A clinical trial of a chimeric antigen receptor (CAR) T-cell treatment for brain tumors that naturally occur in dogs could open the door for a new way to treat pediatric high-grade gliomas, an often-deadly type of brain cancer in children.
“What we see in both canines and pediatric patients is that these tumors respond to radiation, but it doesn't make them go away completely, and then they come back,” says Charlotte Feddersen, MD, PhD, a pediatric hematology and oncology fellow in the CU Anschutz School of Medicine. “We need something else to add to the treatment, but decades of research have not yet revealed what that is.”
Feddersen is hoping to get a step closer to the answer with a collaborative clinical trial combining CAR T-cell therapy — a method for enhancing a patient’s immune cells to make them better cancer-fighters — with verdinexor, an oral cancer drug that works by keeping tumor-suppressing proteins inside the nucleus of cancer cells, where they cause the cells to die.
Run out of the College of Veterinary Medicine and Biomedical Sciences at Colorado State University in Fort Collins and led by Steven Dow, DVM, PhD, and Stephanie McGrath, DVM, the trial is now enrolling dogs with naturally occurring brain cancer to see if the drug and CAR-T combination improves their outcomes.
The results could eventually lead to a similar clinical trial in children, says Feddersen, who works out of the lab of University of Colorado Anschutz Cancer Center members Adam Green, MD, and Michael Verneris, MD.
“Using verdinexor could not only make the tumor cells more susceptible to the CAR T-cells, but we hypothesize it also affects the tumor microenvironment,” Feddersen says. “One of the problems we run into when we use CAR T therapy for brain tumors is that we can get the CARs to the tumor, but they encounter an immune-suppressive environment where the CAR T cells don't propagate, or they die, or they're not as effective. There's a huge push to find ways to make that tumor microenvironment more permissive.”
Feddersen and collogues are basing the trial in part on an ongoing CAR T trial for canine osteosarcoma, but because dogs with brain cancer often present when the disease is in later stages or very symptomatic, she and her collaborators have so far found it difficult to get a dog stabilized to the point that a CAR can be created and administered — a process that typically takes two to three weeks.
“We are working with CSU to do upfront radiation in these dogs, which would better mimic what we do in pediatric patients,” Feddersen says. “A lot of patients with high-grade gliomas get radiation first, then go on to get other types of therapies. We're trying to highlight that a perk of this clinical trial is that you not only get radiation therapy for the canines, which is the standard of care, but then you also get this experimental CAR T-cell therapy afterward.”
CAR T-cell therapy has proved very effective in blood cancers, but researchers are struggling to get them to work as well in solid tumors like brain tumors. Feddersen hopes her research will contribute to the cause.
“We don't currently have in-house manufactured CAR T cells at this institution for pediatric brain tumors, specifically pediatric high-grade gliomas, which is a really underserved population,” she says. “These patients rarely survive a year after their diagnosis. There have been some promising CAR T cell trials at other institutions, and I have some evidence that this CAR works on brain tumors in lab-based animal models. If we could see that it had some effect in dogs, that would go a long way toward providing preliminary effectiveness and safety data to help us be able to offer this to patients at our institution.”