Novel CAR-T and Verdinexor Combination Therapy Enters Canine Trial for Pediatric Brain Cancer Treatment
核心洞察
Researchers at Colorado State University are conducting a clinical trial combining CAR T-cell therapy with verdinexor in dogs with naturally occurring brain tumors (搜索) to develop treatments for pediatric high-grade gliomas (搜索).
The combination therapy aims to overcome the immune-suppressive tumor microenvironment that limits CAR-T effectiveness in solid brain tumors (搜索), unlike their success in blood cancers.
Pediatric high-grade glioma patients rarely survive a year after diagnosis, representing a critical unmet medical need with limited treatment options beyond radiation therapy.
Researchers at the University of Colorado Anschutz and Colorado State University have launched an innovative clinical trial testing a combination of CAR T-cell therapy and verdinexor in dogs with naturally occurring brain tumors (搜索), potentially paving the way for new treatment options for pediatric high-grade gliomas (搜索)—one of the most lethal childhood cancers.
The collaborative trial, led by Steven Dow, DVM, PhD, and Stephanie McGrath, DVM, from Colorado State University's College of Veterinary Medicine and Biomedical Sciences (搜索), is currently enrolling dogs with brain cancer (搜索) to evaluate whether combining chimeric antigen receptor (搜索) (CAR) T-cell therapy with the oral cancer drug verdinexor can improve treatment outcomes.
Addressing Critical Treatment Gaps
"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," explains Charlotte Feddersen, MD, PhD, a pediatric hematology and oncology fellow at 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."
The urgency of finding new treatments is underscored by the devastating prognosis for pediatric high-grade glioma patients, who rarely survive a year after diagnosis. This patient population remains critically underserved, with limited therapeutic options available beyond standard radiation therapy.
Innovative Combination Approach
The trial combines 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.
"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 notes. The combination strategy addresses a fundamental challenge in applying CAR-T therapy to brain tumors (搜索): the immune-suppressive tumor microenvironment.
Overcoming CAR-T Limitations in Solid Tumors
While CAR T-cell therapy has demonstrated remarkable success in blood cancers, researchers have struggled to achieve similar effectiveness in solid tumors like brain cancers. "One of the problems we run into when we use CAR T therapy for brain tumors (搜索) 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," Feddersen explains.
The research team hypothesizes that verdinexor may help create a more permissive tumor microenvironment, potentially enhancing CAR-T cell survival and effectiveness. "There's a huge push to find ways to make that tumor microenvironment more permissive," she adds.
Trial Design and Implementation Challenges
The canine trial builds upon an ongoing CAR T trial for canine osteosarcoma (搜索), but researchers have encountered unique challenges with brain cancer (搜索) cases. Dogs with brain cancer often present when the disease is in advanced stages or highly symptomatic, making it difficult to stabilize patients long enough for CAR cell creation and administration—a process that typically requires two to three weeks.
To address this challenge, the team is implementing upfront radiation therapy in enrolled dogs, better mimicking the treatment sequence used in pediatric patients. "A lot of patients with high-grade gliomas get radiation first, then go on to get other types of therapies," Feddersen explains. "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."
Translational Potential
The canine trial represents a crucial stepping stone toward developing CAR-T therapies for pediatric brain tumors (搜索) at the University of Colorado Anschutz Cancer Center (搜索). "We don't currently have in-house manufactured CAR T cells at this institution for pediatric brain tumors, specifically pediatric high-grade gliomas (搜索), which is a really underserved population," Feddersen states.
Feddersen, who works in the laboratory of University of Colorado Anschutz Cancer Center (搜索) members Adam Green, MD, and Michael Verneris, MD, has preliminary evidence that the CAR construct works on brain tumors (搜索) in laboratory-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."
The trial's results could eventually lead to a similar clinical trial in children, offering new hope for families facing this devastating diagnosis. The innovative approach of combining CAR-T therapy with verdinexor represents a novel strategy to overcome the challenges that have limited immunotherapy success in pediatric brain cancers.