Veterinary Vertex
Veterinary Vertex is a weekly podcast that takes you behind the scenes of the clinical and research discoveries published in the Journal of the American Veterinary Medical Association (JAVMA) and the American Journal of Veterinary Research (AJVR). Tune in to learn about cutting-edge veterinary research and gain in-depth insights you won’t find anywhere else. Come away with knowledge you can put to use in your own practice – along with a healthy dose of inspiration to remind you what you love about veterinary medicine.
Veterinary Vertex
Innovations in Canine Cancer Treatment: Harnessing Immunotherapy
Can dogs benefit from the same revolutionary cancer treatments as humans? Join us as we explore the promising world of canine cancer immunotherapy with our distinguished guest, Dr. Tim Fan. Tim sheds light on breakthrough strategies like monoclonal antibodies, cancer vaccines, and adoptive cellular therapies, transforming how we manage cancer in our beloved pets. Drawing from his recent JAVMA article, he explains how these innovations leverage the immune system's power to fight cancer, offering hope for more effective treatments. Learn how advancements in veterinary medicine are extending pet lives, making the fight against geriatric diseases like cancer more crucial than ever.
Looking ahead, we focus on the future of immunotherapy in veterinary care, especially the potential of AI to personalize treatments by analyzing complex data like the tumor microenvironment. Tim's research, enriched by collaborations with clinical residents and PhD students, provides a unique perspective on setting realistic expectations for immunotherapy's effectiveness. We delve into the necessity of combination therapies to broaden the impact of these treatments, underscoring the importance of evolving strategies in veterinary oncology. This episode is a must-listen for pet owners, and anyone interested in the future of cancer treatment.
Open access article: https://doi.org/10.2460/javma.24.08.0532
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You are listening to Veterinary Vertex, a podcast of the AVMA Journals. In this episode we chat about the promise of immunotherapeutic strategies to advance cancer treatment in pet dogs with our guest, Tim Fan.
Lisa Fortier:Welcome to Veterinary Vertex. I'm Editor-in-Chief, Lisa Fortier, and I'm joined by Associate Editor, Sarah Wright. Today we have Tim joining us. Tim, it was really a pleasure to meet you in 3D last week at the University of Illinois for your Dean and Pam Wilkins' investorship, and I want to thank you for your contributions to our journal and for being here with us today.
Tim Fan:Thank you, Lisa and Sarah, for inviting me, looking forward to chatting about interesting therapies that are coming down the pipeline.
Sarah Wright:So, in addition to being a JAVMA author, Tim and I also both were awarded Veterinary Medical Alumni Association Awards from the University of Illinois. So, congratulations again, Tim, on the Irwin Small Award.
Tim Fan:Thank you, Sarah.
Sarah Wright:Of course, all right, now let's dive right in. So, Tim. Your JAVMA article discusses the promise of immunotherapeutic strategies to advance cancer treatment in pet dogs. Please share with our listeners the background on this article.
Tim Fan:Yeah, I think that this is a really timely review, right? So we know that cancer is increasing in awareness, and that's really driven by how we've made advancements in veterinary medicine, right? So we are really really good at providing preventative measures with regards to vaccines and antiparasitics, we're really good at developing high quality diets, and so all of these things have led to enhancement and longevity in our pet population, and that comes with great, great things because we can spend more time with our beloved pets. But that also carries some potential risks for geriatric diseases, and one of the biggest geriatric diseases we work with is cancer. Right, this is a disease in which DNA tends to be mutated over time and you have higher and higher risk of cancer development, just as a function of living.
Tim Fan:And so you know, we have really relied very heavily upon early detection to try to fight cancer. But, more importantly, we rely upon effective therapeutics, and for the past 50 to 70 years we really have really relied upon surgery and then chemotherapy and, more recently, radiation therapy, and some of those technologies like radiation was late to the game, simply because the infrastructure to support that was limited. I think that the most promising therapy that is on our horizon and within our grasp now is immunotherapy, and this has revolutionized the way that people are treated with cancers for the past 20 to 30 years, and we are now entering into the era of immunotherapy with available reagents that can help pet dogs primarily and ideally, pet cats with cancer. So this is a review article that really talks about some of the most promising or well-developed immunotherapeutic strategies that have been evaluated in pet dogs with cancer, and I think it serves as a highlight for what veterinarians and pet owners can really look forward to in improving the care and longevity of their pets after they're diagnosed with cancer.
Sarah Wright:Yeah, this is such a cool One Health topic. I know, like personally, some people that have been treated with immunotherapy for cancer, so I was really interested to read about it in our pets.
Tim Fan:Thank you.
Sarah Wright:So, what are some of the important take-home messages from this JAVMA article?
Tim Fan:I think the important take-home messages will be there are different ways that you can utilize the immune system to recognize cancer, and these different mechanisms all serve as strategies that can be either used alone, but more likely, more effectively use them in combination, and so I think that the biggest take-home messages is that a lot of therapies that we use for other diseases very effectively, such as atopic dermatitis or osteoarthritis, a lot of those therapies now rely upon the use of monoclonal antibodies, and so we have monoclonal antibodies that are produced specifically in dogs or cats, that have really transformed the management of chronic diseases in interveterinary population, and these same same technologies, such as monoclonal antibodies, are now being targeted towards cancer management, and so that's going to be a great field of therapeutic advancement that I think that we're all really anxiously waiting for, and now we begin to have some of these reagents, these biologics, that have become available for the treatment of cancer specifically. So I think you know, in the article I really talk about these four broad categories of immunotherapies. Monoclonal antibodies obviously are very, very exciting, and they've already shown a great promise and activity for managing other chronic diseases in veterinary medicine. I think that we'll see similar promises and highlights of these monoclonal antibodies when we use it for cancer. So monoclonal antibodies is one component. The other component that I talk about is really vaccine. Cancer vaccine strategies and cancer vaccine strategies have been around for quite some time, with really a melanoma vaccine being around for almost 20 years now, right. So cancer vaccines have continued to develop. They are becoming more and more mainstream to be used to actively elicit a specific immune response against cancer cells in dogs. So cancer vaccines as a component.
Tim Fan:The third component I talk a lot about are adoptive cellular therapies. These are much more sophisticated strategies in which you're collecting immune cells from the actual patient, you're activating those immune cells or you're genetically modifying those immune cells and then re-infusing them back to that cancer patient, so you're really supercharging that patient's own immune cells to fight the cancer more effectively. Those strategies again, are now in conditional approval for use in dogs with cancer. So I think that that really opens up the field to have really quite sophisticated and specific ways to fight cancer with the dog's own immune system. And some of those strategies are CAR T-cells chimeric antigen receptor T-cells that are on the cusp of really being translated to treatments in dogs in a more commercial fashion. And the last thing that I talk about.
Tim Fan:The fourth pillar really for these immunotherapies is cytokine therapies, and cytokines have been around for decades and they have always been limited in their usage, because when you give it systemically you can get a pro-inflammatory response, which cytokines do this pro-inflammation. If it's very significant and if it's systemic, that can cause a lot of side effects. You could have significant side effects that could be life-threatening, and so cytokines systemically administered cytokines have been stymied in their clinical development because of their toxicity. But now there's a lot of localized retention strategies that have come to light through either protein engineering or material science engineering, and so we now have technologies that allow us to localize the deposition of cytokines in areas of interest that actually exert great anti-cancer effects and almost have zero or minimal toxicity. So those are the four pillars that I think are really going to be available for pet owners and veterinarians alike to use in the near future.
Lisa Fortier:Yeah, thanks, Tim. Clearly an amazing teacher and a key opinion leader. I loved how you just described and, in your manuscript, how you laid out the four key pillars because personally, when I hear of immunotherapy, I do primarily think of the monoclonal antibody. So very much appreciate that. What sparked your research interest in immunotherapy?
Tim Fan:So I think that I've always been interested in the immune response.
Tim Fan:I think that immunology is so complex. Like whenever I try to teach it to the professional students or graduate students I think that's one of the most challenging courses because there's so many variables and so many degrees of activation or suppression or suppression.
Tim Fan:I actually did my PhD that really focused on immune manipulation with cytokines to try to fight cancer.
Tim Fan:So, I had this kind of background for over about 20 years now, interested in looking at immunotherapeutic approaches for cancer, and I think that really with the advancements in appreciation for immunotherapy as a potential groundbreaking advancement for veterinary medicine, over the past five years I've really been focused on trying to figure out how can we leverage the immune system more specifically to combat some of the most problematic cancers, not only in dogs but also cats. So, I think long background of interest in immunity kind of more formal graduate training in anti-cancer immunity and how cytokines can be manipulated, and then more over the past five years really working with some exceptional basic scientists that have great interest in stimulating the immune system to fight cancer. I've been really privileged to be involved in some of these what I think will be groundbreaking research studies that advance immunotherapies in dogs, but likewise those same technologies are being advanced for the treatment of human cancer patients. So, it's been really gratifying and rewarding for me to kind of be involved and contribute to the advancement on both sides, not only veterinary medicine but human medicine.
Lisa Fortier:That was going to be my next question, Tim. What are the next steps in research in this topic area?
Tim Fan:So, I think the next steps really will be to look at combination strategies, right? So, most of the studies that are evaluating we always have to show safety and activity as single agents, and we do have activity of immunotherapeutics as single agents, but not surprisingly and we should really expect this that the best therapeutic outcomes will very rarely be driven by a single agent, whether that's a single agent chemotherapy, single agent, radiation therapy, single agent immunotherapy very rarely are you going to get a home run with a single agent, and so I think what we need to be looking for is how do we rationally combine immunotherapeutics that are now emerging on market for us to use? How do we rationally combine that with other conventional therapies? And those conventional therapies can include surgery, they can include radiation, they can include chemotherapy, they can include small molecule inhibitors and, very importantly, they include the combination with other immunotherapeutics. So, combination strategies, rational building upon one another, is really where we're going to have to go.
Lisa Fortier:There's a lot going on right and human and veterinary, and all these four ask pillars that you outlined before. Do you see a role for AI in trying to advance immunotherapy?
Tim Fan:I do. I think that AI will permeate itself. This technology, this advancement will permeate itself in all aspects of human society, right? Whether it's medical, industrial, pharmacologic. And so I think that, very naively, I would say that artificial intelligence will be really important when it comes to understanding and predicting which patients whether you're a dog, cat or human will be most likely to respond right. So, currently we don't have really good ways to preemptively stratify our patient population into which animals will respond and which animals will not respond, and that ends up being suboptimal, right?
Tim Fan:We would like to be able to understand if a dog or a cat or a human tumor has these characteristics, then this type of therapy will be most likely, effective and cause the least toxicity for that patient. So, in many ways, artificial intelligence can allow personalization of therapies, not only exclusively immunotherapy, but any type of therapy. But I think immunotherapy is really really complex, because not only do you have to take into account the tumor cells, but you have to take into account the tumor microenvironment, you have to take into account the host immune response. There's so many variables that it is impossible from a human perspective to be able to filter out those variables weigh, those variables understand interactions that may be occurring without artificial intelligence. So, yes. I think artificial intelligence will be landmark and important in improving our understanding of how to maximize therapeutic outcomes in dogs and cats with cancer.
Sarah Wright:That's fascinating. We'll see what's on the horizon. And, for those of you just joining us, we're discussing the promise of immunotherapeutic strategies to advance cancer treatment in pet dogs with our guest, Tim Fan. So, Tim, a little bit more about you. How did your training prepare you to write this manuscript?
Tim Fan:So, I think that I was really lucky to have some great clinical residents and graduate students to be part of this whole manuscript.
Tim Fan:You know, part of part of the reason why I'm in academics is to obviously help train the next generation of veterinary leaders, and those leaders can be clinical residents, in my case clinical oncology residents.
Tim Fan:That are the two main authors, one and two, Dr Jordan Hamill and Dr Nitrin Chuk. They are clinical residents in medical oncology with us. And then Mateus Barbosa is really one of my PhD students, this great, phenomenal PhD student really interested in immunotherapy. So, they really helped prepare me in many ways right, they did a lot of the research they're learning about these technologies and I was fortunate just to be on the other end to kind of polish it, but certainly it did resonate with a lot of my interests. So a lot of the clinical studies that we're doing here, a lot of the basic science research or translational research that we're doing in my lab, they're all focused on immunotherapies and so it was really great to kind of condense all of the areas that I'm interested in clinically, as well as kind of a translational research aspect, and embody it into this paper that hopefully will be really useful to kind of provide an easy to read and understandable review article for the veterinary profession to refer back to.
Sarah Wright:Yeah, shout out to my classmate, Jordan Hamill, actually one of the authors on this manuscript, so really cool to see her name on there. Now, this next set of questions is going to be very important for our listeners.
Sarah Wright:What is one piece of information the veterinarian should know about the promise of
Tim Fan:We hear about the miraculous responses, and that is true. So when you think about immunotherapies, we believe and we see clinically responder patients have profound, durable, sustained responses, and many times we categorize them as curative responses. Right, and I think we put that into our mind, as this is what immunotherapy can do, and it certainly can do that.
Tim Fan:But the realization is that immunotherapy is life-changing for the minority of patients that are treated. The majority of patients will not reap the greatest benefits of immunotherapy, and we just need to have that recognition from not only the veterinary healthcare professional, but also the pet owner. We have to realize that if you do get a response, it often is a great, durable and often curative response. But that is a minority of the patients, and so this comes back to the idea of well, how do we broaden the swath of patients that can actually benefit from immunotherapies? It is not going to be single agent immunotherapies. There will be 15, 25% of patients that benefit from single agent immunotherapies, but we want more than that. We want to have 50, 70, 80% of patients that benefit, and in order to achieve that, we have to then think about combination therapies.
Sarah Wright:And on the other side of the relationship, what's one thing clients should know about the promise of immunotherapeutic strategies to advance cancer treatment in pet dogs.
Tim Fan:So, for pet owners, I think it's many of the same right? Having being educated, having realistic expectations and then also recognizing that immunotherapies I usually think about it as a double-edged sword. What you're essentially trying to do is amplify your immune response against cancer cells, which are really cells that come from your own body. They may be slightly mutated and so immunotherapies, often, in order for them to be the most effective, they have to what we call break tolerance. Right, you have your immune system that is tolerant of self-tissue, so you don't have autoimmunity. Many times, if we're going to have effective immune responses against cancer, you may kind of run that line of breaking tolerance, and so there will be some risk to pets that are treated with immunotherapies that we are going to induce pro-inflammation systemically that is used to fight the cancer, but there could be side effects of those treatments as well, right? So it's not just roses and hummingbirds and butterflies. Right, there are going to be some risks associated with immunotherapies and we need to educate pet owners on understanding what are the risks and benefits, as well as what are the expectations when we come to immunotherapies.
Tim Fan:I think one of the biggest things that I've learned as a clinician when I'm using immunotherapies is that the benefit may not be immediate, right, and I know that we've treated dogs with intratumoral cytokines, that I don't know if the therapy is working, but then almost a year later the tumor shrinks away, right, and so the timeframe for your immune response to get activated and to launch an effective response can be quite long, and so that would be another thing for pet owners to recognize is that it's not an immediate thing that we see.
Tim Fan:It's different than treating a dog with lymphoma with chemotherapy, in which we give drugs and then within 48 hours, those lymph nodes are really much smaller. We don't typically see that with immunotherapies, because it takes time for you to educate, to amplify the immune response and for that immune response to be effective and that can take months, quite honestly, to happen and for that immune response to be effective, and that can take months, quite honestly, to happen. So that would be something I would want pet owners as well as general practitioners to understand that immunotherapies can have a longer timeframe in order for you to see effects.
Lisa Fortier:One of the things, Tim, I see in the clinical side of immunotherapy in small animals for osteoarthritis is the owners don't really want to spend the money or the time to get an accurate diagnosis. So, you know, the dog is a little bit older and limping a little bit or maybe it's a little weak in the hind end and the owners have heard about these great drugs. Do you face the same sort of? Just give my animal that immunotherapy in oncology.
Tim Fan:I don't think it is. So I think that most pet owners that we treat with immunotherapies, they do recognize that the immunotherapies have to be often for a specific disease setting, right. And so again in the article I'll talk about monoclonal antibodies, specifically for B-cell lymphoma. Right? So these are antibodies that have been identified and developed and we know that they're safe and there is activity. You can't use those monoclonal antibodies for T-cell lymphoma or for histiocytic sarcoma, right? So I think that most pet owners or for histiocytic sarcoma, right? So I think that most pet owners, once we begin to talk to them about the technology and talk to them about the mechanism of action of these immunotherapies, they understand that, oh, we need to probably have a more definitive diagnosis in order for you to get the best personalization of the therapy to benefit their pet. So I don't think that we run across too many misconceptions of a panacea, right? I don't think that people are saying give me a vaccine or give me an antibody and it will cure all forms of cancer.
Lisa Fortier:Good, that's better than what they're facing in the OA field. Thank you again, Tim. As we wind down, we have some fun questions to ask. This is the holiday season, so at least in my house we're always doing puzzles. So, I'm wondering when Tim Fan does a puzzle, do you start with the exterior border pieces or do you start with the inside?
Tim Fan:Depends. I would say, in general I'd like to start with exterior, just because it's easier to kind of know where they're going to go. But interior it depends upon what you see right. So there are very discrete items or colors or patterns. Then it often is easier to you know, you know, match up the interior portions. So usually I do a combination, I do the borders right and then I begin to do the interior on items that I can actually visually see and put together, and then I fill things out.
Lisa Fortier:All right, you're the Switzerland of puzzle doers. Yeah, exactly. Ok, Tim, what is your favorite animal fact?
Tim Fan:Favorite animal fact? I would say that fact. I would say that. So I'm into marine aquaria and I like koi as well, like Japanese koi gardens, and so my favorite animal fact with regards to that is I've always wanted to get like an octopus. But because they're so intelligent, but I know they can squeeze out in between the tiniest crack and so obviously you don't want to have an octopus out of your aquarium in your home. So I've never gotten an octopus, but I've just been fascinated by how they can change their color. They're intelligent and they are able to squeeze out the smallest crack in your aquarium and they are able to squeeze out the smallest crack in your aquarium.
Sarah Wright:So that's cool, I did not know that, all right.
Sarah Wright:If you could have a superpower, what would it be, and why?
Tim Fan:A superpower, I think, maybe the power of persuasion, right Right To be able to develop a very cogent argument to facilitate agreement. I think that would be good. I think, you know, obviously we're living in times in which there's strong opinions, and so I think it would be good to kind of have a more streamlined agreement across the medical fields and all the fields, right. So I so, I think, power of persuasion.
Sarah Wright:All right, and then our last fun question what is the oldest or most interesting item on your desk or in your desk drawer?
Tim Fan:So I thought a little bit about that.
Tim Fan:I'm not sure if it's the oldest or most interesting, but I can make comment on what I think is to me the most heartfelt, right. So obviously I'm a mature, older gentleman and I have kids, right, and so they change so fast, like when they're young, right, and so on my desk I have a picture of my first two sons. I have three sons, but my first two sons were very, very young and I'm taking them to our local lake to go fishing and that's my favorite picture because it's really a candid picture. Our backs are to the camera.
Tim Fan:I'm kind of putting a worm on a hook for one of my sons, and when I look at that I always get a little bit emotional because I know that that was, like you know, 15, 16, 17 years ago and how things have changed, right, they've. They're young men now and in many ways I'm so happy to have had the opportunity to experience, you know, fatherhood and having these great three sons. But at the same time there's this kind of nostalgia, like this kind of feeling in my gut that I just feel like, well, where has the time gone, right, so that's been a very whenever I look at that picture, I kind of get these mixed emotions.
Sarah Wright:Well, thank you so much, Tim. We really appreciate you being here with us today and for sharing your manuscript, too, with JAVMA.
Tim Fan:Thank you Sarah, thank you Lisa.
Sarah Wright:And to our listeners. You can read Tim's article in JAVMA. I'm Sarah Wright with Lisa Fortier. Be on the lookout for next week's episode and don't forget to leave us a rating and review on Apple Podcasts or whatever platform you listen to.
