UC Davis Inhalation Chemotherapy Study for Dogs Fights Lung Metastasis

Inhalation chemotherapy for dogs is just what it sounds like: helping your dog inhale chemotherapy drugs that will hopefully prevent and stop pet cancer lung metastasis. A current clinical trial at UC Davis is re-examining this decades-old treatment, by adding immunotherapy into the mix for dogs with advanced stage osteosarcoma and melanoma.

In our second interview series at the University of California at Davis Veterinary Teaching Hospital, we learn about a new clinical trial led by Dr. Robert B Rebhun, Associate Professor and Associate Researcher of Surgical & Radiological Sciences.

Learn about Inhalation Chemotherapy Study for Dogs

We first learned about inhalation chemotherapy in 2012. It was at another great vet teaching hospital, the University of Missouri. See:

Dr. Selting Explains Inhalation Chemotherapy
for Osteosarcoma Metastasis

Much has happened in pet cancer treatment since then, namely immunotherapy. This is when scientists isolate certain parts of a pet’s immune system and build a personalized treatment to fight various types of diseases, including cancer. The ELIAS® Cancer Immunotherapy (ECI ®) treatment is a perfect example.

At UC Davis, an important inhalation chemotherapy trial is underway. It’s known as “Evaluating a new immunotherapy for advanced stage osteosarcoma and melanoma in dogs,” The purpose is to determine the maximum tolerated dose and efficacy of an immunotherapy protocol against metastatic osteosarcoma or melanoma growing within the lungs. Watch below to find out how it works.

Be sure to catch Part 1 of our UC Davis interview series, “The Vaccine Against Canine Cancer Study.”

Want even more details about this study? Listen to the full-length podcast interview, Dr Robert Rebhun on the IL-15 Canine Cancer Immunotherpay Study at UC Davis, or read the entire transcript below. 

Listen to the full-length podcast 

Or Read the Full Transcript

“Evaluating a new immunotherapy for advanced stage osteosarcoma and melanoma in dogs.”

Studying lung metastasis prevention with IL-15 inhalation chemotherapy.

TRIPAWDS: Hello and thank you for listening. This is Tripawd Talk Radio, Episode #84.

Dr. Robert Rebhun is Associate Professor and Researcher in Surgical and Radiological Sciences at UC Davis. He is working on a new study about immunotherapy for cancer that has spread to the lungs of dogs with osteosarcoma or melanoma. Rene will get the details about the IL-15 study and how it differs from the Interleukin-2 research that has been done. We will learn how it is this inhalation therapy is administered and what Adoptive Cell Transfer means.

This interview is recorded on October 3, 2019. For complete details about the study and info about how to participate, please visit Tri.pet/UCD-IL15. And with that, let’s here from Dr. Rebhun about the work he is doing with the IL-15 study at UC Davis.

REBHUN: My name is Robert Rebhun. I’m a Faculty Medical Oncologist here at UC Davis, Professor and Maxine Adler Endowed Chair in Oncology. And I’ve been at UC Davis for about 11 years now.

TRIPAWDS: Why does so much of your work focus on cancer metastasis? Do you have some kind of connections around or what drew you to it?

REBHUN: Yeah. I think my background, so I went to vet school and then shortly after or immediately after vet school, I went into a PhD research program specifically in the field of metastasis. So I went to human cancer hospital, MD Anderson, to do that PhD and worked with someone who is kind of a very well-known in the metastasis field.

The reason for that is my interest in metastasis is that with advances in local control with both surgical techniques, minimally invasive techniques, and radiation therapy. The majority of patients that we end up losing for many cancers is to metastasis. So I wanted to learn more about that process and that the pathway that cells take and see if targeting that pathway may be able to ultimately improve survival times or cures.

What is the IL-15 Study?

TRIPAWDS: And let’s talk about the study you are doing, the IL-15 study. Can you tell us more about that?

REBHUN: Yeah. So the IL-15, so that’s a – it’s a cytokine so it’s an immunotherapy. It’s not a new concept. There has been cytokine therapy for years and years. Probably the best known is Interleukin-2 or IL-2, which was there was a lot of work done back in the ‘90s.

IL-2 on the human side tended to be very toxic. So although there were responses seen, it was – there were a lot of side effects with IL-2 therapy.

And actually on the veterinary side, again, this concept is not new, Chand Khanna in the ‘90s had done in the how-to in dogs with lung metastasis including dogs with osteosarcoma. And that time, there weren’t a lot of dogs treated but about half of the dogs with osteosarcoma that were treated had responses to the inhaled IL-2. And those dogs actually had very – essentially no side effects from that treatment.

If we kind of fast forward a bit, the issue with that – so that was – it was a special form of IL-2 that would last longer in the body. And so, that’s not commercially available. And then the human IL-2 which is used clinically on the human side is – the price is most of our clients out so that IL-2 for us to buy a clinical grade human IL-2 right now I think is around $3,500. So not a lot of folks can do that so I think that’s why we haven’t really followed up on those initial findings.

TRIPAWDS: And the IL-15, so how is it different then?

REBHUN: IL-15 is actually very similar. It activates essentially the same pathways as IL-2. It’s a little bit more specific and it also – IL-2 because it kind of ramps up the immune system but it also potentially ramps up the brakes of that immune system whereas IL-15 doesn’t really have that component.

And so really, it is trying to activate the body’s own immune system to target the cancer cells. So IL-15 does signal kind of through the same receptors but we do see less toxicity and at least in theory hopefully we will see the activation but we would not see kind of the negative aspect or the inhibition of the immune system in some arms.

The IL-15 when we are – so we are kind of building on that IL-2. But part of this grant is because the technology has come so far and veterinary medicine, the price doesn’t come down for being to do things like sequencing the tumors. And so, what this really is as well, the IL-15 is we hope maybe going to have a little bit better response than the IL-2.

The goal of this actual grant is to not only to see the responses but actually be able to look at the genetics of the individual tumors of kind of this personalized medicine. And so if in that study in the IL-2, I said half of the dogs responded. There weren’t a lot of dogs but the question now that we are trying to answer is OK, well, if we see responses, why? What is it about that tumor that patient that we saw a response because we know that then we can come back to predict potentially based on genetics or individual personalized information. Maybe this dog is going to respond to chemotherapy. Maybe this dog is going to respond to immunotherapy.

Helping Dogs Fight their own Cancer

The goal of this is to kind of build on those findings from the ‘90s that we are looking at IL-2 and say, “Now, can we predict which patients might respond?” And then there is a second arm which is looking at not only do we kind of activate the immune system within the body by giving this IL-15 but if we come back and we – so doing essentially adoptive cell transfer where we kind of grow up and NK, natural killer cells, from the individual patient. We grow those up in the lab for a couple of weeks and get them activated. And then those are the cells that actually respond to the IL-15.

Instead of just banking on the cells within the body, the NK cells may be activated. We are going to actually take out NK cells from that patient. We are going to grow them up and expand them and have them be activated. We are going to give those cells back. And now, we are going to treat with the IL-15. And this is the part that we haven’t gotten to with the trial yet but it’s really what we are kind of building to.

TRIPAWDS: That’s exciting. And how is it administered?

REBHUN: There are a couple of different formulations that we are using. There is the free, just regular IL-15, which we are giving inhaled. And that is really trying to activate the immune system within the lungs. As a lot of people know with osteosarcoma both in the human and canine side, the most common side of metastasis and oftentimes like limiting site is the lungs. And so, we want to see if we can change that microenvironment if we can get higher concentrations through inhaled delivery then the hope is maybe we see less systemic side effects and even more of a response within the lungs.

That is one arm, and that’s actually when we go to the adoptive cell transfer and expanding NK cells. We are going to combine that with inhaled to try and to specifically target lunch metastasis.

And then we have another formulation of the IL-15, it’s an IL-15 Superagonist. And that is currently – it’s an industry product so it’s on the human side. It’s in clinical trials. But through the NIH grant and this company, we also have access to this drug. And so, this one is given systemically. It’s subcutaneous. And so the idea being, well, if we can focus on phlegm metastasis and we can figure out which patients are going to respond to our treatment with high concentrations in the lungs, we also know that this diseases metastasizes elsewhere.

We would like to know if we can see those same things systemically without having too many side effects. So that would be building on just being able to treat one area and hoping that we can get kind of all the sites.

What Dogs are Ideal Candidates for Inhalation Chemotherapy with Immunotherapy?

TRIPAWDS: Who is the ideal candidate for this treatment?

REBHUN: Right now, I mean again, because we are in this early stages, we are looking specifically for dogs that are – that have pulmonary metastasis because we are working at response rates and again, seeing if we can predict what we are looking at and making sure that it’s not toxic and seeing what the response rates are kind of the first step in a lot of the studies. So that’s where we’re at right now. So they need to be healthy. We can’t have – I mean other than metastasis, we can’t have significant comorbidities.

We actually have – we have to make sure that the dogs are willing to undergo the inhalation therapy which we’ve enrolled nine dogs to date in inhaled and we treated several over the years. Again, Chan Khana’s group in the ‘90s found that it was pretty easy to teach these dogs how to do inhaled. So we haven’t had any problem so far with that. But it is something that we know for certain dogs that are really anxious or maybe don’t want to sit still that long, it might not be the best therapy for them.

TRIPAWDS: So it’s literally a mask over their mouth?

REBHUN: Yeah. There are a couple of different ways that we found depending on the dog. Actually, it sounds worse than it is. But there is – we have the kind of regular nose cones that they can use or some dogs actually do better with – that’s actually kind of a big plastic boot where we just put the nebulizer hose in there and they can kind of just breathe within that bag. So it sounds terrible to say, “Put the bag over the head.” You really don’t. You just kind of have their muzzle within this kind of little plastic boot.

We actually have a really nice video online of how to train the dogs because we found that writing and having us discussing and so on, it really is helpful to have a video. And so, one of our residents here created a video and that’s really helpful.

TRIPAWDS: And this is something that the owner does.

REBHUN: Yeah. Yeah. So the owner can do it at home with proper precautions. Yup.

TRIPAWDS: And how long does the process take for one treatment?

REBHUN: This treatment – so this protocol is actually for two weeks and it’s twice a day, so morning and night. It takes – the actual nebulization is anywhere between 8 and 12 minutes. But the setup and cleanup and all those things probably takes 20 or 25 minutes each treatment for the owners.

We do the first treatment here for this trial just to make sure everything is going OK and we don’t have any problems. And then they can do the rest at home.

TRIPAWDS: How far advanced can the lung nets be? I mean are you looking for like really small nets or are you looking – how advanced before you say they can be part of it?

REBHUN: Yeah. I mean really, we want the patients to be able to – because it’s immunotherapy, we want to be able to get – we want to be able to treat them and hope that they have enough time to be able to mount this immune response. And so, it’s not an adoptive immune response. So it should be fairly quick but essentially, the tricky part is once we diagnosed lung metastasis with osteosarcoma, in a more science, we are honestly thinking that we have about two or three months. And sometimes if they are having clinical signs, if they effusions or fluid around the lungs or if they are really advanced, they are not a good candidate to be able to undergo this twice daily inhaled therapy.

But what I will say is that for kind of purposes of measuring the tumor response, we usually say that the tumors have to be greater than one centimeter on chest x-rays. And the reason for that is we want to actually make sure that we know that it’s truly a tumor and we want to be able to accurately measure to say if it has gotten smaller or bigger. And so, sometimes we have just kind of smaller than a centimeter. It can be a little bit hard to measure that response, so that’s really the only criteria right now is that healthy enough to receive this therapy.

I mean IL-15 in people with those limiting toxicities depending on the therapy, maybe elevated liver enzymes have been seen. So we want to make sure that the patient’s pet are in this trial have normal liver function, those sorts of things to make sure that we are not kind of setting them up for failure.

TRIPAWDS: Many thanks to Dr. Rebhun and UC Davis for the work they are doing. Stay tuned to Tripawd Talk for more discussions with faculty from our recent visit to UC Davis. And visit Tripawds.com for years of past interviews and many other free pet amputation resources.

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