Pet Dogs Advance Glioblastoma Research with Amy Heimberger, MD

Erin Spain: [00:00:09] This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Can man's best friend help scientists find new treatments for brain tumors? Today's guest says, "yes." Dr. Amy Heimberger is an international leader in brain tumor research and a neurosurgeon here at Northwestern Medicine. Her expertise is in the field of immunotherapy, and among her recent research includes a promising new study in canine glioblastoma that reduced the volume of some dogs tumors. The findings have promising implications for the human version of this aggressive brain cancer. Dr. Heimberger joins me today to talk about the study and her research and immunotherapy to treat brain cancer. Welcome to the show.

Amy Heimberger: [00:00:58] Delighted to be here!

Erin Spain: [00:00:59] Tell me about immunotherapy and how did you get into this field? And how much time is your research dedicated to this field right now?  

Amy Heimberger: [00:01:06] So actually, I started out training in the field of immunology, so it was extremely fortuitous that I got to work with some of the modern major pioneers in the field of immunology. So between high school and college and also between college and medical school, I couldn't quite figure out what I wanted to do professionally. And so I took time off during both of those intervals to do research in laboratories. And I specifically took two years off right after I finished my undergraduate curriculum at University of Missouri, Columbia at the Howard Hughes Medical Institute at Wash U. And so this is right as the field of immunology was just beginning to blossom back in the day. We were just learning the basics of how T-cells become activated, B cells make antibodies, all of the basics that are now just considered foundational. But those were major discoveries in that time interval, and that's really what generated a significant interest in immunology. And then that continued on during the medical school year. I worked in several immunology labs, and then additionally, I selected a residency at Duke, who had a protected two-year enfolded fellowship. And so I got then to work with some of the major pioneers also in immunotherapy for brain cancer folks like John Sampson and Dr. Darrell Bigner at Duke. And so they really provided an immense background and foundation for me to move ahead in this area.  

Erin Spain: [00:02:26] Tell me about this recent study that you were a part of with veterinarians from Texas A&M. This got a lot of media attention, but it involved treating dogs with glioblastoma, treating them with immunotherapy. And these are people's pets who had become ill and they decided to participate in a phase one clinical trial. Just tell me about some of these interesting ways that you're participating to try to find something that's going to work for humans.

Amy Heimberger: [00:02:49] So this, in my mind, is a win-win for both sides of the street. So let me tell you what the limitation is to the field. Here's how we develop drugs, including immunotherapies. So we figure out a target. There's a whole different sort of series of studies you can do to find a target on a cancer. Then you start developing agents or therapeutics that could be an immunotherapeutic, it could be a chemotherapy, could be a precision medicine initiative. And then you test it on mice. Now these mice are in special environments that are sterile. They're not exposed to the normal environmental factors that you and I exist in day to day. They have a very focused immune system and by focused, I mean, they've been bred in such a way that they lack a lot of the heterogeneous immunological background that humans and even dogs or other animals possess because they're laboratory mice. The other thing that's absolutely crucial here is the tumors are teeny tiny little things. Think about the size of a mouse. It's about the size of my thumbnail. And so a tumor is going to be like a couple millimeters at the most. So I will tell you, there has been thousands upon thousands of investigators that have cured a tumor in a mouse brain. It's not that hard. And so the issue really is that these tumors, they don't recapitulate the environment in these lab animals. They don't have the same experience as you and me. The tumor size is not the same. The immune system is not the same, and even the genetics of the cancer in the mouse is not the same. So what we do with mice is we usually take a single cell and we implant it into the mouse and then we let the tumor grow. But all those cells are the same. So I've now named six or seven limitations of those preclinical mouse models. And so now we're starting to think about, OK, we see a signal what's called a signal of response. In other words, we see an increase in median survival or there is a certain percentage of long term survivors in those mouse experiments. And we say, oh, well, let's now move it into clinical trials for human subjects. And then here's what happens phase one that's really about looking for toxicity. There may or may not necessarily be a signal of response, because mostly that's focused on the dose escalation. Then you move it into phase two studies where you're looking for some kind of biological or signal of response, either progression free survival, overall survival, radiographic response, et cetera. Now, this requires a lot of patience, and many things fall off the rails at this junction, and this is tremendous amounts of money that have gone in just to driving it into these early stage clinical trials. You would be absolutely blown away with the expense of even developing one investigational new drug application for one of your, let's say, articles that you're wanting to move therapeutically into patients. So we've done this over and over and over again, and we've failed continually. So the question is this before you make that final determination of are you going to go into clinical trial? Is there not some way that we could do this better than these artificial systems that we've been using all along? Now, other folks have been doing things like where they've tried to do brain slices and petri dishes, or they've done things like organoids, but they don't really, truly recapitulate the immune systems of a live organism. So ultimately, dogs develop brain cancers and specifically the ones you know, with the little short, little, you know, like boxers, the little short, you know, noses. Those dogs develop high grade malignant gliomas. And typically - I know this is going to sadden you're listening population here - but typically those dogs, those dog patients don't receive any kind of treatment. And here's why. Because if you need radiation, you go in, you lay down on the machine, you get your radiation dose, then you know, the standard of care radiation is over at least a couple weeks, typically for brain tumors. But with a dog, it's not like you can have a conversation when you say, Hey, Fido, I want you to lay here and I want you to behave while we do this radiation. The dog is not going to do that. So essentially the dog, every time you give a single dose of a radiation, the dog has to undergo anesthesia. Now you think about the cost of doing radiation for a human patient and then you think about, Oh, wow, not only do you have to provide the cost of the radiation, you also have to provide the cost of the anesthesia each and every time you do a radiation treatment daily.  Then you think about the fact, OK, now you talk about chemo. Well, here in the United States, drugs are not exactly cheap. And so what happens is that many of these owners, these are beloved companions. They love their dogs, but they just do not have the financial wherewithal to be able to go through this with their companion animal. So sadly, many of these animals are compassionately euthanized, either upon the initial diagnosis or when the symptoms becomes too profound for the owner to bear. Or it just is too cruel for the animal really to keep going. And so the question was, can we do a win-win here in this particular situation? Can we use someone's companion dog to see if something that we think might really have some opportunity in human subjects? Can we actually make some good informed decisions when we move something into clinical trial? And so any time I do a clinical trial, I really want to be able to stand behind it and say, I really believe in this. I really think this could potentially help you. And I'm always so reluctant when we just have the mouse data. So we've actually done a series of clinical trials. Sometimes these are go's, sometimes there are no go's. But what we've done is we've had some wonderful partners at Texas A&M: Jonathan Levine, Beth Boudreau, who's the first author on the STIND paper and the Clinical Cancer Research paper that you cited. They were the vets that actually took care of and have taken care of these animals, whether they receive treatment through a clinical trial or not, and they're just absolutely magnificent to work with. And so what we did was we went down to Texas A&M and we worked on the surgical strategy for them to actually deliver this drug directly into the tumor of dogs that we suspected had high grade glioblastoma. So our high grade gliomas. And so these dogs received treatment at Texas A&M, and then we monitor them with MRI, just like what you would do with patients. Ultimately, we treated about six of these dogs. We did a dose escalation and when we were hitting a dose about 15 micrograms, that's when we started seeing clinical responses and radiographic responses in these dogs. Now there's a couple differences between dogs and humans when we did the study. Number one is, with patients the standard of care is to take the whole tumor out as much as we possibly can. We can't get it all. It's like grains of salt. We can't get every grain of salt, so the tumor always comes back in the setting a glioblastoma. But I've just already cited to you the cost of radiation and now think about adding on a standard of care doggie brain tumor resection. So these dogs did not have resections. All they did was they came in. They had something that we radiograph likely suspected was high grade glioma, and then they received the treatment directly in the tumor. Now the reason why we only got to a certain dose was because the brain is a fixed compartment. It's got a skull cap. And so these brains, the dogs are fairly young relative to humans. And so the dogs don't have a lot of room to expand. As we get older, we have neuronal loss. There's more room and expansion with an inflammatory response in a human subject. You've got even more wiggle room with expansion if, let's say, you get an inflammatory response, if you've resected somebody and debulked the majority of that particular cancer. So the dose escalation was probably not going to be the same for human subjects, we're probably going to be able to go to a much higher dose relative to the dogs because we were limited by the skullcap and the fact that they don't have brain atrophy and no resection. Now, that wasn't really the purpose of the clinical trial in the dogs. The question was, is there a signal of response? In other words, am I going to be able to see something radiographically regress as a "go" signal for phase one to clinical trials? And that's the purpose of the study. That's the reason why we did it. So it was essentially a proof of principle study as a "go." Now what's happening is there's quite a few folks that I think have really started realizing that there's real merit to doing these kinds of analyses before you go into clinical trials for human patients. And so there's a number of other investigators and there's a variety of other folks that are testing a wide variety of therapeutic strategies in canines. And actually, the NIH has a canine network for immunotherapy clinical trials, and they've had that going for six, seven years now, at least, where you know, you can apply for grants to do your immunotherapy in dogs that have a cancer. It doesn't necessarily have to be a brain cancer, but they do have other types of cancers that they treat in this network and then they learn from each other as part of that.

Erin Spain: [00:11:22] How important is this going to be for advancing what you're able to do with these clinical trials? Tell me, like this proof of concept you said. What's next?  

Amy Heimberger: [00:11:30] So right now, what we're doing is we're working on what's called the investigational new drug application, and that takes time and a substantial amount of funding to do that. You publish on something and then you realize that there's like a lag of six or seven years before it actually ends up in clinical trial and people are wondering why does it take so long and why did COVID go so much faster? So with an investigational new drug application - this is a true "first in man" study - there is a tremendous amount of data that you have to provide the FDA with regards to the pharmacokinetics: how the drug compartmentalizes, the toxicity studies. You have to do multiple species of animals. They all have to be in certain accredited labs where the vets sign off on the rigor and reproducibility. You have to do everything from, like assessing bone marrow suppression. You have to make sure that the drug that you're giving doesn't induce any kind of teratogenic effect. It doesn't harm developing fetuses. You can see just with the list that I'm just starting to run through here how much data that you actually have to generate so that we can safely administer these things to a human subject. And so that takes time and it takes a substantial amount of money to do that. So even a small pharmaceutical company a lot of times has to rely on things like venture capital and raising series A, B, et cetera funding to have sufficient funds to do those kinds of studies because it's not just like any little research lab can do it. It has to be done in appropriate laboratories at a certain sort of criterion that meet the guidelines of the FDA before you can proceed ahead. Now when you have tremendous effort and enthusiasm, like when you have half the world behind you wanting to get a COVID vaccine done, it's a little different. As far as the money goes, the effort goes, the data goes, and so things move along much more quickly. But you have to realize we're talking here about a rare cancer. And so these are more challenging in the fact that you don't have the world population per se at risk. And so this specific immune therapeutic strategy is really focused on something called cold cancers, which do not normally have a lot of T-cell infiltration in them. And there are some cancers that are very responsive to things like immune checkpoint inhibitors, things like melanoma, lung cancer, where you see the ads, you know, on the evening news and you know, the antibodies, everybody's like, "Oh, I want the monoclonal antibody," you know, to, you know, this or that. And certainly they do have some very nice responses in those patients. Some respond better than others. But for the most part, things like glioblastoma, pancreatic cancers are certain types of cancers that do not respond, in general, the vast majority of those patients to those particular types of agents. And part of it is that the target of those drugs - T-cells - are not really in the tumor microenvironment of these sort of subset of cancers. And so you have to start working on therapeutic strategies that actually drive either the T-cell responses into the cancer or can reprogram that tumor microenvironment so that they can work. And so that's really what we've been focusing in on the last, let's say, five or six years is strategies that reprogram that really immunosuppressive, what's called a macrophage or myeloid enriched, microenvironment.

Erin Spain: [00:14:42] Well, what do you want to say to people who are listening? Maybe there are family members who are affected. The loved one has glioblastoma and they're trying to find more information about what's happening in this field. What can you tell folks who are listening about what they can expect in the next 10 years, 15 years?  

Amy Heimberger: [00:14:58] Well, I will tell you a story. I used to work in that domain and I still work a little bit in the domain of melanoma, and when I first started out, that was even more dire in many cases when it went to the brain as glioblastoma. And so is very common, I'd walk into the patient's room, let's say, 15, 20 years ago, and pretty much they'd have stage four melanoma brain metastasis, and you'd be like, "Well, I can do some surgery, but you might want to consider hospice or, you know, palliative care," these kinds of things. So it changed dramatically and it changed dramatically in ways that we really didn't see 10 or 15 years ago. We were hoping immunotherapy would be helpful, but there certainly was a lot of naysayers that were not persuaded that that was going to be the case. So I suspect as we move forward, we will think about things in a much more sort of biological based way as far as our therapeutics. A couple of things I'd like us to stop doing is stealing the chemotherapeutics and therapeutic strategies from other malignancies and thinking we can repurpose them for glioblastoma. Cancers are different and glioblastoma is its own entity, and so are we looking at things that are more appropriate to be treated with epigenetic modifiers because that is an epigenetic disease? Should we be thinking about metabolic drugs? I mean, things that really aren't in the mainstream yet that I think are getting ready to come online - those may actually be more applicable in the Achilles heel as opposed to, let's say, a precision medicine initiative in such a heterogeneous cancer like glioblastoma. So I think we are getting there. We're not there by a long shot, but I suspect what we'll find is there will be something that we really aren't appreciating at this moment that will hopefully benefit these poor patients. One of the things I do want to advise, though, is it's very important that the team that you pick really understand this. Sometimes I know there's a little bit of a propensity of wanting to be treated when you're near to the family. But many oncologists don't intrinsically know all the most latest discoveries or the standard of care for these patients. And so sometimes you may not necessarily get the benefits from a care team that works with us every single day. And there's there's a variety of major academic centers across the United States that do brilliant jobs that really have a cohesive team that work together, the neuropsychologist work, the neurosurgeons who work with radiation oncologist, et cetera. And you can't just pick just one or the other. It really needs to be an integrated team for you really to get the best possible outcome when you've been diagnosed with something as serious and sort of more rare, like glioblastoma.

Erin Spain: [00:17:33] Before we go, I want to mention that you're one of seven clinicians and researchers recently named by President Biden to the National Cancer Advisory Board. Now, this plays a very important role in guiding the director of the National Cancer Institute and setting a course for the National Cancer Research Program. Tell me about this honor and what this experience has been like so far.  

Amy Heimberger: [00:17:54] So this is an advisory role to the Cancer Center director, Ned Sharpless, right now, and the role is really to help strategize with regards to initiatives and prioritization of the National Cancer Institute. So this could be anything from our RFAs, requests for applications, or what that stands for. Do we want to work on pediatric brain tumors? So this is what the advisory council does, is sort of look at the new strategic directions of where we should actually be investing the United States funds on as far as what areas of investigation. But also, we do focus groups on diversity, how that could be enriched, education, et cetera. So there's many, many topics that are actually covered at those meetings that takes place several times a year. And so it's an opportunity to actually represent physician scientists that work in the domain of rare cancers such as glioblastoma. But my advocacy is not just for glioblastoma, obviously, it's across pan cancer with a voice in the more rare cancers and how we can help the patients in that setting.

Erin Spain: [00:19:08] Thanks for listening. And be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and review us. Also for medical professionals, this episode of Breakthroughs is available for CME credit. Go to our website feinberg.northwestern.edu and search CME.