PHILADELPHIA — Sasha is still spunky at 12 — a white dog with a smattering of black, floppy ears and a sweet face. Even after she lost her right foreleg to bone cancer, her owners said, she could jump and catch a Frisbee. Unfortunately, in nearly all cases like Sasha’s, the surgery offers just a short respite before the cancer comes roaring back. Her only hope now lies with an experimental treatment being developed at the University of Pennsylvania.
Doctors at Penn’s School of Veterinary Medicine recently pumped a modified listeria bacteria into her bloodstream, hoping to push her immune system to kill remaining cancer cells. If the treatment works, it is likely to be tested next on humans with this type of bone cancer, called osteosarcoma.
Veterinary scientists say such cross-species research is on the rise. While animal research has long played an important role in human medicine, an increasing number of clinical trials for dogs are being designed to help both species. Right now, the vast majority of cancer treatments that work in mice fail in people, said immunologist Carl June, director of translational research at Penn’s Abramson Cancer Center. By testing the treatments in dogs, he said, veterinarians are helping sort out the potential winners.
Osteosarcoma is also easier to study in dogs because it’s relatively common, especially in larger breeds. In humans, it’s an orphan disease, but it takes a vicious toll. It strikes young people, most of them between the ages of 13 and 25. Often their only hope for survival is a radical amputation.
Liliana Ruano said she and her husband, Carlos, wanted a dog that could accompany the North Carolina couple on hiking and camping adventures, and Sasha turned out to be just perfect. They often visit Carlos’s family in Pennsylvania and hike with Sasha in French Creek State Park.
The first sign of trouble came earlier this year, when Sasha started limping. The local veterinarian thought it was an injury; it seemed to get better for awhile, but then it got much worse.
An X-ray revealed bone cancer, and the doctor offered grim choices. They could do nothing and their faithful hiking buddy would die in agony, or they could amputate the leg, which would give her a few months of pain-free life before the cancer returned, usually as a fatal chest tumor. Mild chemotherapy would extend her life slightly.
They opted for the surgery and chemotherapy, and Sasha came through very well. She’s running around and playing Frisbee — for now, anyway.
Concerned that Sasha’s cancer would come back, Liliana found information about the Penn trial on a Facebook page about dogs and cancer. She called to find out more and connected with Nicola Mason, who explained the treatment, its risks and benefits. Mason told them the tumor would have to be of a certain type for Sasha to qualify — expressing a marker called her2/neu. Sasha’s tumor tested positive.
Mason, who has both a veterinary degree and a doctorate in immunology, said osteosarcoma tumors that strike dogs are very similar to those that strike humans. Dog and human lymphomas are also similar, and she is also involved in a trial to treat dog lymphoma.
Treatment with listeria bacteria might sound scary because it’s associated with food poisoning, but it is disabled, Mason said. “It’s modified so it does not cause disease and is rapidly cleared.” But it should still prompt an immune response in Sasha.
Modified listeria has been tested in mice and used in some trials connected with human cervical cancer, she said. For this treatment, the listeria was also genetically modified — a gene was added to allow the bacteria to make a protein called her2/neu — the same one they tested for and was expressed in Sasha’s tumor.
The idea is to train the patient’s immune system with the her2/neu protein the way you might train a bloodhound with a piece of someone’s clothing. The immune cells are geared to attack listeria, but they will also be trained to recognize and attack cancer cells that express the her2/neu. This protein is one of the few marks that distinguishes the cancer cells from healthy ones, so the immune system should go after the cancer.
Though Sasha looks healthy now, amputations almost always leave behind a few malignant cells, which is why dogs often bounce back after an amputation but almost always get a fatal recurrence.
“They are sitting on time bombs,” Mason said. In virtually all cases, stray malignant cells eventually spread to the lungs and kill the dog. “What we’re doing with the immunotherapy is mopping up the cancer cells we can’t see,” she said. So far, they’ve signed up six dogs, and they aim to recruit 9 to 18.
Why can’t the immune system kill the cancer cells without all this help?
Our immune systems do best when fighting foreign cells, said the University of Minnesota’s Jaime Modiano, who is, like Mason, a veterinarian with a doctorate in immunology. Cancer cells are so similar to our own cells that it can be hard for the immune system to recognize them as invaders.
In a given patient, canine or human, cancer cells undergo their own version of natural selection. The ones that evade the immune system survive and proliferate, he said. Cancer cells can evolve a host of evasive maneuvers. The challenge with immunotherapy is getting around all those tricks.
Modiano says clinical trials elsewhere are testing new therapies for brain cancer and other malignancies that strike both canines and humans. Working with dogs gives them information they couldn’t get studying mice or people, he said. There is no shortage of dogs with spontaneous cases, he said, since cancer strikes about one in three dogs.
Studying dogs also allows researchers to learn at an accelerated pace — literally in dog years. If a treatment keeps a terminally ill dog alive for two years, that’s like keeping a human alive for 10 or 15 years.
Penn’s Carl June sees clinical trials with dogs as a way to take advantage of an explosion of untested but promising new approaches to fighting cancer and to accelerate the process of sorting the winners from the losers.
Immune therapies are a good case in point, he said. “This is exactly the sort of thing that should be done on a dog,” he said.
No other large animals routinely get cancer the way dogs and humans do. Monkeys rarely get cancer spontaneously, and many people have ethical concerns about giving cancer to fellow primates. Scientists see some striking similarities in the genetics and biology of dog and human cancers. Cats, too, are starting to be entered in clinical trials, but Mason said dog research is further ahead.
Liliana Ruano says she understands the risks and potential benefits for Sasha. “Dr. Mason spent a lot of time with us to make sure we were comfortable,” she said. Ultimately, she decided to go ahead because of the chance to extend Sasha’s life. “I’m not ready to let her go yet.”