Dr. Dow: Realistically, the idea that a single drug is going to do everything is probably not going to happen.
Dr. Venable: Welcome to the Veterinary Cancer Pioneers Podcast, the show where we delve into the groundbreaking work of veterinary professionals who are dedicated to advancing the field of veterinary oncology. I'm your host, Dr. Rachel Venable, and I'm thrilled to embark on this journey with you.
Dr. Venable: Hello and welcome to the Veterinary Cancer Pioneers podcast. I'm your host, Dr. Rachel Venable, and I'm excited today to bring our guest, Dr. Steve Dow. Dr. Dow is currently a professor of immunology in the Department of Clinical Sciences, and the Director of the Center for Immune and Regenerative Medicine at Colorado State University, and he investigates tumor immune responses and new cancer immunotherapy. So really excited to dive into your research and what all you guys have going on there.
Dr. Dow: Okay. Thank you Rachel, very nice to be with you.
Dr. Venable: Thanks so much for being on our show today. And you know, I always like to start with just having our guests give a little bit of a background about how they got to where they are. You know, how you became a veterinarian or what got you into immunotherapy.
Dr. Dow: Okay. Well, so I did my training at tissue and Internal Medicine to finish my residency and decided research might be something interesting to tackle. So I became involved in studying the neuro immunology of feline and immune deficiency viruses, it was back during the Aids epidemic, is really getting ramped up, and so got a really interesting immunology at that point and then moved to Denver, to the National Jewish Center for my postdoctoral training. And then the environment was immersed in people that really knew a lot about immunology. And so I became interested in using initially gene delivery to deliver immune stimulatory genes into tumor cells to trigger T-cell responses. So we worked with a gene that encodes what's called a super antigen, which is a really potent molecule for activating T lymphocytes and causing them to move into tumors and become activated to kill tumors. So we really wanted to study those I'm most proud of, it is our first study in dogs with melanoma, where we were using gene delivery to deliver to super antigens, then to the tumors. So tumor regression at about half of the treated dogs and a lot of them had long durable remission. So that was really kind of where it first got the bugs were really pursuing immunotherapy, did a lot of work in mouse models, but also had the opportunity to work in dog models with faculty here and CSU, and then also with Robin Elmslie and her group down in Denver. So moved from studying T-cells to looking at more nonspecific immunotherapy. So really activating the innate immune system. So macrophages monocytes, dendritic cells and so developed the gene delivery technology for IV delivery. And then basically moved that up to Fort Collins when I was hired here at CSU and continued to work on that and then began to become more interested in the myeloid cell component of the tumors, which by and large are mainly immune suppressive.
So we've started to think about strategies to either get rid of those cells or to try and reprogram them. So they were so immune suppressive. So a lot of the early work focused on monocytes. And that work continues to today actually. So I think some of the most successful studies we've had have come recently with colleagues, Dan Regan here at CSU, Cheryl London at Tufts, using combinations of drugs to target these myeloid cells to either keep them from moving into tumors or if they are there to reprogram them so they're not as immune suppressive. So that's still that's brings us pretty much up to date to where we are now. And we're continuing to add new strategies to that basic platform of myeloid targeting immunotherapy.
Dr. Venable: Yeah, it's really interesting. It's always interesting to me just the immune system and the different cells and how specific they are, but maybe not as specific as we think they are. So what are some of the more interesting research that you guys do there? Or what have you found that's been pretty exciting advancements that you've seen over the years?
Dr. Dow: Probably just looking at new strategies to target these myeloid cells that you could do a lot of things in mouse models, like, you know, there's lots of reagents we can buy, but as soon as you start to move from a 25 gram mouse to a 21 kilogram dog, these costs just go through the roof. So a lot of the reagents we use in mice, we just can't use them in dogs. So that really prompted us to start to look at practical alternative EVs to target these cells. Until we initiated a series of screening studies, either modeling in vitro or in silico, divide drugs that would target receptors on myeloid cells that could either block them from migrating or change their function. And I think the important thing we did was to restrict that search to only FDA approved drugs and drugs that had been around for a while, so we knew a lot about their safety. They were affordable, we could script them. And so that was really where the screening started. And it's kind of where that whole mildly targeted immunotherapy program originated. So the first, first drug to come out of that screen was the Losartan, which is, as I'm sure most of the listeners know, as a drug for hypertension. Why would anybody think to use that to treat cancer? So that was why the screening was so important, because we could identify drugs that wouldn't be abnormal and then thought of as having immune activity. And so we identified Losartan. And actually pretty much all the drugs in that family of ARBs there angiotensin II receptor blockers have this property of they basically bind to the receptor that monocytes use to migrate and block signaling. And once that happens then they're not mobilized from the bone marrow. They don't move into the tumor. And as a consequence, within a few weeks the tumor gets depleted of macrophages, which is really the cell that we've been most interested in. So the net result of that is you just get spontaneous anti-tumor immunity because the T cells that are in the tumor, they're sort of been paralyzed by the macrophages. Once the macrophages go away, those T-cells start to work again. So Losartan was really the first big breakthrough in terms of a what we call a drug that could be repurposed. So taking a drug for a totally different indication, moving it into the cancer immunotherapy realm.
Dr. Venable: I love that reusing old drugs. Right. Because well, I'm kind of thrifty to begin with. So I just like that idea. But it is great, especially for our dogs. And I think a lot of people don't realize the forethought you guys had because they’re FDA approved, well, then we can use it off label. And like you said, we can actually script it out. We already know a lot about it. You know, a lot of these new drugs coming out. I can only imagine how expensive they would be to try to do any kind of research. So I think it's great. Yeah. When I've script it out, Losartan for dogs and things. It is pretty inexpensive, you know, it's something most people can afford. So when you're doing that screening, I know you were explaining how the monocytes and the cells and things, how they affect the immune system and go through the body, but I still think that's pretty novel, how you guys looked at different drugs and screening them to see how it would affect cancer. How did you guys come up with that, or was there a foundation that you built upon?
Dr. Dow: Yeah. So it's a good question, Rachel. So I think the strategy was to target the immune cell and then secondarily figure out which cancers it made sense to target. And so we had identified Losartan as kind of our lead drug. And we also realized early on that it wasn't going to be effective as a drug by itself. So realistically, the idea that a single drug is going to do everything is probably not going to happen. So, quickly looked around for a second drug to combine. There was some data in mice that a drug called sunitinib had activity in targeting a different myeloid population, so called myeloid derived suppressor cells, which are basically immature monocytes in neutrophils. And so we have a very close homolog of sunitinib and with toceranib or palladia. We looked at combining the two drugs as they had different mechanisms of action. And it turns out that the two together are really quite potent in the mouse models. And so we really designed our first dog studies around that combination of losartan and palladia. And we looked at osteosarcoma because we knew that the metastatic lesions were chock full of monocytes. So we knew that that was a tumor, that if you got rid of the monocytes, you might actually exert some activity in controlling the tumor growth.
The other point to make is that we learned some hard lessons. So we thought, great, here's losartan. You know, as an internist, we know how to dose it. You know, it's a big bouquet. No big deal. But when we did the studies in the first cohort of dogs, we really saw very little activity. We were looking at regression of lesions in dogs with metastatic osteo. So a pretty tough model to tackle. So we're pretty disappointed. We just really weren't really seeing much. And I remember a hallway conversation with Dr. Dan Regan, who was really instrumental in a lot of this work where we just kind of had one issue, should we abandon this program or should we really believe in it, and should we really go back and do well?In retrospect, we should have done in the first place, which is to redo the PK and PD studies. A lot of the data was based on healthy dogs, but was also based on a limited set of parameters, and they weren't really looking for the same endpoint we were. So a lower dose can control blood pressure, but to block monocytes and to engage this receptor, what we learned is you really need much higher doses. So we went back and did our homework, did a proper PK study. And what we learned was that you really need ten times the dose that you'll see in the lumps, for example, to really see that acting is a really, really big dose. And I remember treating our first patient and just kind of hoping he didn't keel over from hypertension. And it was, you know, really cute, golden retriever who gave him his big dose. Everybody sat around watching him. He just sat and watched us back and nothing happened. And so what we learned was that really that dose in a dog that doesn't have preexisting hypertension is just fine. We really have not seen any adverse events associated with hypotension. We do see occasionally inappetence, but it tends to be transient. But it's just a drug that's well tolerated, really high doses in dogs with cancer. And we treated it a variety of cancers now.
Dr. Venable: Now that's really interesting. Just even the dose and and I found that too, when I was first looking and reading through your paper and I was like, okay, this is a lot higher, but they all seem to do fine. So and that's been my experience that the dogs I've put it on have done really well. What other drugs have you guys looked into?
Dr. Dow: The original study, which is published now, was the combination of losartan and palladia and, you know, and we saw good activity in a tumor setting where it's really hard to see anything. You know, even as, you know, these dogs with metastatic osteo just don't do very well. But we also realized there's a third myeloid population we hadn't targeted, which is the neutrophil. So neutrophils when they're recruited to tumors are also immunosuppressive. So we had two drugs targeting monocytes and myeloid derived suppressor cells. So then working with Cheryl London who had done a lot of work already with a drug called ladarixin that blocked the chemokine receptor called CXCR1 and CXCR2, which is what neutrophils need to migrate. We worked with Cheryl. We received funding from the NCI at this point for the Moonshot Program. So in partnership with Cheryl, we added her third drug ladarixin into the two drug combinations. We actually did a lot more screening, that we had six individual small trials with other combinations. But the winning combination was the combination losartan, palladia, and this drug ladarixin. And that when we put that combination together, we really saw good things happening. And we're preparing that manuscript now for submission. So we’ve done a decent, pretty good sized study in dogs with metastatic disease. But we also did an adjuvant trial in dogs. That was kind of what we felt like was kind of a gutsy trial. But we treated dogs where they got no carbo, they got no adjuvant chemo. They only got adjuvant immunotherapy with this triple drug cocktail and essentially saw equivalent outcomes to dogs that were two year old Carbo. So I was the identical medium progression free intervals and median overall survival time. So I think for us, that was a win because it was a totally oral protocol.
You know, very few were minimal side effects could be given essentially indefinitely affordable. So we're really enthusiastic about that triple drug protocol. We're still waiting for that third drug to become available in the veterinary market. In the meantime, we are screening now for other repurposed drugs that we can use to target neutrophils, mainly because we really want to get the triple drug protocol out to the oncology community, you know, because one of our motivations all along has been to develop protocols that that all of us can use. Right? We're not relying on a drug company who may decide six months from now, “Hey, we're done. We don't need any more dog studies, so there goes the drugs”. So we really want to look at drugs that are widely available.
So the fourth drug that we've looked at and we're continuing to look at is propranolol as a beta blocker. So another totally repurposed drug, you know we were not treating bradycardia or arrhythmias. But it also has these really interesting immune properties particularly on the myeloid-derived suppressor cells. So we've evaluated that combination. The propranolol, losartan in a brain tumor trial that was published last year in conjunction with a tumor vaccine that were developing.
Dr. Venable: Interesting. And what do you think about propranolol? Because I've heard of it with commando sarcoma. I think it's, you know, one of the other universities really looks at that, and it seems like the data has kind of gone back and forth over the years. Have you noticed it, like with what you're doing? I know you just said you looked at brain tumors, but I don't know if maybe even screening if you've seen anything with hemangiosarcoma or what tumors do you think you know, so far we talked about osteosarcoma and brain tumors. Any other tumors that could be helpful with these drugs?
Dr. Dow: I think potentially any tumor where there's a strong myeloid component to the tumor microenvironment, hemangio is definitely one that was the top tumor that we identified in a screen of immune infiltrates. It had the highest number of monocytes. Osteo was a close second. But hemangio is chock full of these monocytes that turn into macrophages. To be honest, we really haven't done much beyond just osteo and brain tumors at the moment. Hemangio would be a certainly be a candidate that, as you know, studies in hemangio are tougher. Everything progresses so much more rapidly. It's more difficult to measure metastatic disease and often times it involves the liver as well. So we just kind of steer clear of it. But I do think that that combination could have activity the, losartan and I would include Palladia.
So I know Palladia alone doesn't have activity in it, nor does it have activity in osteo. But you have to keep in mind we're using Palladio in this setting as an immunotherapy, not as a cancer therapy per se. We're not interested in targeting the tumor cells. We're targeting the tumor microenvironment. So I could see an argument for a triple drug combo of losartan, palladia, and propranolol, for example. We've been treated in a small pilot trial dogs with osteo with that combination. And I'd seen a couple of responses. It's just not enough numbers to make a strong statement, but I think there's a strong rationale for thinking that protocol could be effective if it's just figuring out what the outcomes are in hemangio and powering this study appropriately or always challenging.
Dr. Venable: Well, and I like what you said about using palladia is that we're not going after the tumor cells per se, but the immune system changing the immune environment. So I think that really is a different train of thought than how I typically thought of treating. So that makes a really good point. And you also mentioned with the brain tumor that you guys have a vaccine. Can you tell us more about that?
Dr. Dow: Yeah. So the published study and actually Cheryl London and I just received funding from the Morris Animal Foundation to do a study in dogs with osteo with a similar vaccine. But it uses an adjuvant that came out of the early work my lab did with nonspecific immunotherapies, which are the liposomal adjuvant that when you add tumors. In this case, we were using vaccines made from tumor cell lines. So we're taking a lysate from those cells mixing it with the adjuvant. And then that's given subcu at a time interval of typically two weeks initially. And then spacing it out to monthly or every three months. But the advantages using cell lines is we don't need a biopsy from the patient. We don't have to do anything with the tissues from that patient. We can make the vaccine and have it in a store. So it's available when the patient comes in and we can send the vaccine out to referring vets to administer. So that study of brain tumor dogs showed that the two oral drugs and then the vaccine could cause tumor regression in about a third of the treated animals and prolong survival compared to historical controls. And I think the important thing about that study is the dogs didn't have any other treatment, no radiation therapy, no tumor bulging surgically. They only got the oral drugs in the vaccine. And that's essentially what we'll be doing in the osteo trials. So it'll be an adjuvant trial. They'll be getting the triple drug oral immuno plus a series of tumor vaccines. So I think you can kind of see the strategy here, which is to stack combinations where the mechanisms make sense, where they're either additive or synergistic. Realizing the 1 or 2 drugs and targeting those myeloid is probably not enough. But if we targeted the macrophages and neutrophils and then bringing something like a vaccine from the T-cells, that combination should be more effective.
So, you know, it takes time. It's all an iterative process. And we're combining this myeloid targeted cocktail now with Car-T cell therapy. So we have a funded trial now in dogs with osteo where they're getting the two drug cocktails of losartan and propranolol to augment the activity of the chimeric antigen receptor T cells, which is our trial is underway now in dogs with metastatic osteo. So to our knowledge, it's the first trial in dogs that have ever got this Car-T cell. So we're very excited about that trial.
Dr. Venable: Yeah. It sounds like you have a lot of really interesting stuff all going and, you know, just thinking about these tumors, osteosarcoma and brain tumors, those are certainly ones and people that we do, you know, sometimes some crossover research. Is that something that you've done as well?
Dr. Dow: Absolutely. Yeah. That's a really good point. The program from its very initiation was always intended to be translational. They are relevant. And our goal all along has been to move from mice to dogs and then quickly from dogs to either pediatric patients or adult patients. So we've actually had success in that model. So we have a pediatric osteo trial underway now at Children's in Denver. And it's basically exactly the protocol. The two drug cocktails were in the first osteo trials in dogs. Who is this high dose losartan in the kids with sunitinib, which is essentially Palladia. And we're just now at the final cohort where we started to see activity in the dogs. So we're hoping to see activity in the children. That's probably our best example of quickly moving things forward. Again, the trial was easy to do in kids because those are all approved drugs. We didn't require much for the FDA to approve it. Obviously, the drugs were available. They knew how to dose them. So that's probably been our most successful example to date. But we are working with our colleagues at the medical school also for the Car-T cell work because they want to move this. These and these are all new Car T-cells. So they're not Car-T cells that have ever been in people. They've got some clever design features. So everybody's really waiting to see what the dogs do before pulling the trigger on a pediatric trial. So those are really closely tied together. So both pediatric osteo pediatric rhabdomyosarcoma and also pediatric glioma, all trials where we're looking for dogs for guidance.
Dr. Venable: Yeah, I think that's great because I don't think a lot of people understand how many drugs fail when they go from mice to people. You know, I've heard in the oncology world it's a huge fail rate. So I think it's really interesting personally how the dog could be a good in between model, you know, because he gets cancer naturally. They're larger in size, the immune system. So you know, hopefully and I know you guys aren't there yet. But as you see in these human trials, like maybe we'll see better responses than what you would at the mouse, what are your thoughts? Like you said, a lot of this is my opinion, except I've heard something like the fail rate for most oncology drugs is something like 86% or something crazy, something above 80%. But you know, don't quote me because I can't remember the reference for that. But what are your thoughts on all of that using the dog? Is that in between models?
Dr. Dow: Yeah, you're exactly correct, Rachel. It is about a 90% fail rate. And there's a variety of reasons for that. But it does make oncology drug development really risky. It's probably the riskiest of all the drugs that are developed. So we believe that the dog then essentially serves to de-risk drug development to either identify unexpected toxicities. And Cheryl's done a lot of good work in that regard. So combinations that make sense, you know, David Vail and Rob Rebhun at Davis have done some good work in radiation immuno combos. So looking for either failure or for evidence of efficacy to really, you know, really kind of jumpstart and prob the drug moving into patient populations, you know, the owner of beings, as the populations. So I think the dog occupies a really unique dish in that regard is a, you know, realistic animal model to, you know, to de-risk what is a really risky business in oncology drug development. And, you know, I think we're looking at it as a platform technology that can be applied to a lot of other drugs. So, you know, I can take the toceranib and losartan and mix it with a vaccine. I can give it with Car-T cells. We have a trial underway with Keara Boss at CSU, signing a nasal cancer, giving it with radiation therapy, and seeing some really nice results in that trial on dogs that get the combination or T to the nose with the losartan and the propranolol. So it's a versatile platform. And I think what we're doing now is just trying to understand what combinations make sense with that platform.
Dr. Venable: And I liked to how again, these are all drugs that we have. So we're learning. We're getting so much information for the dog helping with people I like. You guys are trying all these different combinations to see, you know what works the best. And you know what makes the most sense. I know you mentioned a couple times combining propranolol and losartan. I personally haven't done that yet. Did you guys see much blood pressure changes with that? That's the only thing that makes me a little worried.
Dr. Dow: No, I mean, not really a couple of dogs. We did have the dose reduced propranolol mainly because of bradycardia. And we do ramp up the propranolol low dose to, you know, targets as a make per kick. We have to be a little careful with that combination. And I should make a note with a high dose losartan that we do exclude dogs that have renal disease or renal insufficiency. Or if we do include them, we're really careful because it can affect renal blood flow. And we're really careful giving inserts concurrently with that combination. Again because of the concern about renal injury. So there are some caveats. It's not everybody can get it. But most dogs that don't have preexisting renal disease generally tolerate either of those combinations pretty well.
Dr. Venable: Interesting. Yeah. No, I think it's great. And you said a lot of this has been published and then otherwise you guys have ongoing trials. Are they all pretty much at CSU or where can people find your research?
Dr. Dow: Most of them right now are at CSU, except for the new multi-center trial. We'll be doing it with Cheryl at Tufts. And that triple drug combo was done with Cheryl at Tufts also. The brain tumor trials will be here. The ongoing Car-T cell trials are here. But there is some, I mean Cheryl is running a triple drug trial at Tufts with a different vaccine strategy. There are other centers that are doing the trials. I know Davis is looking at adaptive immunotherapy in T-cells with radiation, they've got what they call a super cytokine that really activates T cells and NK cells. So I think the field is really moving now to really embrace immunotherapy in canine and hopefully soon feline oncology. We are starting to look at squamous cell carcinoma in cats. Cats have sort of been ignored for too long, right. So we do need some options for them as well.
Dr. Venable: But that's perfect. You're looking at cats because yes. No one looks at poor cats. At least I feel like in oncology they get left behind. So thank you, especially that tumor. That's a rough one. So if we can get any needle movement with that that would be amazing. And you mentioned some really interesting clinical trials. What in general are you seeing like maybe on the horizon, either with people or animals that you think is really exciting emergent technology?
Dr. Dow: Well, I would say at the forefront right now is that the Car-T cell is like everybody's what they know what the latest is on Car-T cells. You know if you have leukemia they were great unfortunate. If you have solid cancers not so great. So that's really where the fear is really focused right now on that technology. It's not going to be an off the shelf technology for dogs and cats. Probably not. And near future for sure. I should point out Nikki Mason's doing some really nice work with an encouraged team program at Penn, and hers might have the potential to be an off the shelf therapy. But the problem with Car-T cells is they're so expensive to manufacture that it really limits access. So I would think, you know, checkpoint molecules and inhibitors are great. They've been obviously around for about 20 years in humans. We have one in the market now. I think we're kind of all waiting to see what the data looks like. But probably the newer, more exciting technologies are these so-called bispecific antibodies that would be delivered like a monoclonal antibody. So you can give them IV subcu, but they serve to bring the T-cell tumor cell together without having to grow the cells outside of the body. So, the data from people with multiple myeloma is just amazing. Patients that have been highly pretreated failed multiple protocols, a few doses of these bispecifics, and they've been in remission, you know, two and three years or so. I think that's probably going to be the biggest breakthrough that I can see being affordable and adaptable to better ecology. It solves a lot of problems. It works with technology that we now have. It's just going to be a matter of picking the right targets and building the right antibodies. But that technology has gotten so much better in the last few years. And as you know, there are a number of products now coming on the market that are based on monoclonal antibody technology. So, you know, Zoetis, Elanco, everybody's kind of getting into the game. So I think well will we that's where the next breakthroughs will come from. And it will be beyond checkpoint antibodies. I think we need to be looking beyond PD-1 and PD-L1 and CTLA-4 antibodies to these. I think these are newer, more promising technologies.
Dr. Venable: Well, I like the biphasic. I never heard of those. So I'll definitely have to keep an eye out for that. And just a lot of these new products that you're talking about, it is really exciting. The monoclonal antibodies and just knowing that more that technologies out that can also come down to veterinary medicine. So definitely excited. And we'll keep an eye out for all those other ones.
Dr. Dow: Yeah they're coming I think you know we get frustrated. It's not as fast as we like. But it's going to happen. And antibodies will become much more widely used in veterinary medicine not just for oncology but internal medicine, surgery. You kind of you may have picked the right target. You could build an antibody.
Dr. Venable: And that's really fascinating. So it'll be great to see where everything goes. And you know this has been an awesome talk. I love hearing about these different drugs and how we can use them. And I just really appreciate you being on our show. And before we wrap up, I always like to ask people who they think would be a good fit for this podcast.
Dr. Dow: Well, obviously the oncology community, but I think more broadly than the general practitioner, because, again, the drugs we've been talking about can be administered, you know, with proper training, but the like the repurposed propranolol and losartan is not a big deal. You know, the toxicity comes with palladia and that combination. So knowing how to manage palladia is probably going to be the most important learning. The other drugs that we're looking at now are all out of the markets. So we're just trying to figure out the next combination. But the combinations we're looking at are all the things that the oncologist or the advanced GP can use. We've just got to figure out the dosing and the right drugs. But I think that's probably where the most immediate impact will come is in some new classes, the repurposed drugs that add to our armamentarium and add to the platform. But they'll all be oral, they'll all have low toxicity, they'll all be cheap, and hopefully they'll all be effective when you use the right combinations.
Dr. Venable: Those are certainly factors that everybody wants, especially vet med. We like it to be less expensive, oral, no dosing, well-tolerated. So that definitely sounds like you know your audience right. Like you know what? That's an animal. Animals what we like.
Dr. Dow: Try to check those boxes.
Dr. Venable: Right. Well this is just been fascinating. Thank you so much, Doctor Dao, for doing this. And then for everyone listening again. He's at Colorado State University and doing a lot of exciting research there. So again, thank you so much for being on our podcast today.
Dr. Dow: Okay. Thank you Rachel, I enjoyed it. It was really nice.
Dr. Venable: Well, that's it for this episode of the Veterinary Cancer Pioneers podcast. If you enjoyed this episode and gained valuable insight, we would be so grateful if you could share our podcast with your friends and colleagues. And it would be even more wonderful if you want to give us a five-star rating, positive review, or any kind of feedback on Apple Podcasts or wherever you listen. The Veterinary Cancer Pioneers Podcast is presented to you by ImpriMed.