Canine Immunotherapy Study Raises Hopes for Human Use

Canine and human oncologists in California have partnered to study whether a protein the body naturally produces could become an important new immunotherapy drug. The approach triggers the body’s defense mechanisms, its T-cells and natural killer (NK) cells, to respond and destroy cancer. The team hopes that positive results in dog trials could help inform the immunotherapy’s eventual use in humans with similar cancers.

In the first-of-its-kind Phase 1 clinical trial, 21 pet dogs of various breeds that had metastatic lung disease resulting from osteosarcoma or melanoma were treated with protein interleukin-15 (IL-15). Although previously recognized for immunotherapy properties, IL-15 has undergone few human clinical trials because of toxicity risks associated with concentrated doses.

“No one previously had administered IL-15 as an inhaled treatment in dogs to deliver it directly to the site of the cancer,” says surgical oncologist Robert J. Canter with University of California Davis Comprehensive Cancer Center. “We came up with that idea as a means of reducing exposure to the rest of the body, in order to improve the benefit-risk ratio, to improve the immune stimulating effects, and to reduce toxicity. In this study, we used interleukin-15 to reinvigorate the immune system to make it recognize the cancer cells that had evaded the immune system and eliminate them.”

The research shows that amplified concentrations of IL-15 can stimulate immune system defenses against some types of cancers in dogs. IL-15 is one of several types of cytokines—substances that have signaling and regulating functions in immune system activity.

“As part of our comparative oncology research, we are strong advocates of clinical trials in companion dogs, especially for immunotherapy, as a way to speed bench-to-bedside translation,” said Canter, who is co-director of the comparative oncology training program at UC Davis. “The cancers that afflict dogs, including sarcomas, brain tumors, lymphoma and melanoma, are incredibly similar to cancers that humans develop.”

In the study, conducted between October 2018 and December 2020, the dogs inhaled a mist containing IL-15 twice daily. Doses were increased over time, to help determine not only effectiveness, but also tolerable levels and the ceilings above which toxicity would result. Dogs exhibited significant responses within 14 days after they began inhaling the IL-15 mist.

Tumors shrank dramatically in two dogs in the study, including one that went into complete remission for more than a year. Cancer that had been growing rapidly in five other dogs stabilized for several months. “Our overall response rate, the clinical benefit rate, was close to 40%,” Canter said.

For that and other reasons, additional studies are needed, says canine oncologist Robert B. Rebhun. “The inhaled IL-15 responses that we’ve seen in dogs are better than prior human studies, but clinical benefit is seen in less than half of the dogs. Using IL-15 in people has led to potentially favorable immune responses but has not yielded good tumor responses. This indicates that combining IL-15 with other immunotherapies may result in additive or synergistic responses.”

Rebhun, who is associate director of the cancer program in the Center for Companion Animal Health, says the study yielded two significant findings: the therapy was well tolerated, and even a short two-week course of inhaled IL-15 could lead to sustained suppression of advanced and diffuse metastatic cancer. Both he and Canter noted that in eventual clinical application, IL-15 likely would be used not as a standalone therapy, but as a reinforcement in combination with other treatments.

“All of the canine patients in this study had advanced metastatic cancer, and the majority already had received prior chemotherapy, radiation therapy and, in some cases, immunotherapy. Studies are ongoing now to see whether we can predict which patients might respond to this therapy based on properties of the tumor or the patient’s immune status,” Rebhun said. “This may help us identify patients that might respond to this therapy, as well as help us understand how to potentially combine other immunotherapies to improve response rates.”

The findings were published recently in Journal for ImmunoTherapy of Cancer.