Reovirus as an oncolytic agent against experimental human malignant gliomas

Background: Reovirus is a naturally occurring oncolytic virus that usurps a ctivated Ras-signaling pathways of tumor cells for its replication. Ras pat hways are activated in most malignant gliomas via upstream signaling by rec eptor tyrosine kinases. The purpose of this study was to determine the effe ctiveness of reovirus as an experimental treatment for malignant gliomas. M ethods: We investigated whether reovirus would infect and lyse human glioma cell lines in vitro. We also tested the effect of injecting live reovirus in vivo on human gliomas grown subcutaneously or orthotopically (i.e., intr acerebrally) in mice. Finally, reovirus was tested ex vivo against low-pass age cell lines derived from human glioma specimens. All P values were two-s ided. Results: Reovirus killed 20 (83 %) of 24 established malignant glioma cell lines tested. It caused a dramatic and often complete tumor regressio n in vivo in two subcutaneous (P = .0002 for both U251N and U87) and in two intracerebral (P = .0004 for U251N and P = .0009 for U87) human malignant glioma mouse models. As expected, serious toxic effects were found in these severely immunocompromised hosts. In a less immunocompromised mouse model, a single intratumoral inoculation of live reovirus led to a dramatic prolo ngation of survival (compared with control mice treated with dead virus; lo g-rank test, P < .0001 for both U251N and U87 cell lines). The animals trea ted with live virus also appeared to be healthier and gained body weight (P = .0001). We then tested the ability of reovirus to infect and kill primar y cultures of brain tumors removed from patients and found that it killed n ine (100 %) of nine glioma specimens but none of the cultured meningiomas. Conclusions: Reovirus has potent activity against human malignant gliomas i n vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.