Genes at Work: New Treatments Enlists Dogs’ Immune Systems

By Alexandra Anderson, October 2017

Canine hemangiosarcoma is a disease of extremes: staggeringly swift and almost uniformly fatal. Accounting for about 7 percent of all forms of cancer in dogs, this highly aggressive sarcoma arises from cells that line blood vessels. It occurs most commonly in the spleen, but can also appear in the heart and the subcutaneous tissue. Middle-aged and senior large breed dogs, especially German Shepherds and Golden Retrievers, are its usual victims.

Exacerbating the difficulty, canine hemangiosarcoma is nearly impossible to detect before it is too late—when the primary tumor begins to hemorrhage. The observable signs of distress in a dog depend on how severely the tumor is bleeding. With a small bleed, dogs seem their usual selves until they have an episode of lethargy, an unspecific symptom that might easily be attributed to the weather or, in older dogs, to the normal course of their dotage. At the opposite extreme, life-threatening hemorrhage may result in a dog unexpectedly collapsing and not being able to get up again. Some dogs may even die suddenly, the only warning a vague bout of listlessness.

More commonly, however, an emergency trip to the vet results in a devastating diagnosis and few good options. Surgery to remove the primary tumor followed by a course of chemotherapy constitute the standard treatment. Yet, because the primary tumor grows so quickly, by the time a dog shows signs of the disease, advanced metastases that chemotherapy cannot eradicate may already be lurking elsewhere in the body, and chemotherapy may only slow down the disease. At best, the affected pooch has a year to live, although the median survival is only six months. What’s more, veterinarians still have no definitive way to screen for hemangiosarcoma. And even if a straightforward diagnostic blood test or imaging examination were available, how often would it have to be done to detect a disease with such a rapid course and for which there are no proven effective treatments to prevent progression?

Searching for Solutions

As bleak as the situation may seem, an ongoing study at the University of Pennsylvania School of Veterinary Medicine (PennVet) in Philadelphia offers hope. Led by Nicola Mason, PhD, BVetMed, an associate professor of medicine and pathology, researchers are investigating whether a simple injection can stop the body from producing a substance called vascular endothelial growth factor (VEGF), which stimulates new blood vessel growth. (Dogs with hemangiosarcoma have elevated levels of VEGF in their blood.) To thrive, cancer cells need the oxygen and nutrients that new blood vessels supply, so turning off VEGF production prevents new vessels from generating, essentially depriving cancer cells of vital resources.

Mason’s experience with the disease goes back to her time as a resident at PennVet, when she encountered Buster, a formidable German Shepherd police dog whom she’s never forgotten. Mason was scheduled to examine Buster, who had been diagnosed with hemangiosarcoma, and provide a second opinion regarding treatment options. On the day of the appointment, however, neither he nor his owner were anywhere to be found, although they’d checked in at the reception desk. Eventually, Mason went outside and saw a police officer standing near a patrol car. Buster was lying inside. “I can’t bring him in through the front door because he can’t walk,” explained Buster’s partner. “I don’t want anyone to see him like this.” Mason, struck by their bond and how the officer looked out for his partner’s reputation and dignity, quickly arranged for them to come in through the back door. Sadly, “I could offer them nothing,” Mason recalls, lamenting how the disease destroyed their partnership. “It wasn’t good enough.”

The elegance of Mason’s new method, which is a type of treatment known as immunotherapy, is that it uses the dog’s own immune system to fight the disease. Rather than a drug, the injection delivers a disabled virus carrying a genetic instruction to the liver; this virus tells the liver and muscle cells to make an antibody against VEGF. If this instruction is effective, then VEGF production by the tumor cells should cease. This in turn would slow down or stop metastatic cell growth. It may even prevent metastatic cells from developing altogether, thus halting the progression of the disease. Mason, who is an immunologist as well as a veterinarian, says that the immune system works best on “minimal residual disease,” those smaller lesions that represent the spread of a primary tumor.

To determine whether the genetic directive actually works, Mason and her colleagues are conducting a pilot study focusing on dogs diagnosed with hemangiosarcoma whose primary tumor is in the spleen. The study works within the standard protocol: dogs diagnosed with hemangiosarcoma undergo a splenectomy (surgery to remove the spleen), then, two weeks later, receive the first dose of doxorubicin, a common chemotherapy drug. Chemotherapy continues for 10 weeks, with a total of five doses, one every other week. Dogs enrolled in the study receive the lone immunotherapy injection or a placebo one week after the first chemotherapy treatment. Then, two weeks after the last chemotherapy treatment and every month thereafter, they undergo imaging tests to restage the cancer.

PennVet provides all chemotherapy, immunotherapy and imaging free of charge at their location in Philadelphia, so dogs must be in the area for the approximately 10-to-12-week study duration. Because dogs cannot be recruited into the study until after they have undergone a splenectomy, enrollment can take place only within a crucial 10-day postsurgical window. In the interests of ensuring that the study’s results are scientifically sound and that the regulations for clinical studies involving animals are followed, Mason has had to make the hard decision to turn away dogs who were more than 10 days past surgery.

Mason and her group designed the trial to determine whether the immunotherapy is safe as well as whether it is effective. The doubleblind strategy, the gold standard of scientific research, means that no one involved—neither she and her colleagues nor the owners— knows whether a dog has received the immunotherapy injection or a placebo. Participants are assigned to one of the two treatment groups at random.

Knowing that their dog may not receive the immunotherapy treatment “definitely puts people off,” says Mason, and is another hurdle toward recruiting canine patients. Ultimately, the study will enroll 16 dogs. After all dogs have undergone every stage of treatment and all follow up results are in, researchers will “unblind” the study to see who received the immunotherapy. At press time, eight dogs have been enrolled, and all are doing well.

One Dog’s Experience

Omaya, a 12-year-old Golden Retriever, is one of them. Her owners, Leigh Clayton and Jay McDonnell, both veterinarians, live in the Baltimore area. Last fall, after a few episodes of visible discomfort, Omaya didn’t eat her breakfast two days in a row. Clayton and McDonnell immediately took her to their vet. Her blood work showed that she was slightly anemic, and an ultrasound revealed fluid and a large mass on her spleen. Although Clayton hoped that the mass was benign, she also understood that its size indicated that Omaya probably had hemangiosarcoma. If so, she knew that she would opt for surgery and chemotherapy for their dog. “As a vet, it’s the world you live in,” she explains.

She wanted to prolong Omaya’s life and also wanted to make sure that her dog was happy and comfortable during the months of treatment. Omaya bounced back from the splenectomy almost immediately and was ready for the biweekly two-hour trips to Philadelphia—“She loves car rides,” Clayton says. Although Omaya was often nervous when she visited her regular vet in Baltimore, she happily left Clayton behind in the waiting room at PennVet and went with the resident to the treatment room. The chemotherapy made Omaya a little nauseous, which is not unusual. She also lost all of her hair, and although coat changes are not uncommon with chemotherapy, Omaya’s alopecia was particularly dramatic. Clayton and McDonnell were shocked by how different their dog looked, but Omaya didn’t seem in the least bit bothered. Now they make the drive to Philadelphia once a month for monitoring, and so far, all of Omaya’s imaging tests have shown no spread of the disease. She’s actually stronger now than she was before the surgery, an indication of how much the tumor had been bothering her.

No one yet knows whether Omaya received the immunotherapy treatment. And if she didn’t? “It’s totally worth it, to find better treatments,” Clayton declares unequivocally. Omaya has already contributed to helping researchers find a way to treat this insidious disease. The experience in turn has forced Clayton to be more aware of their limited time together and more focused on living in the moment and providing Omaya with positive experiences. “She’s my anchor to the world,” Clayton says. “She makes me laugh every day.”

Mason urges all dog owners to consider enrolling their dogs in appropriate clinical trials; regardless of the outcome, information acquired during the trial will certainly help others. Equally valuable, participation gives owners a measure of control in the face of a devastating diagnosis like hemangiosarcoma, as well as offering the possibility that something good might result. “That’s what we hope for and what we come to work every day to do,” says Mason. “I don’t want to see another Buster.”

Mason is still recruiting dogs for the study. If you or someone you know is interested in learning more, go to thebark.us/2uw0LI5, or contact Mason at nmason@vet.upenn.edu. All clinical animal studies in the United States, including Mason’s, are collected in a database maintained by the American Veterinary Medical Association.