MUZZLING CANCER

Searching for a vaccine for Cancer. Reprint of an interview in NOCO STYLE Magazine, October 2019

There are a few examples, two of which come from CSU. One of the first examples was to do what's called "limb-sparing" surgery. So if you have a bone tumor, can you get that tumor out of there and still have a functioning limb? In the 1980s, our director emeritus and a Denver surgeon pioneered a protocol called a cortical allograft, which is where you take out the diseased part of the bone and put a cadaver bone in its place. Before this was ever done in people, it was done in dogs here. Hundreds of dogs were done, and they looked at how well it works and what happens if you do radiation first, what happens if you do chemotherapy first, etc. Pretty close to that exact strategy later moved into humans.
A second example from around the same time, also involving bone cancer, was at the University of Wisconsin with a form of immunotherapy. Rather than trying to find ways to treat the local tumor in the bone, this was a strategy to try and prevent spread. It was evaluated in a whole bunch of dogs, and the dogs who got the immunotherapy lived substantially longer. That paved the way for a huge trial in about 650 people with osteosarcoma, and those results were positive enough that the same exact drug was actually approved in Europe for the treatment of osteosarcoma in humans. A third example, which again comes from Colorado State, was a study from the 2000s using a molecule to treat lympho­ ma. It showed promise in a small number of dogs, and it's now a blockbuster drug treating certain kinds of lymphoma and leukemia in people. That drug is called lmbruvica.

These are all examples of treating patients after they've got cancer. What's the track record of preventative treatments, like the one you're doing now?

There's already one massive success, and that's the HPV vaccine, which dramatically reduces the chances of people getting cervical cancer and some other forms of cancer. But those particular forms of can­cer are caused by a virus, and the vaccine is directed against the virus, not against the cancer cell itself.
To vaccinate against cancer cells you need to target neoantigens, which are proteins that cancer cells produce and
that your immune system can recognize as foreign. The problem with developing a vaccine is that the neoantigens are not the same from cancer to cancer. Even if you look at just one kind of cancer, each tumor has some of these proteins but they're not the same. So there's nothing you could target preventatively like a virus.
My colleague from Arizona State, Stephen Johnston, came up with a new way to look for neoantigens. Almost everybody has been looking for mutations in the DNA of tumor cells. Stephen looked at RNA, which is the intermediate step between DNA and proteins. That allowed him to find a group of neoantigens that appear to be the same not only across a given tumor type but across different kinds of cancer. And even across different species-some of these same RNA-derived neoantigens seem to be present in human tumors and dog tumors. That's the hook that suggests maybe it's possible to develop a preven­tative vaccine against a whole bunch of different cancers.
In mice, this vaccine appears to pre­vent or delay tumor development. But going directly from a study in mice to an expensive, complicated human study is a big leap. You'd be talking about 20 or 30 years, and $250 million to $500 million. Here's where the dog comes in. The ways that dogs get cancer are the same ways that people get cancer. They happen spontaneously. But in dogs, we can test whether this vaccine approach works in five years instead of 25 years, and for $6.5 million instead of maybe $250 million. And if, at the end of the day, it looks like the animals who get this vaccine have either a decreased risk of cancer or a delay before they develop  cancer-so more years of healthy, happy life-then we have a product that we know is useful for dogs, and we have really strong evidence to suggest that this approach should be tried in people. So the dogs win for sure, and potentially the people win as well.

What biological mechanism is supposed to get triggered once the vaccine is injected?

The idea behind this type of vaccine is exactly like vaccinating against infectious diseases. Effectively what you're doing is you're introducing some stuff that looks foreign to the immune system, and you're giving the immune system a heads-up about this potential threat. You're telling it, "If you see some funny-looking cells that have these particular proteins on their surfaces, you want to go to work on them fast."

And if I understand how this works, you're not only training the body to recognize the invaders quickly but also helping the body figure out which of its weapons are most useful in eliminating that type of invasion. 

Yeah, you got it. And theoretically, that's way easier to do when a tumor is just getting ­started, versus waiting until you've got a big tumor that has already figured out how to outsmart the immune system. If you catch a tumor in its infancy, before it's developed what we call "immune evasion strategies," then it might be way easier for a vaccine to actually work.

How will you know at the end of five years if your results are telling you the vaccine does have some potential for human application?

This is a randomized, placebo-controlled, double-blind study. There are two groups of dogs--400 will actually get this vac­cine, and another 400 will get a placebo. The simple question is: At the end of five years, is there any difference in the amount of cancer the two groups get? Or is there any difference in how long it takes them to get cancer? It's really that simple. If there's a statistically significant difference, then we would say it looks like this has some promise.

Could there be noise that creeps into this study? For example, suppose that the test group has greater exposure to some sort of environmental toxin
than the placebo group, just by random chance.

That's highly unlikely in a study of this size, but we are collecting as much of that information as we can. We have zip code information. We have diet information. We have exercise-habit information. We have data about their underlying body condition and health factors. We're collecting that demographic and lifestyle information to make sure that it's balanced between the groups. And moreover, we can actually mine that data for other factors that might be associated with cancer development. We're going to be sitting on this enormous database of information that we can look at independent of the vaccine, so that's an added bonus about the way we're doing the study.

Tell me about your own personal experience with cancer.

I was diagnosed with non-Hodgkin's lymphoma between my first and second years of vet school. I was 23 years old. I had to take a year off to get treated. This form of lymphoma was associated with a 93 percent cure rate, so it was much more of an inconvenience than one of these life­ changing experiences. After I was cured, it wasn't like "Oh, I'm going to devote my life to curing cancer." It was more like, "Well this is a drag, I guess I'm going to have to put things on hold for a year. "I've been lymphoma free since 1992, essentially.  But about two years ago I was actually diagnosed with a second kind of blood cancer. This is a very, very low-grade form of platelet cancer called essential thrombocythemia.  I take a couple of pills
a day, and I'm managed by the cancer center in Fort Collins over on the Harmony campus. The average survival time after diagnosis is 31 years. So it's another one
of those things that's inconvenient, but it's not likely to change the arc of my life.

Learn more about the study at www.vaccs.org