June 6, 2022 — In 2018, Morris Animal Foundation took the unprecedented step of awarding a $775,000 grant to Dr. Nicola Mason, Professor of Medicine at the University of Pennsylvania’s School of Veterinary Medicine, to test a vaccine that could improve longevity and quality of life for dogs with the deadly bone tumor, osteosarcoma. The team used a unique approach to treating a disease that affects more than 15,000 dogs annually and kills more than 85% of its victims within two years.
Osteosarcoma spreads quickly to other parts of the body including the lungs. In some patients, evidence of metastasis (cancer spread) is present at the time of diagnosis. Growth of these metastatic cancer cells ultimately leads to death.
Trying to find a way to target metastatic disease without harming normal cells is an ongoing challenge for both human and veterinary researchers. The tricky part for researchers is finding something that can travel throughout the body, home in on the cancer cells, and kill them without harming nearby normal cells.
The team at the University of Pennsylvania, led by Dr. Mason, had an idea. The team knew that a particular receptor, known as HER2/neu, was expressed by osteosarcoma tumor cells. The team thought that this molecule could be exploited to deliver some kind of targeted therapy to osteosarcoma cells anywhere in the body.
The team also knew that a patient’s own immune system could effectively kill cancer cells without harming normal cells. The problem was getting the immune system to “see” the cancer cells as abnormal instead of ignoring them. The immune system is designed to differentiate between “self” and “non-self” and destroy anything it perceives as a threat. Unfortunately, cancer cells are often seen as “self” by the immune system, and this is one way that cancer evades destruction.
Bacteria are very potent activators of the immune system and one bacterium that is a particularly good at activating the immune system is Listeria monocytogenes. The researchers genetically modified Listeria to make it express HER2/neu and to reduce its virulence. Administration of the modified Listeria aimed to activate the immune system to seek out and destroy cells that express HER2/neu. In this way, the vaccine aimed to stimulate the immune system to destroy metastatic osteosarcoma cells that express HER2/neu and delay or prevent fatal metastatic disease. A small pilot study in dogs demonstrated that this vaccine approach elicited a powerful, targeted immune response directed against HER2/neu in dogs suffering from this type of bone cancer.
The Foundation-funded trial was performed through the Comparative Oncology Trials Consortium at the National Institutes of Health, and tested the novel immunotherapy at 11 of the top, university-based veterinary centers across the United States. The study aimed to identify correlative biomarkers of response in vaccinated patients and compare progression-free survival and overall survival of immunized dogs to a group of dogs that received standard-of-care alone.
The vaccine was administered after the standard osteosarcoma treatment of amputation and chemotherapy. The immune responses of the dogs that received the vaccine are currently being analyzed. The team found that administration of the vaccine was safe and, while not all patients experienced benefit from the vaccine, patients that developed a fever within a few hours of receiving the vaccine experienced longer progression-free survival than those patients that did not develop a fever following vaccination. Furthermore, analysis of blood samples taken from vaccinated patients that experienced prolonged survival times indicated that these patients were able to mount robust immune responses which might contribute to their prolonged survival. Robust immune responses were not observed in patients experiencing shorter progression-free survival times.
“There was no difference in age, breed, weight or sex between dogs that experienced prolonged survival compared with those that had shorter survival times; however, the difference in immune response to vaccination between elite survivors and those with shorter survival times was marked,” said Dr. Mason. “This suggests the ‘fitness’ of the patient’s immune system at the time of vaccination might be an important factor in both predicting and determining patient outcome.”
Consistent with previous studies, the team found that almost one-third of patients developed metastatic disease during chemotherapy. This finding suggests that the overall outcome of immunotherapeutic approaches to prevent metastatic disease might be improved if such immunotherapies are delivered earlier in the course of treatment before metastatic disease becomes established.
“While we are still evaluating the data to look for other biomarkers of response, there is a clear indication that immune fitness plays a major role in determining the outcome of these patients,” said Dr. Mason. “Importantly, if we can understand what the immune defects are in patients that do not respond to vaccination, we might be able to address those defects and therefore improve the overall outcome of osteosarcoma patients. This would represent a terrific advance in treating this disease.”
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