University of Florida researchers have developed a novel strategy to deliver genetic material directly to cells associated with glioblastoma, making the tumors more responsive to immunotherapy treatment.
The promising strategy, described in a study published on July 12 in Nature Communications, could be used in combination with other treatments to increase the effectiveness of therapies for glioblastoma, the most lethal type of brain cancer that is notorious for resisting conventional treatments and evading the body’s immune system.
Led by Christina von Roemeling, Ph.D., the research team screened glioblastoma clinical specimens to identify a protein that is absent in immune cells surrounding the tumor. Next, they developed a method to deliver the genetic material for the protein, called C-X-C motif ligand 9, directly to cells using adeno-associated virus (AAV) gene therapy.
AAV gene therapy involves engineering viruses to deliver DNA to target cells. AAV vectors are the leading platform for gene delivery and have been shown to be safe and minimally invasive. Multiple AAV gene therapies have been approved by the FDA for a variety of diseases.
The gene therapy platform, which the researchers tested in preclinical glioblastoma models, increased the amount of immune cells that infiltrated the tumor, the researchers found. As a result, the tumors were more sensitive to immune checkpoint inhibitors, a type of immunotherapy that works by releasing the brakes on the body’s immune system to attack cancer.
By directly targeting the area surrounding the tumor, the new platform could help overcome the limitations of systemic administration of immunotherapies and chemotherapy, which often have limited effectiveness because of the constraints of the blood-brain barrier and toxic side effects. Furthermore, AAV biotherapy allows for multiple anti-cancer agents to be delivered at the same time, and these agents could be personalized to targets that are specific to an individual’s brain tumor.
“The use of AAV gene therapy has the potential to disrupt the existing treatment paradigm for glioblastoma, which relies on radiation, surgery and cytotoxic chemotherapy,” the authors concluded.
Von Roemeling led the study as a postdoctoral fellow in the lab of Duane Mitchell, M.D., Ph.D., director of the UF Clinical and Translational Science Institute and the UF Brain Tumor Immunotherapy Program and senior author of the paper who serves as associate director for translation and innovation at the UF Health Cancer Center. Von Roemeling is now an assistant professor in the Lillian S. Wells Department of Neurosurgery in the UF College of Medicine and a member of the Cancer Targeting and Therapeutics research program at the UF Health Cancer Center. In addition to numerous co-authors at the University of Florida, collaborators included researchers at Emory University School of Medicine and MD Anderson Cancer Center.
This study received funding from the National Institutes of Health, the UF Health Cancer Center, the Wells Brain Tumor Research Fund, the Adam Michael Rosen Research Fund, the McKnight Brain Institute Fellowship Award, and the Circle of Hope Foundation.
Read the full study.
Behind The Paper
AAV-CXCL9 combination immunotherapy
Researchers contributed a blog post explaining the significance of the promising strategy in the treatment of glioblastoma.
