April 12, 2018

Brain tumor therapy is going to the dogs

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Both dogs and people get brain tumors, and UAB researchers are studying a therapy developed for humans that might also work on dogs.

melissa chambers 2018Renee Chambers, DVM, M.D.People share many things with the dogs in their lives. Unfortunately, that can include a tendency to develop brain tumors. Dogs and humans are among the few species that spontaneously develop naturally occurring brain tumors. Those tumors have a lot in common, too, which has led scientists at the University of Alabama at Birmingham to wonder whether studying tumors in dogs will help treat humans, and whether studying tumors in humans will help treat man’s best friend.

“Brain tumors in dogs and humans are remarkably similar,” said Renee Chambers, DVM, M.D., professor in the Department of Neurosurgery at UAB School of Medicine. “They share similar rates of incidence and mortality, and they share similar symptoms such as seizures, which is often the first symptom observed in both humans and dogs. Treatment is very much the same too, with surgery, radiation and chemotherapy the standard of care.”

Chambers, who is a veterinarian as well as a UAB neurosurgeon, brings a unique perspective on the link between human and canine tumors.

“There are many shared factors between people and their pet dogs,” she said. “Dogs live in our houses, sharing the same environment and the same sleep patterns, for example. Some lucky dogs even share their owner’s diet. It is not unreasonable to assume that the dog will be a highly useful model of human brain tumors.”

And vice versa. Chambers says that, because of the similarities, new therapies being developed for humans might work on dogs. To that end, UAB is partnering with veterinary schools to conduct the first immunotherapy study for brain tumors in pet dogs using an oncolytic herpes simplex virus known as M032.

M032 was developed at UAB by neurosurgeon James Markert, M.D., who has been studying viral therapies for brain tumors for more than 25 years. M032 is a second-generation virus, following on the heels of a previously genetically engineered virus known as G207.

“Both G207 and M032 have been engineered to minimize the production of any toxic effects for the patient receiving the therapy,” said Markert, chair of the UAB Department of Neurosurgery. “Both are now in human studies, an M032 study in adults at UAB, along with a companion pediatric study of G207 underway at Children’s of Alabama. These studies mark the first time one institution has conducted trials of genetically engineered herpes virus in both adult and pediatric — and now canine — populations.”

The five-year, $2.6 million project is funded by the Beau Biden Cancer Moonshot program through the National Cancer Institute’s Center for Cancer Research. The goal is to treat about 14 dogs per year at the participating veterinary schools.

Chambers is working with a network of regional colleges of Veterinary Medicine, including Auburn University, University of Georgia and Mississippi State University, to use M032 to treat their canine patients with naturally occurring brain tumors. Veterinarians at those institutions will use M032 under guidelines established at UAB, which serves as the coordinating center for the study.

chambers puppy stream“Dogs live in our houses, sharing the same environment and the same sleep patterns, for example. Some lucky dogs even share their owner’s diet. It is not unreasonable to assume that the dog will be a highly useful model of human brain tumors.”

“We anticipate that M032 will be as safe and effective in dogs as it is proving to be in humans,” Chambers said. “It opens up an exciting new research pathway, while providing the potential of a therapy that could benefit both humans and canines with brain tumors.

The five-year, $2.6 million project is funded by the Comparative Oncology Program of the National Cancer Institute. The goal is to treat about 14 dogs per year at the participating veterinary schools.

“The hope is that this research will benefit both dogs and people,” Chambers said. “Given the relatively short lifespan of the dog compared to a human, the timetable for results is accelerated. We talk of ‘translational medicine,’ moving research from the laboratory bench to the hospital bedside. This project is a revolution in the approach, also translating research findings from human to animal and back to human, to the benefit of both.”

The M032 virus has been designed to infect tumor cells while leaving healthy cells alone. It then replicates in the tumor cell, which kills the cell and causes it to act as a factory to produce new viruses. As the tumor cell dies, progeny viruses are released from the cell. These viruses infect other tumor cells in the vicinity and continue the process of tumor killing. But M032 also has a secret weapon — the virus was engineered to carry the human gene for interleukin-12, a powerful protein that stimulates and activates killer T lymphocytes that are part of the patient’s own immune system. 

“This protein is expressed in the infected tumor cell as the virus is replicating,” said G. Yancey Gillespie, Ph.D., professor of neurosurgery and co-investigator. “Interestingly, dog T cells are also activated by human interleukin-12. It is our hypothesis that stimulating the immune system within the tumor bed itself, rather than systemically, will have a long-lasting anti-tumor effect, even after the virus has gone.”

“The body’s immune system is designed to patrol for foreign cells in the body, including mutated cancer cells,” Markert said. “The immune system’s cells have an off-switch, known as a checkpoint. The checkpoint keeps T-cells in ‘off-mode’, keeping them from attacking healthy cells. It is supposed to turn the T-cells on in the presence of a foreign cell or threat, prompting them to attack.”

Markert says tumor cells are very good at fooling the checkpoint so T-cells remains in the off-mode. Drugs known as checkpoint inhibitors turn T-cells on, stimulating them to attack the tumor.

According to Chambers, the first step of the new project will be to determine an optimal and safe dose of the virus for canine patients. “We will then combine this therapy with a checkpoint inhibitor, which is expected to keep the immune system ‘turned-on’ to capture and kill even more tumor cells,” she said.

Study investigators David Crossman, Ph.D., and Mike Crowley, Ph.D., will also conduct genomic sequencing of the tumors to determine how the dog’s genome predicts response or toxicities. Any mutations that are present in both the dog tumors and the human tumors will be studied further to discern their significance in the development of the tumor and their value as potential targets for new therapies.

“This work is important not only to canine brain tumor therapies but also to devising safer and more effective therapies for humans,” Chambers said. “It will critically inform the medical community on whether this combination approach, using an oncolytic virus followed by a checkpoint inhibitor, will be the next step in the successful treatment of brain tumors in both people and pets.”

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