In the search for new methods to treat glioblastoma multiforme, the most aggressive, common, lethal and therapy-resistant cancer of the brain, researchers from the University of Chicago have combined two unconventional strategies into an even more unconventional one.
Loading neural stem cells with a virus that selectively infects and kills cancerous brain cells, and then delivering them in combination with chemo-radiotherapy, Maciej Lesniak, MD, Director of Neuro-Oncology Research and Neurosurgical Oncology, and his team were able to dramatically increase median survival time in a mouse model of glioblastoma. The results of this study were published Aug. 7 in STEM CELLS Translational Medicine.
“Depending on the model of tumor—how aggressive it is, whether it’s a stem cell based tumor or not—we achieved survival rates that were 50 to 70 percent greater than any other control or experimental group,” Lesniak said.
Targeting and killing cancerous cells with genetically engineered viruses is not a new concept to science. But clinical trials have shown that the utility of these viruses as a therapy is limited by their inability to disperse throughout a tumor mass. For Lesniak and his team, the natural course of action was to put virus in something that does.
They found their vehicle in HB1.F3-CD, a previously FDA approved neural stem cell line. Although stem cells are typically known for their ability to turn into different cell types and for their utility in regenerative medicine, they also have an innate ability to travel and spread in the body, particularly in tumor masses.
Lesniak and his team demonstrated the efficacy of this pairing by loading neural stem cells with CRAd-Survivin-pk7—a genetically engineered virus, which infects and kills glioblastoma cells—in an earlier study published May 2 of this year in the Journal of the National Cancer Institute.
Treating a mouse model of glioblastoma with the combination of stem cells and virus was up to 50 percent more effective, based on median survival, than with the virus alone. In addition, the safety profile of this therapy appeared strong enough for Lesniak to conclude that phase I human clinical trials were warranted.
In their recent study, Lesniak and his team coupled the viral-neural stem cell therapy with the established standard of care for glioblastoma patients—radiation and a chemotherapy agent called temozolomide. When all therapies were applied together at the same time to treat a mouse model of glioblastoma, median survival increased around 46 percent, compared to treatment with radiation and temozolomide alone.
Importantly, the team identified a critical timing window. If applied before chemo-radio therapy, the viral-neural stem cell therapy was up to 30 percent more effective than when applied after.
“One of the critical questions was whether the work would be better for newly diagnosed patients or recurrent patients. Our results indicated that viral-neural stem cell therapy, when applied to newly diagnosed patients and then followed with chemo-radiation, works better than any other clinical scenario,” Lesniak said.
The team is completing FDA-directed studies and expects to start a human clinical trial to patients with newly diagnosed glioblastoma multiforme in early 2014.
“Our study argues in favor of using stem cells to deliver oncolytic viruses in combination with established chemo-radiotherapy therapy for the treatment of patients with glioblastoma multiforme,” Lesniak said.