The Path Ahead for Combination Therapy Approaches to Canine Cancer Treatment

Dr. Gerry Post:

It really is fascinating to be a veterinary oncologist during these times. In terms of that level of excitement, why are you so excited about PetCure? And how has the company and business model changed really the landscape of veterinary radiation oncology?

Dr. Neal Mauldin:

PetCure was born out of a simple concept to try to put together a national network of radiation therapy centers that shared the same mission, shared the same protocols, was driven by an independent scientific advisory board helping us make those nascent clinical decisions about where did we head. And for us it really was about access. There's about a hundred veterinary radiation oncologists running around. And for a lot of families, if you're not close to a facility, then radiation therapy is just out of reach, there's logistic issues that just make it almost impossible. Our goal from the early days was to try to find a way to expand access and to allow patients to have an opportunity that they may not have otherwise had.

A huge part of that is being technologically driven. As we move into the age of being able to do single or three fraction protocols and being able to gather data that helps us understand how those compare to conventional fractionation, it becomes more feasible for a family that's 10 hours away from a site to consider radiation therapy if we can go from CT scan to final treatment in five days. If we can get it done in a week, that's a doable thing now.

Dr. Gerry Post:

Fantastic. And speaking of access, our second webinar really dealt with that concept of access and Michael Blackwell, who was the Dean at University of Tennessee's vet school spoke quite eloquently about access to veterinary care in general. And we as specialists think that we're all over the place, but there's clearly not enough. Not only there are not enough specialists, but the number of people who have access to veterinary care at all is not at a high enough level.

Dr. Gerry Post:

So I would really encourage everybody who has any desire to learn more about access to veterinary care to watch that webinar. But I agree with you, Neil, that there needs to be more access to radiation oncology. One of the other things that I think was really fascinating about PetCure and what you have done is the pursuit of really directed clinical trials and radiation therapy as a fundamental part of the mission of PetCure. And I'm just wondering whether you could talk to us about the trials and tribulations, the challenges, the opportunities that you've seen in that trial design.

Dr. Neal Mauldin:

Early on, we were very committed to the idea of developing standards of care and having that be the starting point for every patient with whatever the tumor might be. And then to also develop a series of OAR metrics, so normal tissue metrics, that could help us make objective decisions about the need to push harder on this patient, or we need to back off on this patient. And that's one of our guidelines is every patient starts at the standard of care. And if they are removed from that then there has to be an objective reason for it. The other thing we realized very early on is that veterinarians are busy people, clinicians are getting slammed in the clinic all day long. And the last thing that they want to do is abstract medical records at the end of a 12 hour clinic day.

We made a commitment early on to have a dedicated clinical data team whose job was to do just that.  Dr. Glenna Mauldin was the director of our clinical research unit at PetCure and had a data team that was purely dedicated to that data abstraction. As you may know we were recently acquired and became part of the Pathway Family. And Pathway has made that similar commitment. Glenna is now heading up their clinical research team at Pathway. And we're very gratified to see that we were able to make the statement that we believe this is an important thing. We believe being able to not only gather a large group of patients, but to actually do something with the data after we have. To us that's a mission critical thing. And we're really pleased to see that Pathway shared that vision.

And in terms of that abstraction of the data, how difficult was it to get that outcome data?

Dr. Neal Mauldin:

It's a lot of work. Right now we have about seven data sets that we're preparing for display and publication. And that is, I've got giant binders of data all over the house because the hardest part, especially with multiple sites, all of which maybe are using different practice management software, is being able to pull the information you want out of those hospitals and get it then into a standard form that you're comfortable with and that you can eventually get to be in a statistics ready place. That is a huge part of what Glenna's data team does.

And in terms of the difficulty, what are the lessons that you and Glenna have learned about from this process?

Dr. Neal Mauldin:

One of the big learnings for us, because just like others that have kind of gone into the endeavor, we had very high expectations that we were going to solve the problem of cancer and we were going to have the definitive understanding of thyroid tumors in dogs. And it's a big task. We are much more focused now and we are doing our best to ask reasonable questions that we should be able to answer. So rather than massive retrospective reviews of 500 bone tumor cases, we're doing much more targeted such as let's treat 25 lung tumors and describe what we saw in those patients.

Now we're still doing the data abstraction on the 500 bone tumors, but it's a Herculean task to really get those numbers where you want them to be, to pull the important things out. And we've all been there if we were in a residency and having to do our resident project and trying to abstract data out of medical records we had never seen before. That is what Glenna's team spends the majority of their time on, is getting data in a usable format.

Dr. Gerry Post:

What are some of the clinical trials that PetCure has completed? And what are some clinical trials that are still in progress?

Dr. Neal Mauldin:

We are not running any clinical trials today, though our plan is to launch one. We've got about five ideas and we'll be announcing the next round of trials probably in the next few weeks. We did a large liquid fiducial study which was using a liquid fiducial to help us try and create an objective target volume, planning target volume so we could take a patient that had a microscopically resected tumor and still treat it with stereotactic fractionation. We entered about 170 cases in that trial over an 18 month period. And that data is really getting mature. It's one of the ones we'll be reporting on hopefully in the near future.

Actually that is one, we're about to move into a second phase of using the fiducial actually intra-op and use it to help us define resection cavities. We finished a trial in conjunction with Varian looking at changes in T-cell populations for osteosarcoma dogs that were treated with stereotactic fractionation. That study was interrupted by COVID and is sort of on hiatus right now.

There were some interesting early results there, but nothing groundbreaking when we did a more in depth data analysis. I'm not sure where that study might lead us, but the radio-immuno-oncology side of things is a huge interest right now. I can't imagine we won't be back in that arena pretty soon. We have completed a lung tumor trial, so we've got 25 dogs treated on protocol. That data's being abstracted. And then probably the other big one that Glenna presented the results at the ACVIM, a year before last, is a low-dose rate half body RT paper that we've got some very interesting results in that group of patients and are interested in making that a standard of care protocol across PetCure.

Well, when you and I were together at AMC, if you wanted to get funded you probably put the word anti-angiogenic in your grant proposal somewhere. And these days, at least on the radiation therapy side, you got to sprinkle the word abscopal (“The abscopal effect occurs when radiation treatment—or another type of local therapy—not only shrinks the targeted tumor but also leads to the shrinkage of untreated tumors elsewhere in the body. Although the precise biological mechanisms responsible for the abscopal effect are still being investigated, the immune system is thought to play an important role") in there a few times. We actually have a case report in in preparation now of a dog that had the abscopal effect and it is pretty fascinating stuff. And when you and I were chatting about this webinar I made the statement that when I was in my residency training, a radiation oncologist didn't even know there was an immune system. And now we're to the point where we're fascinated by the immune system and there's just huge amounts of work being done there. And exciting stuff.

Dr. Gerry Post:

It has really just proved the point of the intersection between so many different specialties, immunology, radiation, oncology, they're all coming together hopefully for the benefit of the patient and the improvement in the delivery of care.

Dr. Neal Mauldin:

It's amazing to see, as we move into a blade of doses of radiation we know there are significant changes in the tumor micro environment. We know there is a significant local immune effect. And then our friend, the abscopal effect comes in when that local immune effect gets magnified into an actual systemic effect. The other word that really didn't exist back when I was being trained is radiogenomics and the interest in, why do you have a subset of patients that even though their planning metrics and everything are exactly as they should be still have a overexuberant toxicity profile.

And the generally accepted incidents rate is anywhere from 3-5% of patients even if their planning and their targeting and everything is exactly right are going to have a catastrophic outcome. And so there's lots of work on that front. Now the NIH has a radiogenomics consortium that their entire interest is in identifying why do certain people have overly aggressive, delayed toxicity and life-threatening and even... Certainly life altering, a potentially life-threatening toxicity when they should not have based on the predictive assays that we would otherwise use.

Dr. Gerry Post:

I was just doing a little bit of research before the webinar about radiogenomics and from my understanding it's not only predicting which people will have overexuberant response in terms of toxicity, but also potentially determining which tumors based upon their genomics are going to respond better to the radiation therapy.

Dr. Neal Mauldin:

Well, and in a practical term we dose down in radiation oncology. So if we have 5% of the population that are going to have that overly aggressive response and overly aggressive toxicity, and we bring our radiation protocols down to keep that from happening in that 5%, we're potentially under-dosing the other 95%. We could push harder and perhaps have a different outcome, or perhaps not. And then also the point of is if we knew ahead of time you have a genetic profile that makes you more sensitive, then we could hopefully avoid that catastrophic toxicity, but also maybe your tumor doesn't... You can't handle a hundred percent of the dose, but your tumor doesn't need a hundred percent of the dose to have a good outcome. So yeah.

Dr. Gerry Post:

Really fantastic stuff, and some of it, correct me if I'm wrong, really relates at least in people to not only the mutations, but single nucleotide variance rather than just mutations.

Dr. Neal Mauldin:

Yes, well, that's why it's such a needle in a haystack hunt right now, because the original thought was that there were going to be genetic predispositions or preconditions that were standard across the population that would allow us to predict that. That's not really true, it's the snips that probably hold the key, and trying to do that kind of data analysis is just a huge undertaking. But I mean, it would be fascinating to go back through and say, "Okay, we had these dogs who on review of their record everything looks exactly right, but we had an outcome that we weren't expecting and why did that?" We all learn about ATM and all of that, but it's not that. That's a different thing. This is why did that patient, what one specific thing made that patient do what he did.

Dr. Gerry Post:

In terms of what we were talking about in terms of the difficulty in getting outcome data, what changes do you think could be made in kind of organized veterinarian medicine to assist in getting more accurate outcome information more rapidly in terms of things like systematizing the coding of veterinary diagnoses and things like that?

Dr. Neal Mauldin:

It's a challenge and I think it's just that if we're serious about it we have to start to invest in the industry infrastructure to pull it off. For us to treat all of our patients we use a program called ARIA, which is a medical record. It's a very customizable medical record, but it also has a lot of built-in coding from the human side that we're trying to slowly adopt to what we're doing on the veterinary side. Now a lot of that coding is for reimbursement, so it's not all that helpful to us, but SNOMED (Systematized Nomenclature of Medicine) and all of those things that have been worked on over the years, but they never quite make it into the mainstream. Not every veterinary medical oncologist is using SNOMED to classify their lesions.

And so it becomes difficult. We've all been there where we have two different diagnoses on the same biopsy and how do we resolve those kinds of issues. But I think it really is an infrastructure issue. We have to recognize the value of that data and we have to put processes in place to help us get it that doesn't rely on the clinician that is, like I said, they're exhausted at the end of the day.

Dr. Gerry Post:

Sure, absolutely. And to be clear the coding would not only help radiation oncologist, medical oncologist, it would really help the entire industry in terms of both prospective and retrospective trials and studies. So I think it would be incredibly valuable for the field as a whole, but I do agree that it is an incredible mountain to climb in terms of work.

Dr. Neal Mauldin:

It's a big ask. And there are early adopters, there are late adopters, and then there are non adopters that you got to drag screaming across the finish line. And it's a very tough cultural change it would be to pull off.

Dr. Gerry Post:

In terms of Combination therapy whether talking about chemo and radiation therapy, chemo and targeted therapy, radiation therapy, targeted therapy, et cetera, will be the future of both human and veterinary oncology. What are your thoughts about combinatorial therapy?

Dr. Neal Mauldin:

Well, I think that it is the future and that it'll be multi-modal and it will also become much more individualized. We hear a lot about personalized medicine on the human side of radiation and medical oncology and all of human medicine. And I worry a bit about the accessibility of can we personalize medicine in the veterinary world based on the resources we may or may not have available? But there are companies out there I hear that are trying to do some of that kind of stuff and I think that's where the future lies.

Dr. Neal Mauldin:

I think that as we understand more about the changes that happen when we not only do the... The whole idea for us is how do we take the abscopal effect from a one in a thousand or a one in a million phenomenon to, yeah, okay, we've got this tumor. If we tweak the immune system this way at the right time, we can make that a more common event. It's a mountainous task, but it is what people are interested in. Like I say, radio immuno oncology is a thing and I think it's going to become a bigger thing.

Dr. Gerry Post:

And you are really the perfect person to ask this question just because you are triple boarded. In terms of the radio-immuno-oncology where is the progress in that field in veterinary oncology?

Dr. Neal Mauldin:

Right now, probably the most common use of it or the most common thought about it would really be using ablative doses of radiation to expose parts of the tumor that are not normally seen by the immune system. We tend to call that insight to vaccination. But that's probably the simplest. And then when we started our project with Varian, the whole idea was we wanted to try and understand what happened to different T-cell subsets in patients that were irradiated with ablative doses. So I think we still have to understand what changes occurred naturally before we can start having significant conversations about how do we try and manipulate that it anyway.

Dr. Gerry Post:

Yeah. I mean, it's interesting just as kind of a thought experiment utilizing things like checkpoint inhibitors in combination with radiation oncology in order to accelerate the abscopal effect.

Dr. Neal Mauldin:

Yeah. I mean, PD, PD-L1, RANK and RANKL, those both get tossed around a lot as probably being real potentials. I guess, if I was writing an NIH grant I would have the word of abscopal and PD-L1 in there somewhere. But I think we have a rudimentary understanding of some of the big picture changes that might be beneficial. But we don't really have that clear of an understanding yet of the actual micro environment changes.

Dr. Gerry Post:

Sure. So going from kind of the micro changes to more of the global changes, given that both you and I have been in this industry for quite some time I'm wondering if you can comment on what tech changes, technology changes you've seen in radiation oncology specifically, and in veterinary medicine in general. I think that both you and I have really to some extent been in the golden period of veterinary technology changes so far, and I'd love to hear your comments on how you think tech has changed radiation oncology specifically, in veterinary medicine in general.

Dr. Neal Mauldin:

For the more global veterinary community, I think the biggest thing really is just access. The ability to read a CT scan for somebody that's nowhere near one of your facilities. The tele-health side of things I think is an important component. You have a family that may be willing to drive 12 hours to get radiation therapy, but they shouldn't do it without any idea of whether that's even an appropriate choice. So we focused on that very aggressively early on, even pre COVID, because again, our entire thought was we need to increase access. We need to give people the ability to talk to a radiation oncologist if they're so inclined so we can have these conversations. On the radiation specific side, the changes are almost too numerous to count.

Dr. Neal Mauldin:

The changes that have happened in the last five years, last 10 years in the world of radiation oncology are just amazing compared to what was a fairly static delivery system before. I'd say the biggest changes really are the improvement in dynamic collimation and the ability to modulate the fluence of a particular field and really pick where you want the radiation to go. And then really the biggest thing I think that's made stereotactic a much more plausible form of therapy is the image guided part of it.

Dr. Neal Mauldin:

The fact that we've got KV imaging in the form of a cone beam CT that allows us to actually do a fusion between the planning CT and the treatment day CT and align based off of those two things. We've come a long way from the days at AMC where we had an old cobalt unit down in the vault with a dental x-ray unit mounted on the beam stop to try to get images. But it's almost Star Trekkie stuff now that we can do. And that is amazing, just watching what's happened over the last five years it's just amazing transformation in the technology.

Dr. Gerry Post:

We've been talking about access in terms of enabling people to get their pets to a location that has radiation whether or not a radiation oncologist is there, but does your approach deal with accessibility from a financial perspective?

Dr. Neal Mauldin:

I would say if the question is radiation therapy or does remote access make it a more accessible treatment from a financial perspective? I would say right now today probably not. It is still an expensive proposition to build a vault. It's an expensive proposition to put in one of these machines. So I'd say access in this setting is access to information, not a significant change in how much things cost in that setting.

Dr. Gerry Post:

But one of the things you said just earlier was that you and your company were committed to not making people drive 12 hours if their pet really didn't need it. And so talking to those people ahead of time to ensure that their pet would benefit or likely benefit from radiation in a way is to some extent saving them money that would be lost in terms of travel time, in terms of all of that.

Dr. Neal Mauldin:

Well, and we do believe very strongly that we need to spell out everything right up front. The first time that we're talking about a course of stereotactic radiation costing $9,000 or $10,000, shouldn't be after you have driven 12 hours. And so I do believe as the technology advances and becomes more uniform and more available I think costs will start to drop. But they're not there yet. It's still an expensive proposition from a treatment perspective.

Dr. Gerry Post:

It is. And in terms of financial accessibility, I think the more that pet insurance permeates the United States, the more accessible things like radiation therapy will be to pet owners in this country.

Dr. Neal Mauldin:

Radiation oncology people tend to look at the cost because especially with the stereotactic protocol it's a cost crammed into a very small timeframe. It probably doesn't cost as much to irradiate a brain tumor sterotactically as it does to treat a meter square dog for lymphoma over the life of their treatment. It's just we're talking an 18 month period versus a one to three day period from a cost perspective.

Dr. Gerry Post:

Going back to just clinical trials, specifically in clinical trials, specifically in clinical practice,  you have tons of experience whether it be from your time at Animal Medical Center, your time at PetCure and you certainly can compare that to your time in academia, but can you comment on the implementation challenges as well as the opportunities of doing clinical trials in a clinical practice?

Dr. Neal Mauldin:

Well, I think that the biggest thing is proper study setup. Don't get too aggressive. Again, early days we probably asked too bigger questions. So keeping the questions manageable, there's always some time requirement from the actual people on the ground, trying to keep that as efficient and as minimal as possible is really important. And clinicians or clinicians they have to see the benefit to their patient to want to, or I guess the potential benefit, to want to sign up because it does. No matter how hard you try, it still adds a wrinkle to the day that wouldn't be there if they weren't participating.

Dr. Neal Mauldin:

GPC trials are fantastic, but they are time consuming. You have to have the infrastructure to deal with that and to be sure that data is collected as it's supposed to be collected. Whereas a purely clinical we're going to treat 50 of these exactly the same way and go from there. That's a much more tangible and much easier to administer kind of trial to do.

Dr. Gerry Post:

Fantastic. And in terms of PetCure, are you focusing on one or the other or are you focusing on both over the long-term of the company?

Dr. Neal Mauldin:

I'd say both. I mean, we do think that a retrospective review of patients treated to a standard of care protocol is still worthwhile. So right now I have, I think the last time I looked, we have somewhere between 250 and 300 brain tumors that are all treated exactly the same way. And I think that'll be valuable information to talk about. But I also think there's tumors we know are reasonable targets for radiation especially stereotactic. We know brain tumors, we know prostate, but there's other things like adrenal and liver and lung that are very much appropriate targets. We just don't know very much about them on the veterinary side yet. So those are the kinds of things we're really interested in exploring.

Dr. Gerry Post:

In terms of your multi-modal approach, you've talked about clinical trials really looking at radiation oncology. Given that your lovely wife is a medical oncologist, have you looked and thought about multi-modal trials looking at medical oncology and radiation oncology for the same patient and characterizing responses there?

Dr. Neal Mauldin:

We have and I would say that's a future state for us. In the world of oncology medical oncology is the group with the nuance and radiation oncology is the I have a hammer so everything looks like a nail group. So standardizing protocols and getting buy in on the radiation oncology side is actually a relatively easy task compared to I think what it will be on the medical oncology side. But having said that, we think that is absolutely a valid thing to do. In that setting I think the most important component of that is philosophical alignment.

That you are working with medical oncologists that actively want to participate in that trial rather than trying to make it a trial and forcing people to participate. I don't think that would be successful, but if you get buy-in early on I think that would be a great thing to do. We have interests in all kinds of neuroendocrine, carcinomas and PALLADIA, how could we change the outcome of that disease? And so those kinds of trials I think you'll see us do in the future.

Dr. Gerry Post:

It's so exciting all of the things that are available by  using which is really real world data in terms of the data that we're getting from these medical records, that we're able to either abstract ourselves or we're having the clinicians abstract for us, but I think that's really a huge untapped market. An untapped market for veterinarians as well as human oncologists. I know that there's a big push at the FDA in the utilization of real world evidence and real world data. And I think that is going to absolutely spill over into the veterinary medical community as well.

Dr. Neal Mauldin:

Well, I think it's one of our greatest strengths and we always talk about the translational impact. But I don't think we've leveraged it perhaps as well as we could yet. But the entire one medicine concept and really focusing on the species may be different, but a lot of the basic mechanisms are not. I think that... One of the researchers I used to work with at Sloan Kettering, he used to say that decorative statements supported by data are called facts and decorative statements in the absence of data I'll say he said it's called dogma, but he had a little bit more of a perhaps not quite as correct term for it. And that's it, right? We need to get to making decorative statements that are supported by facts, not starting our statements with, "Well, I feel that," or, "I think that," or, "Our data suggests that."

Because that's not what we should be about. It should be let's try to definitively answer this question, but I know that's perhaps a little naive, but it's still what I think.

Christina Kelly Lopes:

That relates to the One Health concept which is our parent company. We partnered with ACI and they had a drug already approved for metastatic breast cancer. We interrogated that drug in the setting of hemangiosarcoma in dogs as they were looking at the drug for angiosarcoma in humans. We presented data together at AACR,  two years ago and the drug is at Mass General in the human clinic and also the leading institute in Australia. We joined forces and it's impacting angiosarcoma patients today.

Dr. Gerry Post:

I think One Health perspective is certainly for the veterinary oncologists something  baked into our DNA from the beginning. I think all of us in our training really do believe that we're in essence comparative oncologists at our very core. One question that one of our attendees had asked is, PetCure uses an approach where the pet parents reach out directly. And then in collaboration with the veterinarian treatment is pursued if appropriate, similar to FidoCure. The question is what challenges has that parent interaction presented to PetCure with the parents and with the vets? And then as a follow-up, is there a difference when that vet PetCure interaction is with a General Practitioner  or whether it's a specialist?

Dr. Neal Mauldin:

PetCure maintains what we call a pet advocate center. And the pet advocates are veterinary technicians. Most of them had a quite extensive veterinary oncology background before they got into that. And really what their role is is when we have a family call in and say, "I've just been told my dog has cancer. I found you guys on the internet and I want to know if this is appropriate." And their goal is to, the pet advocate role then is to get medical records together, ask for permission from the client to contact their primary care vet. I would say we don't often differentiate at all between is it a generalist or a specialist?

It's just like, "We really need to take a look at the records. And is it okay for us to reach out and do that?" The biggest challenges is that in this day and age whenever somebody gets unwelcomed news probably the very first thing they do is go to Google and find out what the internet has to say. And that's probably one of the biggest challenges is having people that are very upset or frustrated that they found out their dog or cat or lizard has cancer and now they're trying to get answers and they just want to talk to somebody. And being able to help them kind of navigate that is really what that pet advocate's center is about.

A big part is the tele-health process because a lot of times those conversations go, "Can we get the medical records so we have a good idea of what we're talking about?" And then having one of our medical oncologists review the medical record and then if they say, "Yes, I think this is a reasonable radiation therapy candidate," or, "At least it's something that should be discussed," then the next step in that process would be to try to set up a telehealth visit with them so that one of our oncologists could talk to them. We do imaging reviews as a part of that. We really intend them to be cross-sectional imaging, CT or MRI, but we'll look at any images that we have as part of that process as well.

Dr. Gerry Post:

That's an incredible service that PetCure adds, similar to FidoCure's approach in talking to pet parents. I think the two dovetail nicely and really center around access. We really do believe that we would like to improve access to care for all pet parents.