UAB Brain Tumor Trial in Progress

Malignant gliomas are the most frequent primary brain tumors in adults, accounting for half of the 17,000 brain tumors diagnosed in the United States each year. Glioblastoma multiforme, the most malignant type, remains refractory to available treatment, with a median survival of 1 year with aggressive therapy. A UAB-based study proposes that infusing an oncolytic respiratory enteric orphan virus, or reovirus, will result in viral replication within tumor cells that lyses and kills the cancerous cells while sparing normal tissue.

Principal investigator and UAB neurosurgeon James M. Markert, MD, plans to enroll 15 participants with recurrent malignant glioma in the multisite phase 1/2 trial. The primary objective is determining the maximum tolerated dose, dose limiting toxicity, and the safety profile for the reovirus. Secondary objectives are evaluating viral replication, immune response, and evidence of antitumor activity.

Reovirus commonly inhabits lungs and intestines, and most individuals carry the virus without developing illness or symptoms. “Healthy cells prevent reovirus from replicating, so generally no clinical manifestations of infection are present,” says Markert, “but in people with glioblastoma, the malignant cells’ DNA has mutated, eliminating their protective properties.” Reoviruses infect tumor cells and destroy them without collateral damage to normal cells.

Malignant gliomas’ aggressive, migratory nature makes them very difficult to treat, even with a combination of surgery, radiotherapy, and chemotherapy. Gliomas travel along axons, forming fingers that are hard to demarcate from normal surrounding brain tissue. Moreover, most imaging techniques cannot visualize areas with a low density of invading glioma cells and neoplastic capillaries, and neurosurgeons cannot remove cancerous extensions without damaging normal brain. Radiation slows growth, but tumors return.

Markert’s work expands on previous research indicating reoviruses may travel the same axons in pursuit of glioma cells, destroying those that migrate from the original tumor mass. In a previous clinical study, Forsyth et al stereotactically administered reovirus at 1 of 3 dose levels without producing negative side effects (J Clin Oncol. [Meeting Abstracts] 2006;24:1563). Markert’s phase 1 trial will pinpoint the time for the reovirus to reach peak concentration and the maximum tolerated dose.

Markert surgically positions two catheters in the tumor mass and infuses the reoviruses over a 3-day period. This spreads the virus slowly along the cancerous white matter tracks, increasing the volume of virus so it invades tumor cells. This method, termed convection-enhanced delivery, may more effectively target the cancerous extensions compared with the single dose used in the previous trial, Markert says.

Scientists are studying other oncolytic viral agents including herpesvirus, adenovirus, and poliovirus. Several new agents show promise when combined with traditional therapies such as radiation. “Gliomas are our arch nemesis. Despite advances in other areas of medicine, we have not made headway with these tumors. Harnessing biologic agents to target malignancy can make a big difference in our war on glioma,” he says.

For more information:
Dr. James Markert
1.800.UAB.MIST
mist@uabmc.edu