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Melanie Cole (Host): Osteosarcoma is the most common form of bone cancer in dogs today. Our guest discusses promising results from years of studies and what's ahead to improve survival for dogs with this aggressive form of cancer. Welcome to UF Vet Med Voice with the University of Florida College of Veterinary Medicine. I'm Melanie Cole. Joining me today is Dr. Rowan Milner. He's a professor of oncology, board certified in medical oncology, and the director of Clinical and translational Research in the Department of Small Animal Clinical Sciences at the University of Florida College of Veterinary Medicine. Dr. Milner, thank you so much for joining us today. I'd like you to start by just giving us a little bit of an overview of Osteosarcoma in Dogs. How common is it? Is it fast moving? Is it a dangerous cancer in dogs? Give us a little overview in the scope of the problem that we're looking at today.

Dr Rowan Milner: Thank you, Melanie, for having me on the show. Yes, it's a really malignant cancer. It's probably one of the most mutated cancers that oncologists deal with, whether it's human or animal. And because of that, it is a rapidly metastasizing cancer. So it goes. Primary, tumor in bone, although there are exceptions where it can occur in the spleen, and memory tissue as well, but primarily in, canines. In dogs, we see it in their long bones. And so, it starts off there and very typically begins with some form of lameness and in a very rapid progression.

It goes from being a relatively small tumor to growing really big, very, very quickly. And the majority of dogs, sadly with traditional or what we call standard treatment, which is amputation and chemotherapy. The median survival time, is about nine months, and if you're lucky, it'll get to 12 months. Now, what median means is that 50% of dogs have made it to that point and the other 50% have not. And by the time two years elapses, most of those dogs with standard of care have passed away. They've passed away because of the metastatic process, and that's even with chemotherapy.

And with amputation. And so, it's a rapidly progressive cancer, and the real bane of, existence for medical oncologists, in the veterinary field. And it's sadly, it's a bad disease in humans as well. but the odds are a little bit better there. But there. Subgroup of people that get a form of osteosarcoma that is similar to the dog that can be really, progressive and quick to, cause problems. so I hope that provides you with a little bit of background. And of course it's more common in dogs than it is in humans.

Melanie Cole (Host): Well, it certainly does provide us plenty of background. So as you stated, it's highly metastatic. So, Dr. Milner, let's jump right into this building on the technology you originally developed to treat melanoma in animals. Tell us how it came about that you developed a vaccine that targets the GD3 antigen to treat melanoma and now osteosarcoma. And rather than being administered to prevent a dog from developing cancer, as we know, many vaccines, that's what they mostly do, but it's given to a dog as a treatment. Once it's developed, discuss some of these promising results. This is absolutely fascinating.

Dr Rowan Milner: I can actually remember the day it was probably close on 18 years ago. And I remember becoming increasingly frustrated with dealing with dogs with oral melanoma. just a little bit about that and humans, so the melanoma that. Dogs get, can get it on their skin, in their mouths, in their eye. And in other places as well is not the same as human melanoma that is sun induced. and so the dog is, equivalent to a kind of melanoma called mucosal melanoma, which is a more malignant form. it's kind of crazy to think how malignant can you be more than malignant, if you know what I mean.

But it's a rapidly, progressive disease and 18 years ago, I remember standing there and thinking, we really do need to do something for this cancer because with standard of care, at that time it was chemotherapy and surgical removal. The median survival time is roughly a year in these dogs with the oral, high grade, oral melanoma, and roughly at that time I had discussed this with a colleague of mine at here at the vet school. Dr. Janet Yamamoto, of how we could enhance the immune response of these dogs because we know that you can get a autoimmune reaction to melanocytes, which is of course where melanoma cells come from.

And that disease is called vitiligo. Right? And so, it was a natural progression, to think about, immunotherapy. And immunotherapy is a bigger term. It encompasses these cancer vaccines that we are talking about now, but it also encompasses some of these new targeted therapies that kind of block pathways and allow the immune system to kick in. So we set about looking for a target for a cancer vaccine. And in the process of doing research, discussing this with Dr. Yamamoto, we realized that, GD3, which is a ganglioside, now, it's not a protein, and that's really important.

It's a gangliaside and the gangliasides, there's a lot of hemology between what's in the dog, what's in the human, what's in the cow, and so on. It's not like a protein, which differ, significantly from each other. And if you get given a protein from a dog, say for instance, or a dog, it's a human protein. There's an intense reaction to it, right? So GD3 looked very promising. there's a lot of it found on melanoma and a small amount on nervous tissue and melanocytes. So it was a natural target. However, it's not a protein and therefore not a very strong antigen.

And by antigen we understand the body's ability to recognize it as foreign. In fact, it belongs to the body. So there ia less of an immune response to it anyway. So what we had to do is we said about, we realized that GD3 was present in melanoma and we took a whole bunch of cancer cell lines and showed that it was present and then we needed to mimic, an infectious process. So, most vaccines have a component to them called the adjuvant. And an adjuvant is what tells the body where to go to when the vaccine has been given. So if you get a injection in your arm for covid, for instance, you can remember how painful it was afterwards.

That's what the adjuvant does, that locks the body's immune system into that. And we needed to set about Not causing an overreaction, but causing enough of a reaction that you would get an immune response to GD3. And in the process we didn't realize that what we'd actually created was a liposome. And in the process of developing this further, we realized that what we'd done, the adjuvant for the vaccine was a liposome. And these liposomes are interesting because they kind of mimic bacteria and. When you put the GD3 into the liposome and then give it to the dog's body, the dog says, oh, this is an invader because it's a bacteria and we are gonna respond to it.

And that response is a very specific kind of response. It's what is known as an a natural killer cell response. And these are the cells that are known to have a profound effect on cancers. So fast forward a couple of years and in the process of. Doing research more and more work was being done by us and with others that recognize that in fact, GD3 is not only present in melanoma, it's also present in bone cancer in osteosarcoma. But what's interesting is the normal. So as I said, melanocytes, which are the precursors, or get mutated and become melanoma, have GD3 on them. But the cells that make bone normally in the body, osteoblasts don't have GD3 on them.

But when they become a cancer, this. Pathway is switched on selectively for the cancer, and you then get GD3 on the surface. And we've now shown that it's present in osteosarcoma. It's also present in Heman Angiosarcoma, which is where we are now with a new clinical trial. It's also present in in a disease called histiocytic sarcoma and various brain cancers and some selective memory tumors have it on. So what we have with our vaccine is a kind of off the shelf immunotherapy that can target multiple tumors without being specifically designed for the individual patient.

In other words so when they use the term precision medicine, very often than not it means that you're gonna make something for that person or that animal specifically. Whereas our vaccine does not require that. Well, all you need to show is that in fact there is GD3 present. And, we have over the years developed, a lot of research to actually identify GD3 in, different cancers, which has taken a lot of work because, initially people really didn't think there was much around. But in the process of normally submitting samples to a path, they'll preserve it in formula and so on, and that destroys the GD3. So we were able to show that this was presence in these different cancers using flow cytometry, and other molecular techniques.

Melanie Cole (Host): That is absolutely amazing, Dr. Milner. So with all of this that you've just told us, how do you envision this research translating into care for humans, to veterinary medicine, vice versa? How do you see this changing the landscape, and how do you feel it will impact more veterinary care as you get into this in other clinical trials?

Dr Rowan Milner: Well, in the publication that we'll be submitting shortly on melanoma, I can tell you that we know, and it will be in the publication that, remember earlier on I had said to you that, if you just do surgery and maybe chemotherapy with oral melanoma, you get a median survival time of about a year. Correct. So when we use this vaccine, our median survival time is. Tripled and in sometimes quad tripled. So you're talking about survivals of over a thousand days. So we know that in the case of the melanoma vaccine, the GD3 vaccine in melanoma, it rarely does change the survival outcome for dogs with this disease.

Now there's no such thing as cure in a lot of cancers. What you're doing with our vaccine is controlling the metastatic process, and we are doing that successfully and in the case of melanoma, we are doing that in three out of four dogs, so about 75 to 70% of dogs have a sustained prolonged survival, with this vaccine. In the case of osteosarcoma, which we began studying in 2015, the data is more newer. And it's a lot more of a harder a nut to crack, because as I said to you before, osteosarcoma is one of the most mutated cancers out there. But we know from our information that we are making a difference in one out of two dogs, with the vaccine.

And in about 40% of dogs, we are providing a prolonged survival compared to, the nine months we are seeing dogs about, 30 to 40% of them that are living much longer lives. Now, why is it not as good as, for instance, melanoma? Well, they different cancers and osteosarcoma, we know to have components in it that make it harder to treat. It's also harder for the immune cells to get into these cancers, into osteosarcoma, and there are a lot of sarcomas that are like that versus something like melanoma. So melanoma is what we would call a hot tumor.

And then, there's a lot of immune cells within it, things like macrophages and so on. And in the case of osteosarcoma, that's less so a lot of the immune cells come to the outside of the cancer and can't get in. And that's what we call typically a cold cancer. So a lot of research that we are doing at the moment is how do we change a cancer that's cold into a cancer that is hot? In other words, the immune system can get its cells into that. And so my colleagues, myself, Dr. Bekel, Dr. Shimitsu and others here and the College of Veterinary Medicine and the College of Medicine, Dr. Elias Sayer, John Ligan and others are looking into how we can change this.

Because what applies to the dog's cold tumors applies also to the humans. Now, you asked me how this vaccine could maybe offer hope in the human field. So, To make that leap from a canine trial to a human trial requires what is known as an FDA IND approval, and that is a very expensive, exercise to go through and you will need lots of money to be able to set up a manufacturing process to be able to make that transition. So a lot of these steps that we've got to go through requires time, and it requires recruiting donors.

That requires recruiting, maybe a company that's interested it, and so on. So not everything that is successful necessarily makes it. Into the marketplace as such. But since we have a clinical trial running here at UF, it is open to people to come to uf. But currently it can only be done at the University of Florida. The vaccine that is.

Melanie Cole (Host): Well, that segues beautifully. Dr. Milner, I'd like you to tell us how you're working closely with clinician scientists and other researchers to help them meet their scientific goals. You are such an amazing educator. What does that look like, and how satisfying is that portion of your career? And you can also, during that portion, tell us about how you're currently overseeing three vaccine studies for dogs with Apendicular, osteosarcoma, Heman, angiosarcoma, melanoma? You could tell us about anything that you might have missed when you're telling us about that, but I'd like to know how satisfying that must be for you when you're really working with these other clinicians and helping them to advance this field.

Dr Rowan Milner: I think the thing that is common to me, common to my colleagues in veterinary medical oncology and to our colleagues in pediatric oncology, because that's where osteo sarcomas go to. And then in the case of humans with melanoma, is that we have the shared vision of wanting to make a difference for cancers that honestly, over, and particularly we are talking about osteosarcoma and what that's true for Hemangio, that over the last three to four decades, there's been no change in actual outcomes, both for dogs and for humans.

And what that means is that we need to. Get better at treating these rarely malignant diseases. So as I mentioned earlier on in the podcast, that these are devastating cancers because the metastatic process It just is progressive keeps going and so most of these immunotherapies are going in and targeting in that. So I have, affiliated faculty status in pediatric oncology. And so much of what we do, relates to humans and vice versa. So we learning from them, they are from us, and we have a number of, trials that we share. So we also have an RNA vaccine trial here that was developed in pediatric oncology.

And the purpose behind that is, why we are researching any dogs is that that information can be taken into a human, clinical trial through an investigational drug, application. So we are moving this on a broad front because nobody has all of the answers. There are good things. And then the other things that are definitely not working. And then there are a number of things that are working. And the advantage to the GD3 vaccine is that it would be considered what you would call an off the shelf kind of immunotherapy. And this is similar to say for instance, a drug that you would take, that would enhance your immune response.

Versus something like a precision medicine application, which an example of this is an adoptive T-cell therapy, that means, car T-cells. And actually in the lay press there's a lot of talk about that, but it's at the moment specific to the patient. And so that is the advantage to this vaccine. Like everything in cancer treatment. It's probably never gonna be just one thing, right? It's like there's no one cure for the common cold. Well, there's no one cure for all cancers. And like most things, I would say that surgery and chemotherapy and radiation are not gonna go away.

So what is unique about, the GD3 vaccine that we are doing is that we administering this vaccine while chemotherapy is being given. And that's really important because A lot of immunotherapies out there that have been, used and are being researched are often given after chemotherapy has been given. Now a lot of dogs, as I mentioned early, there's 50% make it to nine months. So those ones that failed early are very often than not failing when they're getting chemotherapy. And this was why in the case of the osteosarcoma vaccine, we give a vaccine while we were giving chemotherapy.

And we've shown that does make a difference. Now, could we do better? We think that is the case. and focusing on what is called the tumor microenvironment is the way to go. And that is our main focus.

Melanie Cole (Host): that was just so amazing. Dr. Milner, I'd like you to wrap up for us as to anything that you'd like other providers to know what you're doing at the University of Florida College of Veterinary Medicine, how referring vets can get in on these trials, what you would like them to take away from this fascinating podcast?

Dr Rowan Milner: . Well, let me just say this, that for quite a long time, immunotherapy as it related to cancer, was somewhat considered to be out there, right? It was, an extra treatment. It maybe wasn't a hundred percent legitimate and so on. But now over the last 20 years, it's clearly shown that immunotherpy can provide and does make a difference in overall survival and can give good quality of life. For instance, the GD3 based vaccine is not associated with side effects, which is really, really important. As far as being able to access these trials as. This point in time, unfortunately, they can only be accessed, via the clinical trials program, here at the University of Florida, which I oversee.

And, we have a website which I can provide you with that link. or otherwise you can just go to vetmed.UFL.edu, which is the College of Veterinary Medicines webpage. And then from there go to research. And under research there's clinical trials, link onto that, and you go to oncology and that will take you to our page where we are researching, osteosarcoma melanoma and hemangio sarcoma. With this vaccine we also. The RNA vaccine listed there on the trial. So we've got a lot of things going on and life is busy, but we feel we are beginning to make a difference. Like everything, this world's not perfect. Right? And So we are learning and we feel we are making a difference, and that's the most important thing. We share this vision with our medical colleagues of, improving survival and quality of life, for all patients.

Melanie Cole (Host): Well, that certainly is what it's all about, and beautifully said. Dr. Milner, thank you so much for joining us, sharing your research, your incredible expertise. For more information about the UF College of Veterinary Medicine, please visit vetmed.ufl.edu/ufachievers, and to listen to more podcasts from our experts, you can visit vetmed.ufl.edu. That concludes today's episode of UF Vet Med. Brought to you by the University of Florida College of Veterinary Medicine, Advancing Animal, Human and Environmental Health. I'm Melanie Cole.