taking a pill. You can take a 250 milligram pill, or you can take a 500 milligram pill or one gram. So you can dose at various levels, or you can decide not to dose it all. That's never been possible with cell therapy. With cell therapy, you infuse the cells, the cells produce the, uh, the car T or they produce whatever other protein you've engineered the cells to produce. They produce it at a rate that the cell chooses to produce the, uh, the protein. And the only real control you have is the number of cells that you infuse into the patient. So there's not a lot of control over the dose of the protein that these cells are producing. It would be the equivalent of me giving you a bottle of pills and saying, well, there's some big pills in here, and there's some small pills in here. And just, you know, I'm not really sure how many of the big pills there are. How many of the small poles there are, we think it'll be okay. And sometimes you get on your dose and sometimes you get overdosed. And sometimes it's in between, in your, okay, what we've done by engineering these cells to have a tag on the protein. That's the therapeutic protein is give the, the cell therapy, a drug like properties. We buy dosing, a small amount of this pill that activates the protein of interest. And you get a small dose. If you don't give the pill at all, you get no dose of this therapeutic protein the cells are making. And if you give a higher dose of this pill, then you are, you are giving the body will make a large amount of the protein of interest. So we think this will make therapeutic cell therapy much safer, not just for patients in oncology, but for cell therapy or other populations where having a tight dose control over the dose of the protein that the cells are making is important.
Speaker 1:So let me just clarify this. Are you guys actually, is obsidian actually handling the genetic engineering of the cells?
Speaker 2:Yes, we do. We, uh, we genetically engineer the cells.
Speaker 1:Okay. Okay. So you guys would handle something like car T cell therapy kind of put your own spin on it. And then that's when you have the pills they would take, which is the on and off switch too, to kind of, I guess it would be patient dependent if they would need it. Right. Well, you would to take the pill
Speaker 2:In order to activate the therapy. And so everyone would, the pill that we use is a drug called acetazolamide. It's a drug that's been approved by the FDA. It's been around for 70 years. It was originally developed as a, as a diarrhetic to treat high blood pressure. And so it's quite safe. And so the patient would take this drug called a seed, a Zola mine, and they would take it every day. And by taking it every day, the therapeutic protein would be in the, on, would be on, it would be producing the therapeutic protein. But if, for example, the patient had a side effect, the physician could say, stop taking your acetazolamide. And those cells would no longer be making that therapeutic protein in a way that would affect the patient.
Speaker 1:Okay. All right. That's makes a lot of sense. So basically, so you guys are, are genetically engineering, the cells to react in a way to the AC Z. So when everything's going fine and they're taking it, the thing that you've genetically modified is turned on, and then as soon as they stop taking it, it gets turned off
Speaker 2:Exciting because in oncology, we often give patients therapeutics that have fairly significant side effects. It's the unfortunate downside of treatments in oncology. And some of the treatments that are most interesting and most exciting are most, the most toxic. There are a number of different approaches, therapeutic approaches that physicians would like to use in cell therapy, but they can't use them safely because there isn't enough control over the production of these really exciting proteins to be able to administer them in the context of cell therapy safely using the obsidian technology. It allows physicians to have that control the ability to turn off the cell therapy course, the advantage of our approaches. You can turn it off, but you can also turn it back on. And so with the suicide switch, you can only turn it off. And you can imagine that as a patient and as a physician, it would be a terrible moment. If you were providing a patient with their last option for therapy, and you had to essentially turn a switch on that would completely inactivate for good that cell therapy. In our case, you can just simply stop taking the acetazolamide. And then once the patient's side effects go away or start to resolve that patient could take the acetazolamide. You would activate that protein of interest again, and you could do it in a way that's like turning a dial. You can start with a low dose of Zola light and slowly increase the dose. Therefore slowly increasing the production of that protein, that therapeutic protein in a way that physicians would feel was, was safe for the patient.
Speaker 1:Even if you turn it off for a year, two years, it would still turn back on by taking the ACC.
Speaker 2:As long as those engineered cells are still in the patient that are still circulating in the patient, you can turn that back on. And that has advantages. If, for example, a physician, for example, might choose eventually to tell the patient to no longer take the acetazolamide if they appear to have been cured. But if that cancer reactivates, then the patient could start taking the acetazolamide and that therapeutic protein would start to be produced again.
Speaker 1:Okay, cool. And for more applications outside of oncology, I had a call with a and cell therapeutics, an interview. We think two episodes, three episodes ago, and they're working on cell therapy with spinal cord injuries, macular degeneration. Do they run into some of the same issues of cytokine storm stuff? The side effects that other cell therapies like car T have, is that something that your guys technology could potentially help as well?
Speaker 2:So the cytokine storm is generally associated with cell therapies where you're engineering immune cells. If you're activating immune cells, that's where you get this side effect. There's actually some really interesting and exciting applications for the cider drive technology across a range of ways that cell therapies can be applied with cell therapy, your engineering, the cells, to produce any protein of interest in oncology, you are engineering the cells to produce these homing receptors or your engineering them to produce cytokines or immune modulators that would assist the body in fighting cancer. That you can imagine that you could also engineering cell to produce an antibody. We believe that the cited drive platform is really applicable across all applications of cell therapy. As I mentioned earlier, with my analogy around pill sizes in a bottle, I don't think most patients and physicians would like to know the dose of the therapy that they are receiving and would like to know that if they wanted to discontinue that there would be that they could. And that's what this side of drive technology does. There's a range of applications of the site or drive technology outside of oncology, where we also think that this ability to provide drug-like properties is really important. For example, when you engineer a cell, you can engineer a cell to make any protein. You could engineer a cell to make a monoclonal antibody, for example, which a monoclonal antibodies are therapeutics that are used across a range of diseases. Like for example, rheumatoid arthritis and engineering, the cells to make a monoclonal antibody. You're basically making a little bio in the South. And you could imagine that if you are making a cell into a bio factory and it's producing a monoclonal antibody, that patient didn't have to continually give themselves injections of the monoclonal antibody. And instead the body would produce these monoclonal antibodies. You don't want to be able to mimic how therapies are currently administered, which is by giving the patient a specific dose. Our technology would allow you to do that with cell therapy. And this is particularly important in diseases where, what we call the risk benefit is narrower, where there's less tolerance for side effects because the disease may neatly life-threatening in cancer. There is a great tolerance for side effects, particularly as patients have less and less options. And their disease is very life-threatening where the disease isn't immediately life-threatening and the patient has a relatively good quality of life, your need for having very tight control over that therapy that you're providing is really important. And this is what the cyto of drive technology does, is it gives that drug like property to any protein that is that a cell is engineered to produce. This is really exciting because it will allow the use of cell therapy across a much wider range of diseases or range of applications. The technology at at obsidian is to be able to open up cell therapy, opened up this ability to engineer cells, to a much wider range of patients and do that in a safe and effective way.
Speaker 1:That all makes a lot more sense coming into this interview. I was still a little bit on the fence about understanding things, but I think you've done a really, really fantastic way of, of describing what sido drive is and what upsetting therapeutics, what your guys' goal is. And the way I'm understanding it is basically you guys are, are it's an on and off switch that people can take the pill and turn the properties of the gene engineering that you've done on and off. That's pretty a sci-fi.
Speaker 2:So you can think of it as a, as a, as on and off, but also everything in between. So it's like a real status, like a dial. You can turn it all the way off. You can turn it all the on and anything in between.
Speaker 1:That's super cool. So I want to talk just briefly about obsidian therapeutics and what you guys, what the status of it is. And I'm curious how long until this technology platform would be available to the public to use. I mean, you guys are, um, have you guys entered phase one trials yet?
Speaker 2:We haven't entered phase one trials, but we hope to enter trials within the next two years.
Speaker 1:Okay. And what I'm curious about is because you're using like a 50 to 60 at the ACC is 50 to 60 years old. Does that give you any type of benefit when it comes to clinical trials getting through a little bit quicker because it's a, it's a tried and tested. It's an old molecule.
Speaker 2:I think so. And that's why we chose to identify a drug that's already been approved by the FDA and has many years of, of experience. So we understand the safety of the drug very, very well because it's been used for many years. The nice thing about acetazolamide is it's actually not used much anymore. It's primarily used now for preventing altitude sickness. Its use is limited. It doesn't work very well for anything other than altitude sickness and has years and years of safety experience. And so we think it was a really, it's been really nice choice for that drug to use, to control the cell there.
Speaker 1:And if everything goes well, obviously phase three trials finishing phase three trials can take a very long time in a moderately good case scenario. When would this technology be available to the public
Speaker 2:Earliest that it could be available? It would be in the next five years.
Speaker 1:I've definitely heard a lot longer for, uh, completing trials. So that's not too bad.
Speaker 2:It will, of course depend on, on the application and the data, but that would be a, an optimistic and aggressive approach to getting the drug to the patients. But of course, getting this platform to the patients for us is, is really important. We think that it's really going to change the way that cell therapy is administered.
Speaker 1:And I'm sure there will be a lot of people who are very excited about this interview and probably pretty excited about obsidian, where would be the best way for them to stay up to date on progression that you guys are making. Is there an email list or maybe they should follow social media? Yeah.
Speaker 2:The best way to follow us as our website, which is obsidian, tx.com, which has information on how to email us and links to our social media accounts.
Speaker 1:Okay, great. So this was an awesome interview and I'd like to finish off every interview with just a few fun questions that I like to ask some scientists to kind of give me some hope for the future in a best case scenario, how do you see cyto drive impacting humanity?
Speaker 2:The best case scenario? I think that cider drive technology will provide the access to really exciting, novel cutting edge therapies that have been limited to a really small proportion of patients that have medical illnesses and it will make it become more, um, more mainstream, the ability to engineer cells to function in a more optimal way. It's kind of the Holy grail to be able to alter the function and control the function of a cell. That's not either not functioning as we would like it to function or where we'd like it to have additional functionality in order to control or eliminate disease would be life-changing for a range of patient people. And so we hope that our platform will be able to achieve that vision for a much broader range of people. That's a great answer.
Speaker 1:Sure. And for the final question, what are you most excited about in the world of biotech outside of the world of absurd?
Speaker 2:Well, you know, as I mentioned earlier, it's an unbelievably exciting time to be working in drug development right now, when I first joined the industry, monoclonal antibodies were probably the most exciting thing going on. They were unique and innovative, but it was small molecules and antibodies. And there, there wasn't too much else. Uh, gene therapy, gene editing, cell therapy, they were all kind of like you said earlier, scifi, I think what's most exciting right now is maybe not even the, the specific platforms that are being developed and innovated, and it's the breadth and the number of different approaches that are being taken. Now it's the number of shots on goal, not just with a particular therapeutic, the number of very different platforms that ultimately will have different and somewhat overlapping for various diseases. That's actually what excites me the most is the number of shots on goal with a range of exciting, innovative platforms that 10 or 15 years ago we only imagined.
Speaker 1:Yeah, it blows my mind. I mean, I'm still pretty young. I'm 31 years old or so, but every time I have a conversation with somebody about the new stuff, that's on the horizon and what's come out in the past 15 years. It's really, really exciting stuff. So Catherine, thank you so much for joining me. I think the audience is going to love this episode and I'd certainly appreciate you educating me on so many things today.
Speaker 2:Yeah. It's been my pleasure. I've really enjoyed speaking with you.
Speaker 1:If you got this far, I just want to say thank you so much for listening. If this was all interesting to you, I'd love to connect on Instagram and hear your feedback. I'll also be posting clips from the latest episodes as well as anything else. I find interesting about the biotech industry. You can find me on Instagram at simple biotech. And if you're interested in the companies that I'm looking at and the companies that I'm excited about, connect with me on angel list at angel.co/james rule. That's James R U H L E. Thank you so much and be safe out there.
Speaker 3:[inaudible].