Bruce Walcheck, PhD, says the relationship between human and veterinary medicine is circular. He is partnering with Jianming Wu, DVM, PhD to leverage that cycle to advance immunotherapies in the fight against cancer in dogs and humans alike. “The science behind immunotherapy is much more advanced on the human side, so our labs can make greater strides when we transfer what we know from humans to dogs,” he says. “We can also take what we learn from researching the immune system in dogs and apply it to human medicine. It benefits both human and veterinary patients.”

Fate Therapeutics, a California-based biotechnology company, licensed a recombinant receptor — an enhanced receptor that binds to the Fc region of IgG antibodies — that Walcheck, a professor in the Department of Veterinary and Biomedical Sciences at the University of Minnesota College of Veterinary Medicine (CVM), and Wu, associate professor in VBS, developed in collaboration. Now, the patent is in progress. The scientists use engineered cytotoxic lymphocytes — or, natural killer (NK) cells — to produce their novel receptor. The NK cells are derived from induced pluripotent stem cells (iPSCs) and grown in a lab. 

“These engineered cells can be delivered ‘off the shelf’ — similar to a pill, but stored as frozen cells after being generated in a production facility,” says Walcheck. “It's easier for hospital infrastructures to accommodate and incorporate this treatment.” The therapy can be delivered to patients by injections, and is currently in a human clinical trial run by Jeffrey Miller, MD, professor in the U’s Medical School, which is still enrolling participants.

The trial on the East Bank is groundbreaking: “This is the first-ever engineered iPSC-derived cell therapy cleared for clinical investigation worldwide,” Walcheck says. He and Wu are hoping similar trials will take place in dogs in the future to advance veterinary medicine.

The natural Fc receptor on NK cells has some regulatory features that limit NK cell killing of tumor cells, but Walcheck and Wu’s process bolsters the receptors’ ability to recognize antibodies attached to tumor cells. Their strategy also directs NK cells to many different types of tumor antigens and cancer cells. The researchers say that NK cells are the chosen vehicle for this therapy because they have their own advantages in killing tumor cells, while producing fewer side-effects in treatment. However, the same method can be used to modify other immune cells, such as T-cells and macrophages. 

Adoptive cell therapy (ACT) — which collects and uses a donor’s or patient’s immune cells to fight cancer — are important modes of treating cancer in humans, and are being developed for animals. Chimeric antigen receptor T-cell (CAR T-cell) therapy is an ACT that has advanced the furthest in clinical development. It has made headlines over the past couple of years, as it was approved by the Food and Drug Administration in 2017 for the treatment of children with acute lymphoblastic leukemia and for adults with advanced lymphomas. 

CAR T-cell therapy uses genetically engineered T-cells to produce an artificial T-cell receptor. This T-cell receptor incorporates a fragment of an antibody to recognize a specific antigen on human tumor cells. “But a limitation is that patients can develop a resistance to that approach,” says Walcheck, “and tumor cells escape.” Meaning, tumor cells expressing the antigen the T-cells are binding to are killed off. Meanwhile, other tumor cells lacking that specific antigen are given a chance to expand. Tumor cells may also actively decrease the amount of that specific antigen in response. 

“A CAR receptor only recognizes one tumor antigen but if that tumor escapes and gets rid of that antigen, then that CAR T-cell doesn’t work anymore,” Wu says. “An advantage to our approach is that the Fc receptor in combination with various therapeutic antibodies can recognize many different antigens at the same time, reducing the tumor’s ability to escape.” 

CAR T-cell therapy paved the way for Walcheck and Wu to engineer immune cells with tumor targeting receptors. The duo says that CAR T-cell therapy is like a single bullet hitting one target on a tumor. That can be helpful in fighting cancer, but their strategy uses several bullets to hit multiple targets on the tumor or multiple tumors.

Walcheck and Wu believe the Fc receptor technique could also be used in combination with CARs expressed in NK cells or T-cells. “This could be either a one-two punch, with the Fc receptor and CAR expressed in separate cells, or done at the same time with both receptors in the same cell,” Walcheck says. “We need to investigate more to determine which method might work better.” 

Immunotherapy is still in an early stage in veterinary medicine. “One issue is that the immune system is not as well understood in dogs as it is in humans,” says Wu. “We are asking ourselves, if it works in humans, will it also work in dogs, too? Part of our focus is trying to gain that understanding.” 

The pair is already gaining on those answers at a steady pace: Wu has already cloned dog versions of the Fc receptors in order to enhance their function. He and Walcheck are acquiring canine cell lines and expertise from others, such as the labs of Jaime Modiano, VMD, PhD, Perlman Professor of Oncology and Comparative Medicine, and Antonella Borgatti, DVM, MS, associate professor in the CVM’s Department of Veterinary Clinical Sciences. 

“It all comes down to the tools you have available,” says Walcheck. “Collaboration has brought a lot of different expertise and research tools to the project, which has greatly helped move our research from discovery to translational with the potential of being used in the clinic. Human and veterinary medicine certainly inform one another and investments in human medicine help veterinary medicine and vice versa.”