The invisible, prickly and globular measles virus, coated with spear-like proteins useful for gaining entrance to host cells, enters a person’s body through his or her respiratory system. There it multiplies, spawning viral clones that infect the mucous membrane throughout the respiratory tract, making a home in the lining of the nasal cavity, larynx, trachea and bronchial tree. Next, the virus embarks on system domination as it spreads to the lymph nodes and bloodstream, eventually infecting the conjunctiva, respiratory, urinary and GI tracts, endothelial cells and the central nervous system. In unvaccinated people, many who live in developing countries, the measles virus infection manifests as a high fever, runny nose, cough, red and watery eyes, and the signature full-body measles rash.
Yet in Dr. Corey Raffel’s lab, where the measles virus is commonly used as an agent of infection, there are no signs of a rash. In fact, the measles virus is targeting brain tumors.
As a principal investigator in the Center for Childhood Cancer at The Research Institute at Nationwide Children’s Hospital, Dr. Raffel is exploring virotherapy using modified measles virus. According to his studies, the use of modified measles virus may represent a new treatment for a childhood brain tumor known as medulloblastoma.
Medulloblastoma is the most common malignant central nervous system tumor of childhood, accounting for about 20 percent of pediatric brain tumors. These tumors are located in the cerebellum, the area of the brain that controls balance and other complex motor functions. Refinements in treatment have increased the 5-year survival to close to 70 percent, but treatment still involves invasive surgery, radiation therapy and chemotherapy.
“There is still an urgent need to investigate alternative therapeutic approaches that are more effective and have less toxic side effects,” said Corey Raffel, MD, PhD, chief of Neurosurgery at Nationwide Children’s Hospital. Vaccine strains of measles virus have been used to kill tumor cells in a number of tumor types including one type of adult brain tumor. “Measles virus is an oncolytic virus, a live virus that can selectively kill cancer cells,” said Dr. Raffel. “Other oncolytic viruses have been explored as possible treatment modalities for medulloblastoma.”
Specifically, Dr. Raffel studies the Edmonston measles strain, which targets the cell surface receptor CD46 to gain entry into susceptible cells. Established medulloblastoma cell lines express the measles receptor, CD46. Medulloblastoma specimens removed from patients have a high level of CD46 expression. “The fact that all of the surgical medulloblastoma specimens that we examined expressed the measles virus receptor leads us to believe that measles virus may have some advantages over other viruses,” said Dr. Raffel.
This has led Dr. Raffel and his team to examine the effect Edmonston strain has on medulloblastoma cells. Having demonstrated receptor expression, the team treated the medulloblastoma cell lines with the modified measles virus. Within 72 hours, all cell lines exhibited significant tumor cell death. The team also administered the modified measles virus to mouse models of medulloblastoma. Medulloblastoma cells were injected into the brains for immunocompromised mice. Seven days later, the same site was injected with measles virus every other day for 10 days. Treatment with measles virus resulted in statistically increased survival compared to animals treated with inactivated virus. By the end of the study period, pathological review of the animals confirmed that eight of 12 treated animals were tumor free.
“Our study demonstrates that a modified measles virus has therapeutic potential in the treatment of intracerebral medulloblastoma,” said Dr. Raffel. “These results provide initial data to be pursued with additional studies toward the goal of using the virus in a clinical trial for the treatment of medulloblastoma. Measles virus therapy could be applied to the tumor bed following surgical resection to target microscopic residual disease. This approach could potentially alleviate the need for radiation and chemotherapy.”
The data also suggest that the measles virus may be a potential therapy for tumors that have spread to the cerebral spinal fluid. “When tumor cells gain access to the cerebral spinal fluid and the subarachnoid space, current therapy is largely ineffective,” said Dr. Raffel. “We have preliminary data in the lab demonstrating efficacy of measles virus in treating disseminated tumor in a mouse model of CSF disease.” More research is needed before progressing to clinical trials, including investigating the optimal dose schedule for injection of the virus. Dr. Raffel also intends to examine how modifications of the virus might lead to more effective treatment of the tumor.
“Overall, the results suggest that use of modified measles virus may represent a new treatment for medulloblastoma,” he said.
(Above) Dr. Raffel’s team administered a modified measles virus to mouse models of medulloblastoma. By the end of the study period, eight of 12 treated animals were tumor-free. As seen here, a microscopic view of a brain of a mouse not treated with the modified measles virus (left) shows significant tumor growth. A similar view of a mouse that received the modified measles virus treatment (right) shows no evidence of a tumor.
Studebaker AW, Kreofsky CR, Pierson CR, Russell SJ, Galanis E, Raffel C. Treatment of medulloblastoma with a modified measles virus. Neuro Oncol. 2010 Oct;12(10):1034-42.