A special type of cell essential to the ability of olfactory neurons to regenerate may be genetically engineered to deliver anticancer therapy to glioblastomas, according to Massachusetts General Hospital (MGH) researchers who published their study (“Olfactory Ensheathing Cells: A Trojan Horse for Glioma Gene Therapy”) in the Journal of the National Cancer Institute. The team describes using olfactory ensheathing cells (OECs) to deliver an anticancer agent only to tumor cells and how the treatment reduced tumor size and prolonged survival in a mouse model.
“We show for the first time that autologous transplantation of OECs can target and deliver therapeutic transgenes to brain tumors upon intranasal delivery, the natural route of OECs to the CNS, which could be extended to other types of cancer,” write the investigators.
“Glioblastomas are the most aggressive and malignant type of brain tumors, and despite intensive treatment with surgery, chemotherapy, and radiation therapy, they almost always recur, leading to a five-year survival rate of less than 10%,” says senior author Bakhos Tannous, PhD, associate professor of neurology at Harvard Medical School, and associate neuroscientist at the neuro-oncology division in the MGH department of neurology. “Olfactory ensheathing cells, which are present in the nose throughout life in all mammals, including humans, can migrate from the nasal cavity to sites of inflammation and have the potential of acting as a 'Trojan horse,' delivering cell-killing therapies that bypass the barriers that keep other anticancer agents out of the brain.”
Olfactory neurons have the ability to regenerate, which is rare within the nervous system. New neurons in the nasal cavity must project axons to the olfactory bulb within the brain itself. OECs surround the growing axons, assisting in their regeneration and also engulfing debris from dead and damaged cells. The ability of OECs to promote neural regeneration has led to studies of their potential in the treatment of spinal cord injuries and the neurodegenerative disorder amyotrophic lateral sclerosis.
Because of the direct connection between the nasal cavity and the brain, intranasal drug delivery is being studied as a means of bypassing the blood-brain barrier. The ability of OECs to travel into the brain and their attraction to inflammatory molecules, including those secreted by tumor cells, led the MGH team to investigate their potential use against glioblastomas. They first showed that labeled OECs introduced into the nasal cavity of mice with experimentally induced human gliomas not only traveled to sites where tumor cells had been injected but also followed tumor-initiating cells as they infiltrated adjacent brain tissue.
The team then genetically engineered OECs to express fusion protein CU that converts nontoxic prodrug 5-FC into a cell-killing chemotherapy agent (5-FU). After confirming in cellular experiments the ability of CU-expressing OECs to convert 5-FC to 5-FU, leading to the death of tumor cells, the team administered either CU-expressing OECs or a control agent into the nasal cavities of mice a week after tumor-initiating cells had been injected into the animals' brains. Seven days later, both groups of animals received daily injections of 5-FC for another seven days. Two weeks after that, mice that had received the transgenic OECs has significantly smaller tumors at the injection site, less tumor migration through the brain, and greater death of tumor cells than the control group. The single OEC treatment also led to significantly longer average survival among the treated mice.
“Our findings indicate that, upon intranasal delivery, CU-expressing OECs migrate through their natural route towards the brain, target brain tumors in a very specific manner and convert 5-FC into an active 5-FU drug at the tumor site, leading to an efficient, tumor-cell-killing effect through what is called a 'bystander effect',” says Litia Carvalho, PhD, a postdoctoral fellow in Dr. Tannous's lab and the lead author of the study.
Dr. Tannous adds, “Due to their strong attraction to inflammatory cues secreted by tumor cells, we believe OECs could be used as a therapeutic tool against different types of brain cancer and tumors located in other parts of the body, something we are actively investigating.”