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Immunotherapy Arms Canines to Fight Cancer

By: Sacha Adorno Published: Sep 1, 2017

Dr. Nicola Mason, at right, with a canine participant in the CAR T cell trial for dogs with B cell malignancies, including B cell lymphoma or leukemiaWhen Kasey bounded on the bed, her owner Dave Sabey knew something was wrong. The precocious, playful two-year-old pup, who performed this routine every night with great joy, jumped around nervously, heart racing. Assuming a torn ligament, Sabey brought her to their veterinarian, who took a radiograph of the Labrador’s rear left leg. It revealed a lesion on Kasey’s left distal tibia consistent with a diagnosis of osteosarcoma, the most common bone tumor found in dogs. This vet visit began a journey that ended at Penn Vet.

Mrs. Kasey“Kasey wasn’t expected to live beyond a year at most,” said Sabey, who with his wife and Kasey splits time between Seattle and Montana. “We went ahead with the recommended course of standard treatment, which was amputation and chemotherapy, but wanted to do more. I learned about an osteosarcoma clinical trial at Penn Vet led by Dr. Mason and called immediately.”

Dr. Nicola Mason, Associate Professor of Medicine and Pathobiology at Penn Vet, runs a translational research lab that focuses on harnessing a dog’s immune system to kill cancer. The approach—immunotherapy—is among the most promising new developments in cancer research in many decades.

From her desk in Philadelphia, Mason took Sabey’s call. After discussion and testing, she determined that Kasey qualified for an osteosarcoma trial open at the time. And, in 2013, the indefatigable dog started making regular trips across the country to participate in research that is catching national and international attention for the promise it holds for dogs and humans.

Arming the Immune System With Vaccine

The study that Kasey enrolled in uses a vaccine to jump start the immune system to recognize and eliminate metastatic cancer cells. It aims to prevent recurrence of the disease in dogs that have already received standard care for osteosarcoma and are in remission.

This photo shows Listeria bacteria cells genetically modified by the Mason laboratory to express the tumor protein HER2/neu, as well as reduce its virulence.Participating dogs received three doses of a vaccine that is based on Listeria monocytogenes, a bacteria that in its original form can cause food poisoning. For the vaccine, the Listeria has been genetically modified to reduce its virulence so it won’t cause disease in the patient. It has also been modified to express the tumor protein HER2/neu, which is over-expressed in some solid cancers, including osteosarcoma, so that it will trigger an immune response to fight HER2/neu expressing cells.

Mason’s close ties to Penn Medicine, where similar research focuses feverishly on advancing treatments and cures for human cancers, sparked this specific trial in dogs.

“It’s a great story,” Mason explained. “In 1999, when I was a PhD student in the Immunology Graduate Group at Penn, I performed a laboratory rotation with Dr. Yvonne Paterson, a Penn microbiologist who pioneered the use of Listeria to fight different HER-2/neu positive cancers. Years later, Yvonne invited me to talk to her students about my immunotherapy work with dogs. I told them about the high number of dogs we were seeing with osteosarcoma and that this tumor expresses HER-2/neu. Yvonne said, ‘I’ve got a vaccine for that’!”

Paterson had been testing the ADXSHER2 vaccine in mice, and it was working. But she and Mason understood an even better test of the immunotherapy’s safety and effectiveness would be with dogs. Dogs develop cancer spontaneously, and many of the cancers have similar genetics, biology, clinical presentation, and therapeutic responses as their human counterparts. In most cases, researchers use mouse models to assess the effectiveness of cancer therapies. But mouse models are increasingly recognized as poor predictors of safety and therapeutic response to new treatments. To advance translational cancer research, researchers need better models that more accurately recapitulate the human disease—so that what Mason and Paterson would learn about the vaccine in dogs would be much more translatable to human cancer research.

The study launched in 2012 with Sasha, an American Bulldog. “After administering the vaccine, I kept a very close eye on Sasha for 72 hours, spending a lot of time with her in her run,” said Mason. But Sasha responded well—surviving another 738 days before succumbing to her disease.

Dr. Mason assists Radiology staff in positioning a clinical trial participant for x-rays.Since then, 18 dogs have received the vaccine, and the median survival time of vaccinated dogs is 956 days. “For 20 to 30 years, the average survival for dogs with osteosarcoma post-amputation and chemo has been around 320 days,” said Mason. “This approach has tripled that time, and it’s very exciting to think we may be working on something really big here.”

This trial closed in 2016. Mason recently received a $1 million grant from the Morris Animal Foundation to extend her studies and  perform a clinical trial to test this vaccine approach in 80 dogs with osteosarcoma. The National Cancer Institute’s Comparative Oncology Program will run the trial, which will include testing the vaccine in patients who develop metastatic disease during chemotherapy.

One Health Connections

The collaboration between Mason and Paterson, Professor of Microbiology at Penn and former Associate Dean for Research at Penn’s School of Nursing, earned them the University of Pennsylvania One Health Award in 2013. The award recognizes exemplary contributions toward expanding interdisciplinary education and improving health care for the benefit of humans, animals, and the environment.

Since then, the promising results of Mason’s dog studies have paved the way for similar clinical trials in humans. “Our dog data were pivotal in supporting an Investigational New Drug application for this vaccine in human clinical trials for adults with HER-2/neu positive tumors,” said Mason.

Osteosarcoma in humans is rare. In the United States, around 800 cases are diagnosed a year, mostly in children and teenagers. Mason is currently working on a similar trial for children in collaboration with the Children’s Oncology Group, a National Cancer Institute supported clinical trials group and the largest organization in the world devoted exclusively to childhood and adolescent cancer research.

“Dr. Mason’s results with vaccine therapy in dogs with osteosarcoma are the most exciting data I’ve seen for treatment of this disease,” said Dr. Kristy Weber, Chief of Orthopedic Oncology and Director of the Sarcoma Program at Penn Medicine’s Abramson Cancer Center. “We have seen no substantial improvement in the survival of children with this malignant bone tumor in more than three decades, and her work gives me hope that this success in dogs can be translated to children.”

Putting Cells to Work

Vaccination is only one of the groundbreaking immunotherapies Mason’s lab is investigating. Another is chimeric antigen receptor (CAR) T cell therapy, an approach that has shown promising results for humans, especially in liquid tumors like lymphoma and leukemia. Further amplifying the interconnection between animal and human health, this research stems from Mason’s association with Dr. Carl June, Richard W. Vague Professor in Immunotherapy at Abramson Cancer Center, who is at the forefront of CAR T cell research.

Dr. NIcola Mason, Associate Professor of Medicine and PathobiologyMason is currently conducting a CAR T cell trial for dogs with B cell malignancies, including B cell lymphoma or leukemia. The study uses T cells genetically modified to express a chimeric receptor that recognizes B cells. Upon recognition of a B cell, the genetically modified T cell activates and kills the B cell target.

“This is such an exciting approach,” said Mason. “It’s a living treatment. We collect T cells from an individual patient’s blood and genetically modify them to re-direct their specificity. In the lab, we expand these modified cells until there are many billions of them, capable of recognizing and killing malignant B cells. Then we put this great army of genetically modified T cells, known as CAR T cells, back into the patient’s body. Ideally, they’ll engraft, recognize the cancer cells they’re trained to target, proliferate, and kill the target cells.”

The Long Game

“In the short term, it’s likely that the use of immunotherapy will change cancer from a terminal disease to a chronic disease and patients will enjoy longer survival times. Long term, my hope is that immunotherapies are ultimately going to enable us to move toward a cure,” Mason said.

Sabey has both the short and long term in sight. He wants more quality time with his beloved Kasey. At the same time, he wants to contribute to an ultimate eradication of cancer. “We had nothing to lose with Kasey,” said Sabey. “We knew the statistics. This trial was our last hope. Without it our girl would be dead, but she’s still a vibrant, almost six-year-old dog.”

Among the Sabeys’ family and friends, Kasey is now known as Mrs. Kasey—the added prefix a moniker from her cancer journey. “We call her Mrs. Kasey, like a teacher, because she has taught us about spirit, resilience, and strength in the face of disease,” Sabey explained, adding, “She is teaching science so much about cancer. It’s the greatest role she could have.”