By: Susan McKenna
Dr. Timothy Fan (ACPP), veterinary oncologist and professor at the University of Illinois College of Veterinary Medicine and a Program Leader for the Cancer Center at Illinois, is leading two clinical trials using similar immunotherapies to treat dogs with malignant melanoma. The novel approaches, developed in partnership with cancer researchers based in Boston, have yielded encouraging results in canine patients, and human trials using the same therapeutic platforms are expected to begin in 2023.
According to the American Veterinary Medical Association, almost half of dogs over the age of 10 will develop cancer. Melanoma is one of the most aggressive forms of canine cancer given its potential to spread to other parts of the body. It usually presents as darkly colored (pigmented) tumors in the dog’s mouth or nail bed but can also arise from haired skin. The traditional treatment regimen consists of often-extensive surgery and multiple radiation sessions. Still, cancer cells routinely remain or regenerate and ultimately can metastasize to other organs. Most dogs with advanced metastatic disease live only a few months after treatment.
“We were pretty good at shrinking tumors, but then the tumors would spread and treatment options become very limited,” said Dr. Fan. “The goal of the current trials is to train the dog’s own immune cells to be very effective at controlling the tumor locally as well as targeting cancer cells throughout the body.”
The Butterfly Effect
The breakthrough trials came about because of a chance meeting in 2019 between Dr. Fan and Dr. K. Dane Wittrup, a biopharmaceutical engineer from the Massachusetts Institute of Technology. Dr. Fan attended an invited talk given by Dr. Wittrup at the University of Illinois, where he had served on the faculty between 1989 and 1999. Afterward, the two scientists discovered how well their research interests connected, and a powerful collaboration was born from this seemingly random encounter.
“Tim knew the potential patients. He immediately saw that there was an opportunity,” said Dr. Wittrup. “And we both had enough belief in this approach that we used our discretionary funds to try this out.”
“Many of these research collaborations start organically, and as the research grows, there continues to be an expanding arena of opportunities,” added Dr. Fan.
No Recurrence More than One Year Later
The new immunotherapy involves a course of injections of cytokines — protein molecules that help control the immune response — that bind with collagen, a protein that surrounds and promotes the growth of cancer cells. In this way, the cytokines remain within the tumor microenvironment. The first canine melanoma trial started in 2021, two years after Drs. Fan and Wittrup had met.
Dr. Wittrup and his team developed the injection formula, while Dr. Fan and his team enrolled eligible canine patients at the University of Illinois Veterinary Teaching Hospital and oversaw their treatment.
In contrast to the low survival times for dogs undergoing traditional treatment for melanoma, the 13 dogs enrolled in the first trial all demonstrated measurable tumor shrinkage following treatment. Some patients achieved 100% cancer reduction, with no local recurrence or spreading of the cancer more than a year after treatment.
Industry Funds Second Trial
A second canine clinical trial, launched in June 2022, builds on the success of the first. This trial is sponsored by Ankyra Therapeutics, a Boston-based biotech company co-founded by Dr. Wittrup. Dr. Howard L. Kaufman, a clinical associate physician at Massachusetts General Hospital and a lecturer in surgery at Harvard Medical School, serves as president and CEO of Ankyra.
Ankyra’s cancer-related interests include a formal research-and-development agreement with the National Cancer Institute (NCI), an agency of the National Institutes of Health. Dr. Fan’s Comparative Oncology Research Laboratory has been an active participant in the NCI’s Comparative Oncology Program since 2003, working toward therapies to help the more than 1 million dogs that develop cancer each year, as estimated by the NCI.
Because of Dr. Fan’s work with Dr. Wittrup and his standing as a cancer researcher — Dr. Amy LeBlanc, director of the NCI’s Comparative Oncology Program, also recommended Dr. Fan to Dr. Kaufman — Ankyra recruited Dr. Fan to lead the trial. The new approach uses what the company calls “a novel anchored immunotherapy platform,” which includes an injection of the cytokine drug attached to an inert “anchor” that results in retaining the cancer drug within the cancer cell microenvironment, triggers an immune response to attack the cancer, and avoids side effects since the drug stays in the tumor locality, preventing a full-body immune flareup.
“A lot of immunotherapies lead to side effects,” said Dr. Fan. “Your whole body is trying to fight something, which leads to whole-body inflammation and wide-ranging side effects. Ankyra’s technological platform is designed to localize the inflammation within the tumor region and minimize the systemic inflammation, or a runaway immune response.”
The myriad of side effects that can result from acute inflammation ranges from breathing and digestive problems to organ and systems damage.
The Science Behind Immunotherapy
Immunotherapy is not new. It was first explored for humans more than 35 years ago. However, “it only worked in a few cancers, and not all patients responded,” Dr. Kaufman explained. And it wasn’t until 1992 that the cytokine interleukin-2 (IL-2) was approved by the FDA for use in treating kidney cancer and later, melanoma.
“When I first started taking care of patients with advanced malignant melanoma, life expectancy was about three months,” Dr. Kaufman said.
“In 2011, we saw the approval of the first human drug targeting an immune checkpoint, which is a protein on the surface of T-cells [part of the body’s immune system], and studies showed that targeting the T-cells could treat some patients with melanoma. Today, there are several immune checkpoint inhibitor immunotherapy drugs approved for use in 37 different kinds of cancer,” he said.
“After I helped get one of the melanoma drugs approved, I asked, ‘Can we use this in dogs?’” (In addition to their shared expertise in immunotherapy and oncology, Drs. Kaufman, Wittrup, and Fan are all dog owners.)
Ankyra Adds Innovations
The Ankyra clinical trial differs from the earlier trial in that it eliminates the use of radiation and uses a different cytokine, a new way to retain the cytokines within the cancer microenvironment, and a new dosage escalation scheme.
To trigger the immune response, the new trial uses a new drug, named cANK-101, that Ankyra created from canine interleukin-12 (IL-12). The first trial used an IL-2 and IL-12 combination.
Another innovation from Ankyra is the use of aluminum-hydroxide, a chemical compound commonly found in vaccines, to retain the cytokines within the immediate vicinity of the injection. Dr. Kaufman said that studies in mouse models showed that this approach helped the cytokines to both stay in the tumor environment for up to 30 days without leaking out, and the cytokine was able to attract “killer” T-cells to the tumor site, where they are thought to kill cancer cells.
“The ability to keep the cytokines local is what makes Ankyra’s approach innovative,” said Dr. Fan.
The Ankyra trial also explores a range of escalating dosages. Three dogs will receive the first specific dose, three more dogs will get the next-level dose, and then three additional dogs will receive the highest dose. If the researchers note concerning side effects, they will continue to refine the dosages and add more dogs to the study. Monitoring and follow-up will continue on a schedule similar to that used in the 2021 trial, i.e., until the team sees tumors growing or not recurring.
An Answer for Cancer?
The two trials will yield a lot of information about how effective this novel treatment is and help determine the best approach for drug delivery and dosage. Findings will be evaluated to improve patient care, inform human trials, and advance knowledge of cancer biology.
“We’re looking for clinical endpoints that answer crucial questions: Does the dog’s tumor shrink? Do CT scans track the size of the tumor? Do we have anti-cancer activity? How well is the therapy tolerated? And we’ve already predicted it will be well tolerated. Do the dogs develop a fever or other signs of systemic effects?” said Dr. Fan.
“For the research endpoints, we want to know: Are we able to show that there is an increase in the number of immune cells? Is there an increase of lymphocytes [white blood cells that produce antibodies or kill cancer cells]?”
Although Ankyra was founded with a focus on human cancer therapy, the company now envisions developing therapies that work for companion animals. “We want to continue to develop immuno-oncology drugs to treat cancer,” Dr. Kaufman said, “and we would like to say that we had an impact on cancer in both humans and dogs.”
The Human Connection
Because these trials involve pet dogs with naturally occurring cancers, as opposed to mouse models with induced cancer, the success to date is extremely promising.
“When you look at the historical records about how long these dogs survived and whether their tumors ever regressed, the answers were ‘not too long’ and ‘never,’” said Dr. Wittrup. “The similarities between dogs and humans at the molecular and cellular level are strong. It will give us a huge tailwind in terms of seeing similar effects in people.”
“If the new treatment is effective, it could have two very important spinoffs,” Dr. Fan said. “It could open the door for new therapies that could be widely available and transformative for veterinarians to add to the toolbox for dogs with melanoma.
“And the results of this trial can inform and guide a similar trial for people. The first hurdle is: Does it work for melanoma? If the response to this trial is positive, there is a possibility that it could be expanded to other types of cancerous tumors.”
For further reading, click here to hear more about Max and Dezzi, two of the patients in the original canine melanoma immunotherapy trial.
By: Susan McKenna
Photos By: College of Veterinary Medicine