Dr. Mamula: It really brought to the surface the need for better therapies in treating canine cancers. There are too few options out there for our dogs with various types of cancers.
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 am so excited to have our guest here today. It is Dr. Mark Mamula. With him, I'm excited to have him come here because many of you know he has an interesting vaccine that we are looking at in dogs. Just to give you guys some more of his background, he is a professor of medicine at Yale University School of Medicine. He investigates early events that disrupt the immune tolerance to cell proteins and autoimmune disease, and tumor biology.
He holds a degree from UCLA, Notre Dame, and the University of Oklahoma. Dr. Mamula is also a co-founder of Therajan, which is a company developing experimental canine EGFR and her two peptide Immunotherapeutics. And his treatment is a form of immunotherapy currently under review by the USDA, and this is the vaccine trial that we're going to be talking about quite a bit today. And so he's been involved with multiple trials over the past eight years. And Dr. Mamula thank you so much for being on our show today.
Dr. Mamula: Thank you again for having me. It's a complete honor. As I mentioned earlier, you've had a lot, many luminaries in the field of veterinary cancer biology already on this program. Many of the thought leaders, many who have pioneered therapies, clinical management of a very difficult disease in dogs. And I'm happy to be among them, of course. So thank you again for having me.
Dr. Venable: Well, yes. Thank you. Yeah. It's been exciting, you know, to talk to everybody and learn more about their background and what they're working on. So I really enjoy doing this. And I think a lot of people and certainly in our niche, likes listening and hearing what everyone's doing. So I'd like to know a little bit more about your background and kind of with that, you know, you're at the Yale University School of Medicine. How did you get involved with dogs? How exactly did that happen?
Dr. Mamula: Terrific questions there. By way of background, I'm an immunologist by training. I know you had Dr. Mason on your program, and her background is a bit akin to my own in studying pathways of immune response of my own in autoimmune diseases, for example, lupus and type 1 diabetes, which we continue to do in my Yale laboratories. And as you know, these are diseases where the immune system starts to attack self tissues.
In the case of type 1 diabetes, antibodies and cell mediated mediated immune responses attack the pancreas until you no longer are capable of making insulin. Of course, lupus is another such disease where the immune system attacks various tissues. It's a bit more complicated. It'll go best in that the targets of those immune responses can be various, including joints, skin, central nervous system, lungs, for example. So tumor immunology is not, light. Understanding the pathways of autoimmune diseases in tumor immunology, of course. And it's not just my lab, but many other labs in this field. Tried to learn ways that our immune systems can view. A tumor is foreign. It really is a self tissue, of course, but the trick is to get an immune response to view that tumor is foreign and of course, attack it and hopefully destroy it or slow down its growth or prevent metastases.
All of the above honestly. So that was the transition from being an immunologist to what turned out to be a more recent fascination with applying all of the immunology we've learned to developing therapies in cancer. How I got into canine cancers was a bit of personal experience in having my own dog passed away from an inoperable hemangioma sarcoma about 10 or 12 years ago now, and it really brought to the surface the need or better therapies in treating canine cancers. I suppose many in your field also share that opinion that there are too few options out there for our dogs with various types of cancers.
Dr. Venable: Yeah, and I'm so sorry you had to go through that. That's a tough one.
Dr. Mamula: Well, it's actually put me in a unique position of knowing both sides of the fence in a way here, having been a close family of a patient, as well as now providing therapies to families of patients so they really don't have to explain much to me. I get many, many emails, and this is one of the terrific parts of what this career has become is in getting emails from owners saying, my dog has X, y, z in this cancer and that it could be a companion animal. It could be a service animal to these families, and now it has cancer. And can you give us advice or can we enroll in your clinical trial? So providing a real service to the community is one of the things that helps me sleep well at night, at least knowing we're creating new options for families with pets with cancer.
Dr. Venable: And it's true. It is a lovely thing trying to help people try and help treat cancer. And you know, the Yale vaccine that it gets called because you're from Yale, but it's looking at your EGFR, Her2. So where did that come about? How did you focus on that specifically with dogs with cancer there?
Dr. Mamula: That is also a very good question. We originally got into the cancer field thinking about strategies for treating melanoma, the proteins that are on the surface of melanomas, both in humans and in dogs are very well understood. TRP was one of them, for example. So we began developing or attempting to develop immune-based therapies for attacking melanomas. And the work went quite well. And we and others have identified pathways to emphasize or to amplify, I suppose, immune therapies in melanoma. But I realized quickly that that is a very aggressive, difficult to treat cancer, not only in dogs, in humans, but in mouse models of melanoma as well. These are cancers that really continue to be problematic for treatment.
And again, from my background in autoimmune diseases, diseases that are based in how antibodies bind and attack issues, we thought to look at tumor family proteins for which antibody therapies have been effective. And you don't have to look very far, at least in human cancers, to realize that this EGFR and HER2 family of proteins, there are now many therapies that are designed to amplify immunity to EGFR and HER2, Herbotox, Herceptin.
Any number of other well, monoclonal antibodies continue to be successfully used in treating human cancers that express these tumor proteins. So we thought, okay, we've got a cancer or family of cancers that are known to be susceptible to immune therapies in human cancers. How can we apply these to dog cancers? And that's how we very simple pathway to getting into utilizing what we know about human cancers into treating dog cancers by virtue of EGFR and HER2 immunotherapies.
Dr. Venable: What kind of challenges have you faced just trying to to make this vaccine? I know, you know, coming up with any new therapy, there's so many hurdles and such a process, especially when you start then getting into regulatory and things. So what are some of the big hurdles that you guys ran into?
Dr. Mamula: There is an obvious major one, which is it's terrific to be an immunologist here at Yale University. I have many smart colleagues that I tap resources here at Yale. But the resource that we unfortunately do not have is a veterinary school here. The medical school here is focused on creating therapies for human clinical trials, of course, but creating therapies for canine clinical trials or implementing therapies or dog cancers has been at least early on, very difficult to navigate.
But we've been fortunate and literally by persistence, my persistence and the persistence of many that I work with, as well as a number of veterinary oncologists who were willing to take a chance on this novel type of therapy that have since become not only colleagues and friends, but sites, for now, being a reservoir, a place for us to find populations of canine cancer patients.
So we now have what has evolved to be a very nice network of clinics around the country at the moment dozen clinics, they include clinics in the gosh, I think I'll get all of them right. Cincinnati, Cleveland, Pittsburgh. We have one in here in Connecticut, two in Northern Virginia, Salt Lake City, Pittsburgh, Chicago, Seattle, Washington, Washington State University, and now one in Ventura, California, as well as, you know, in Phoenix outside of Phoenix.
Dr. Venable: That's awesome. I know pet owners because, yeah, in Phoenix, Dr. Hershey had talked about your vaccine when she was on the podcast, and I work with her quite a bit here in Arizona. I know we get a lot of pet owners and sometimes vets asking about this too. What's a good place? What would you recommend people look to find out where they can find this vaccine? Where they could get treat?
Dr. Mamula: Yes. Thank you for asking that. Well, there are a number of places to find where we are actively participating in clinical trials. I would most frequently encourage them to see the Canine Cancer Alliance website. I'll mention that again. The Canine Cancer Alliance, they are a terrific nonprofit organization. They are based outside of Seattle, and they generously raise funds to support the clinical trials that we are now performing around the country.
Our therapy at the moment is provided at no cost to patients. There are some costs that patient families incur, typical vet office visits or other therapies that the particular clinical trial site may utilize in a given patient. All of the sites are managed and run by board-certified veterinary oncologist. So they're all terrific. All of our patients get honestly the best care that one can find in this country at our clinical trial sites. It's not to say that you can't find good clinical care elsewhere, of course, but as you know, the field there are not many veterinary oncologists in this country. Maybe 300-400?
Dr. Venable: It's low. It depends. Last I heard, I want to say it was just under 500, but that was registered. That wasn't who was actually working. So I think if you look at who's in clinic patients, it's probably closer to the 3 to 400 would be my assumption I think.
Dr. Mamula: Ah I see. So what I think is an advantage to our methods, this clinical trial is in getting our therapy in the hands of real clinic users that will ultimately be dispensing and administering this therapy. And again, it's not to demean academic centers that hold their own clinical trials, but I found that it it really can be an advantage. And I get very different questions from private clinic owners that are managing our therapies, as opposed to some of the academic clinical trial sites that have different criteria for either accepting patients or a unique access to patients compared to private clinics.
Dr. Venable: What are some of those questions? Do you have any on the topic? I'm just curious, what are sort of the differences that you see between those two?
Dr. Mamula: Well, there are certainly administrative differences between academic medical centers. Translated, that means extra paperwork for everyone. I'm sure are aware the academic sites have large groups of committees, so-called IOCA committees that manage animal care and new therapy strategies at academic centers that require many rounds of purview in accepting or approving new therapies like ours. The paper work and the ability to do these things in private clinics is significantly easier, in part because I won't say it's easy, but it in part is managed more stringently by the clinic owner and in private clinics. We do have several MedVet consortia clinics in our group. There are certain layers of administrative issues that we had to navigate there. But again, they've been a terrific proponent and, colleague in our own clinical trials.
Dr. Venable: And I think that all makes sense, right? When you're private practice, especially a single owner, you're just really dealing with one person versus universities. There's so many people. And, you know, kind of makes sense why universities have so much, you know, just to double check things. There's probably so much more comes to them. But that makes a lot of sense. And to kind of get back a little bit on just how the vaccine works, if you can describe just a little bit of how does this EGFR, HER2, how do you finding that it works for these cancers and in what cancers are you using it in?
Dr. Mamula: Terrific questions again. So I'll give you a little bit of background about what EGFR and her two, how they participate in tumor growth and how and why it's important to prevent the pathways that are used by these tumors broken. This is a family of four different proteins that are three of which are frequently found on, again, many tumor types. And I'll go over that in just a minute. But the important thing about this family of proteins is that there are signals and they sit on the surface of these tumors, and they signal they are tickled at the surface by their ligands, and they send signals to the nucleus of the tumor cell to grow and divide, and sometimes metastasize or even mutate in order to survive.
We all know that cancer really is a battle between the tumor cell that is trying to survive, and it will do anything to try and do that. It will mutate when it needs to to try and avoid therapy. It will divide and it will metastasize again in order to survive. And the battle is with various therapies that try to prevent it from dividing and prevent it from growing. And that can be small molecule inhibitors, as you know, it can be other chemotherapies or it can be immunotherapies. So it's in trying it to overcome what the tumor has learned, and the tumor being smart enough to trying to attempt to avoid being subject to chemotherapies is really the battle here. So again, this therapy that we've developed is not the overall strategy that has been used in other cancer types.
And simply put, it falls into the family of what has been called a cancer neoantigen therapy. So what does that mean? Well, the Neoantigen is really just something that your immune system has never seen before. Parts of cancer, proteins and cancer cells have never been seen by your immune system, but it's not limited to cancer cells. There are cells.
Different tissues in you and me and the dogs that have also not been seen by the immune system. Why is that important? Well, if they've not been seen by the immune system, this means that the immune system could possibly bump into them, and they can view them as being foreign. What does that mean? It means our immune systems are trained to kill off things that are for bacteria, viruses, for example, the most foreign things we could have get literally under our skin, right? So our immune cells typically very easily see those bacteria viruses at bay and view them as foreign. And their role is to kill off cells that are infected with these foreign things. So again, the trick is to find a part of a tumor or a tumor protein, in this case EGFR, Her2 that the immune system deems as foreign and can make an immune response against it.
And that's what we've done. It was a tedious process. Again, I took targets that human cancers were subject to antibody based therapies in on these three proteins, EGFR, HER2 and HER3. And I will bore you with all the details. But we did a lot of sequence and structure function analysis. These proteins had that crystallized. We know a lot about their shape and how they signal cancer cells.
So we took small pieces of the EGFR and HER2 proteins, tested them in mice originally to see if any of them could be the trigger immune responses. And the answer ultimately was yes. Although we did fail in finding in investigating certain sites on these proteins. So I won't say that we immediately hit the home run, but we found that sequence of short region of the EGFR protein that when we mixed it in a typical vaccine formulation, we could get very strong immune responses against not only the short piece of the protein, but ultimately would also bind living cancer cells. It would bind them, and it would actually kill cancer cells in a petri dish. And we thought, okay, this is exactly how human therapies were screened. This is how Herceptin, Herbotox were screened in the laboratories, first by generating antibodies to these proteins and then asking, how well do they kill tumor cells? It's exactly what we did.
So very, very simply put, the strategy that we've employed is by putting this small part of the EGFR protein into a formulation that is a very simple subcutaneous injection, two of them actually three weeks apart. So a dog patient will show up at the clinic. Then the patient will get a subcutaneous injection at day one, come back three weeks later, a second identical injection to boost the immune response.
And then we're able to measure antibodies against the tumor proteins after that. So then the trick is to ask, does it work? Of course, the important thing. Does it slow tumor growth? Does it stop tumor growth or at best of course, does it reverse tumor growth. And any three of those outcomes I think we would all be happy not only in treating human cancers, but in our dog cancers as well.
Dr. Venable: Yes. And so you started out with the petri dish, like you said, how they started with the classic, the famous human products, and you've moved into the dog and you guys have published on this, with the safety and now you've got ongoing studies. What are you seeing? I don't know if you can report, kind of what you guys are seeing so far. Do you have enough data to kind of say how things are going?
Dr. Mamula: I can, I presented this at, annual meetings of the Veterinary Cancer Society. We also have, two publications and a third one in the process. Our clinical trials at the moment include hemangiosarcoma, osteosarcoma, and transitional cell carcinoma, also known as bladder cancer in dogs and all three of these cancers are known to express EGFR and or HER2 on the surface of these proteins.
So these are the cancer types that we've chosen for this clinical trial. There are a number of other canine and human cancers that express the EGFR and HER2 family. Those include a long list like anal carcinoma, soft tissue carcinomas, a pituitary adenoma, mammary cancers, gliomas. There's some question whether mast cell tumors express these proteins. Thyroid carcinomas express these certain lung cancers.
Non-small cell lung cancers express EGFR in HER2 and epithelial nasal carcinomas as well. So there are a lot of potential targets. And literally the menu of dog cancers that could possibly exist. It may be easier to define what tumors do not express these proteins. And that's a pretty simple one. It's so-called liquid tumors. Leukemias and lymphomas do not express these tumor family proteins.
Dr. Venable: Oh, that's a really interesting. And so with these so you have several cancers that express this. So what made you guys decide I guess two things I always wonder, especially with immunotherapy, because I feel like there really is a reason for why you guys do this, why subcu on the neck and why three weeks apart?
Dr. Mamula: This is a standard strategy for many other vaccinations. Honestly, you may recall when you got your first cycle of COVID vaccinations was identical to that you went in at day one and day 21 plus or minus. And got the booster COVID mRNA vaccine. The vector there was obviously a little different than our own, but the strategy is the same.
Their immune systems respond in very nicely, predictable ways. When you get infected with the virus or a bacteria, you make natural antibodies against them. You first make IgM class antibodies, typically within the first 10 days to 14 days of being infected. The same is with the vaccination, again, because the skin is formed by the host, the dog, or the human.
So within the first two weeks, dogs and humans start to make IgM responses against vaccines. That can be Covid, that could be flu, measles, or it can be our EGFR, HER2 vaccine. At about three weeks to four weeks after the vaccinations, you start to make what I would consider more important antibodies that help you clear both pathogens as well as cancer cells.
And those are IgG class antibodies. Also, at that same time, your developed what are called cell mediated immune response various subsets of T cell called T lymphocytes. These are all derived from bone marrow and developed in various places in the thymus or other peripheral lymphoid organs. And much like antibodies, they are in charge of attacking foreign things like the bacteria, the virus, or hopefully the tumor.
So the trick is again, to get an early immune response IgM and that boost it with another dose of the vaccine or the pathogen. And that really gets to the levels of the immune response is at their peak. The theory is that the better, stronger, more or more high titer IgG response is against a tumor would potentially lead to better clinical outcomes.
We don't know that to be the case yet, but that's a topic of some of our clinical trials. And just like in a human treating human cancers, there's not one therapy that treats all of a single type of cancer. You know that when a human walks into the clinic with a particular cancer, whether it's a lung cancer, a breast cancer, a colon cancer, one type of therapy, whether it's chemotherapy or an immune therapy, may work in one patient and not in another.
We don't know why that difference exists between patients, either in humans or in dogs, but we're trying to learn what that is. Is it mutations in a particular tumor that is found in one dog and not in another? There are many groups dedicated to identifying those pathways. Or is it changes in the cell surface circling back to EGFR and HER2, these tumor proteins are very, very dynamic in their expression on tumors.
They change frequently over the course of a tumor growing. So for example, if one does pathology on a tumor at day one when the tumors noticed, and you can see EGFR on the surface or HER2 on the surface, if that same tumor is sampled 3 months or 4 months or 6 months later, the representation or the expression of those proteins can be very, very different.
They rearranged receptors rearranged on a continuum. Throughout the course of this cancer. It's known both in humans and in dogs, that sites of metastases may have very, very different expression of these EGFR, HER2 proteins compared to the primary tumor site. And this is, again, what makes it very difficult to treat these tumors. Tumor at the original site that has lots of EGFR may be susceptible to this therapy, while the metastases may not be. Again, because of expression, a difference of expression of these proteins. And this is again, one reason that both humans and dogs become refractory or resistant to various specific immune or small molecule therapies. Is that again, the tumor has changed? It no longer expresses the target of the therapy that you're using. Again, whether it's a monoclonal antibody, an immunotherapy like ours, or small molecule inhibitors, for example.
Dr. Venable: It does always blow my mind how cancer becomes so smart. Like how does it know to change so much and work around and then just the immune system. It always blows my mind. And as you're seeing, you know, the lesions could be totally different. Make up really in some sense from the primary. So how do you see the use for these kind of drugs? Do you see it in combination with other more traditional things? You think maybe eventually these will be more solo therapies? Where do you see this heading again?
Dr. Mamula: Again, great question. It's really logical that if you're trying to clear the pathogen, a bacteria or a virus or clear a tumor, the best way to do that is to attack as many different sites and as many different pathways on that bacteria and that virus and that tumor cell as possible. So translated, that means combination therapies are bound to be the best therapies for treating tumors.
We already know this in treating human tumors. For this listening audience, if anyone here is interested in understanding or finding information on the most recent, the most cutting edge clinical trials, there is a terrific website. It's very easy to remember, clinicaltrials.gov. It is a site that our government sponsors. You will find the latest clinical trial, the latest therapies being tested in any type of cancer that you would choose to find information for. It's a very user friendly site. It's available to the public. You can type in the cancer of your choice and look to see what types of therapies are available where they're located in many cases, enrollment criteria, whether the clinical trial is active. It even gives you contact information, phone numbers and email addresses to inquire about these. So it's a very simple process.
In a similar manner for canine cancers, there are now emerging repositories that are sponsored by the government to map it, to identify genetic mutations that really address the question that you raised, which is how and what are the mechanisms of why these tumors become so resistant to therapies. So there is an evolving and emerging consortium of investigators that are contributing lots of genetic data about their canine cancer patients to a central repository.
And it's a very valuable tool to investigators like myself and many others to help try to identify and answer the questions why some dogs become resistant to therapies. But back to the original point about attacking in so many different places on the tumor as possible. That is why things like combination therapies including radiation, small molecule inhibitors of these pathways, as well as various immune therapies will undoubtedly be the best strategies for really treating these types of cancers, both in humans and in dogs.
There are unfortunately barriers to studying these types of combination therapies. In dogs. It can oftentimes be financial barriers, of course, and sometimes in humans. But clearly a difficult, I'll say, problem to overcome are the fact that it's really the families of dog owners that dictate the types of therapies that will get used in their dog patients, in your dog patients, of course, as a human and with reasonable health care, you don't have that option entirely.
If you had cancer and walked into a human clinic, there would be standards of care that you would most likely be treated with. People bringing their cancer bearing dogs into the veterinary oncologists. I mean, I envy your position and having to, in fact, be a proponent for various therapies for your own patients, knowing that this will be a financial burden to the families and may influence or dictate how they treat their dog with cancer. Our goal is to make an available economical strategy and another tool in the toolbox for veterinary oncologists to use.
Dr. Venable: I like that because it is now the whole piece, like you were saying, that, you know, financial, all the different options, what they want to do or not, it can get quite complex and it is it's challenging for people and and that's something that I realize too, over the years in people like when you have cancer, they don't have nearly the flexibility that we do.
You know, we use so much stuff off label and, you know, so you can really get creative and have, you know, I think I almost always give people three different levels of options, you know, kind of here is the one who I think would work the best, but it also is the most expensive and usually has the most side effects.
And then we kind of work down the tiers, you know, till we get to what works for the family. Or maybe they want that top option versus like you said in people, you kind of just get told like, here's the standard and this is what we do, you know? So I think there's some plus and minuses with that. Certainly be nice to not have as much of the financial conversations. But but yeah, no, it would be great to have something else, certainly something affordable. I really like hearing people when they're including that in part of their strategy. You know, when you're looking at, you know, not only ultimately does this work and is it safe, but is it something that the market can actually bear, you know, can people actually afford it?
So that's exciting to hear that this won't be, you know, crazy expensive like some of the products and and kind of with that, what do you see the trajectory I don't know where you guys are in the scheme of things as far as is becoming commercially available.
Dr. Mamula: So again, you mentioned our company, TheraJan. We do have a website TheraJan.com and that will hopefully ultimately manage this therapy as a veterinary product. We have paperwork submitted to the USDA. They have been reviewing our clinical data, as well as all of the other minutia of how we make the product in great detail, I might add, and we're hopeful that they'll act as efficiently and as soon as possible. We're anxious to get this therapy out into the hands of clinicians like yourself. And I'm learning about how to manage besides the science and the medicine, which I find most fascinating. Of course, I've spent a lifetime doing that. I'm forced to learn how to manage, hopefully a successful business. That's honestly the much harder part. I'm trying not to mess up these strategies of taking this from literally laboratory bench to the clinics or to the to your clinics, of course.
And that's not always a straightforward pathway. There's not a a set of rules to help us do that is, you know, the drugs that you use in your arsenal of treating cancers, you find and you use based on the publications you read, the experience that perhaps the drug has in treating human cancers, but that does not always translate perfectly to treating dog cancers.
A patient with a dog with cancer comes in and says, okay, you give them three options and they say, well, what's the best option? What are the survival statistics for using drugs A, B, or C? And I know that you frequently have to say, we don't really know because we've not used it enough or it's not been used in this way, or it's not been used for this cancer. Or the numbers or the data are just not out there yet. But the biology in the medicine and its perhaps use in human cancers indicate that this could be a very effective strategy for treating your dog. Am I wrong about that? I'm putting words into a clinician’s mouth here about how you treat your own dogs.
Dr. Venable: But it is true. Yeah, there's a lot of cancers where, you know, I can get some stats. I'm a big data head, so I like to give stats. But there are certainly cases where I have to tell people, you know, take this with a grain of salt because we've only really investigated this on a handful of animals or, you know, or we really don't have this, but I'm extrapolating it from this type of carcinoma or something, you know?
So, lymphoma, I feel like that one's fairly straightforward stats to some degree. But a lot of the other cancers, not as much, especially, you know, like hemangiosarcoma. Yes, we have statistics with like doxorubicin and things, but none of it's very good. So it is kind of what else can we try to do thinking outside the box.
And that's where we don't really have as much of the data or things like that. And your vaccine I certainly have used with Dr. Hershey's clinic there in Arizona. And so it's definitely been interesting to use and see how it's going. What have you guys noticed as far as side effects? What kind of side effects are you guys seeing?
Dr. Mamula: That's a good question. And you also asked question earlier about the potential efficacy that we've have seen. And if I could share that and I certainly will. Side effects I'll address first, which we have not noticed any changes in. And things like energy, appetite, normal activities that the dogs have either before or no changes between before and after our therapy.
We get many anecdotal opinions. I will get emails from owners saying, “Oh, my dog seems tired or lethargic”, but then I'll get just as many emails that say, “Oh, your vaccine must be working. He's got a lot of energy. He's eating well now,” and the answer is that we can't take the credit or the blame for either of those, post vaccine outcomes, because I think, as you appreciate, dogs are sometimes difficult to understand for where their sources of either energy or appetite come from. They certainly don't express pain very well. And that is one big difference between human patients and canine patients. Cancers in particular, can be very progressed, or very far along before the dog expresses a behavior, a something that even the family members that know the dog very well will even recognize and a cancer or anything else, infectious disease or anything else.
And I'll tell you from personal experience, I that I was really surprised by my own dog having cancer. By the time, she was a yellow Labrador retriever. By the time she was symptomatic, Comanche or sarcoma was, very progressed and had metastasized to several sites already. So, and she had typical behavior, the only side effects getting back to the side effects that we see are a small amount of inflammation, typically at the side of injection.
This doesn't happen in every dog, happens in about 1 in 5 dogs. About 20% of dogs will get a lump under the skin. Some will get larger, potentially even the size of a golf ball in late, neutrophils or other sterile fluids. It's what the people in your field describe as sterile abscess. And that's not honestly a horrible thing in humans. To get vaccinations, you'll frequently feel a little bit of pain at the side of injection in your arm, for example, as an immunologist, that's a very good thing. It means that inflammatory cells, it means that immune cells, B lymphocytes and T lymphocytes have come to the site of that vaccine. They're nibbling that vaccine, they're traveling back to the lymph node. They're active making antibodies, and they're active and develop against that vaccine. So a little bit of pain is actually a good thing. The dogs don't seem to mind. It's an inflammation that really they that it's not painful to the dog. Warm compresses help it go away in about ten days 10 to 14 days. So that really is the single what I call side effect for our therapy as far as outcomes.
And we've published some of these and we've certainly presented lots of this data at the Veterinary Cancer Society meetings. We've published that osteosarcoma is treated with standard of care, which typically means surgery, amputation and carboplatin, along with our therapy, significantly increases 12 month survival. In median survival, we have a number of dogs that have survived three and four years after their osteosarcoma had become diagnosed.
We have had now six cases, in osteosarcoma, where metastases to the lung have occurred, but that those metastases has have resolved and disappeared over the course of anywhere from 3 to 8 months after radiologic evidence of those metastases. So that really was one of the most exciting clinical observations among our clinical trials. And seeing metastases disappear, as you know, next to the lung in osteosarcoma is the single greatest cause of morbidity and mortality of death in dogs with this cancer, Mets to the lung and elsewhere. So we're excited to see some progress, some very nice outcomes in treating Mets for hemangioma sarcoma. Our clinical trial had are continues to pass hemangioma sarcoma by stage by stage one, two and three. Stage one and two again treated with surgery typically as well as our therapy and sometimes doxorubicin the survival hemangiosarcoma stage one and two are dramatically increased by 30-40% compared to standard of care alone compared to surgery at doxorubicin alone.
Rance Sellon, Dr. Sellon at Washington State University, participates in our clinical trial primarily in osteosarcoma. He's pioneered a therapy that utilizes palliative radiation, no chemotherapy. This is for osteosarcoma even along bone osteosarcoma radiation therapy with and without our EGFR therapy and survival is remarkably increased compared to his control groups that get radiation alone. So again, clinical outcomes look very good at this point. And these are all things that the USDA are examining.
Dr. Venable: Well that's exciting. And with, metastasis with osteosarcoma. Are you giving the vaccine once you're seeing metastases or are you saying these dogs had already had the vaccine? They develop mets, but then the mets seem to be transient, which with the wet version is that.
Dr. Mamula: That is a question that addresses some comments we made, we discussed earlier, which is in three cases. The dogs that received our therapy only did so after they failed other therapies. So for example, our first case was a dog with osteosarcoma. Had amputation was beginning to fail. Other chemotherapies, had five rounds of carboplatin, had a metastasis to the lung, and then received our immunotherapy. About the dog survived by eight months that lung met had disappeared. The dog survived another three years, three and a half years, and then unfortunately got a hemangioma sarcoma after surviving his osteosarcoma. Another, and this happened in 3 or 4 other cases that had failed conventional therapies and were enrolled in our study and resolved their pets. However, we're not perfect. We don't cure or we don't even get good outcomes in every patient. Again, for the reasons we discussed earlier, some individual cancers in the individual dogs are highly aggressive, more so than the same cancer in other dogs. We have had dogs on our therapy that have gotten metastases over the course of our own treatment. So just again, like in treating human diseases, there are really just some cancers that become too aggressive, that become untreatable or become refractory to any kind of therapy, unfortunately.
Dr. Venable: I it would be nice to have that magic bullet, but I think we all know it's not that simple. And but it is exciting to hear you guys are seeing some good responses and and it is going to be more of this multimodal approach. Right. And I think as we go on and learn more about all, you know, cancer in dogs and people, I think it will become more of this, okay, for this tumor, and in this specific patient, we're going to use XYZ versus another dog with the same tumor. But it doesn't quite have all the same characteristics. We'll use something different I think we'll get it a little more personalized. At least that's what I'm hoping for, because I think we'll hopefully get better outcomes with that. And I think knowing your vaccine and if they have those EGFR mutations, HER2, you know, that would make sense using the vaccine.
So certainly I'm excited and waiting to see as more things develop and certainly will be on the lookout for your vaccine when we can get it commercial. And before we wrap up, I am curious are there any advancements and veterinary, especially immunotherapy that you're excited about? Is there anything coming down the pipeline or anything that you've heard about?
Dr. Mamula: I am, you probably know about the gilvetmab, PD-1 immunotherapy that it's been approved by the USDA for two different cancer types. We are actually an arm of our own clinical trial utilizes gilvetmab. This is a study sponsored by Merck. We requested to collaborate with Merck and this particular product in treating canine hemangiosarcoma.
So those dogs will get our EGFR therapy. They will get gilvetmab. This is only at one of our clinical trial sites. Dr. Chelsea Tripp in Edmonds, Washington. But we're now increasingly enrolling dogs in this particular arm of the trial. We're very anxious to see how those dogs do in this particular trial. Gilvetmab has not been extensively used in hemangiosarcoma, again, based on human trials with PD-1 inhibitors. The data suggest that it should be or could be effective in treating these dog cancers. But again, we hope to know a lot more about that in the coming next 6 or 8 months.
Dr. Venable: Oh that's awesome. I will certainly look out for that. And then, you know, at the end of the podcast, I always like to ask people, you know, who else do you think would be a good fit for this podcast?
Dr. Mamula: You have many bright colleagues that you could tout that are doing very interesting, exciting pieces of work, both clinically and experimentally, in this field of canine cancer therapy, I can certainly recommend many of the bright veterinary oncologists they're taking part in our own clinical trials. Those would be Dr. Chelsea Tripp, for example, at the Bridge Animal Referral Center in Edmonds, Washington.
Dr. Brendan Boostrom, it meant Vet in Northern Virginia would be another terrific interview for this group. They are both very bright, very forward thinking clinicians, veterinary oncologists that have already participated not only in our own clinical trials, but many others that are unrelated to our own, which really is a reflection of their own interests in moving the field forward, moving therapies forward, or treating dog cancers.
Dr. Venable: Yeah, those are definitely two great people. We'll certainly reach out to them. And yeah, I agree with you. I think people willing to do trials, willing to try new things. I mean that that's how we will move the needle forward, try to gain some ground, win more on this battle with cancer. So just thank you so much for being on our podcast today.
I learned a lot about different immunotherapies and about the vaccine and different technology and how we're using it. So again, Dr. Mamula, thank you so much for being on our show.
Dr. Mamula: Thank you again for having me. It was terrific to be with you.
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.