Reovirus as an oncolytic agent against experimental human malignant gliomas.
BACKGROUND
Reovirus is a naturally occurring oncolytic virus that usurps activated Ras-signaling pathways of tumor cells for its replication. Ras pathways are activated in most malignant gliomas via upstream signaling by receptor tyrosine kinases. The purpose of this study was to determine the effectiveness of reovirus as an experimental treatment for malignant gliomas.


METHODS
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., intracerebrally) in mice. Finally, reovirus was tested ex vivo against low-passage cell lines derived from human glioma specimens. All P values were two-sided.


RESULTS
Reovirus killed 20 (83%) of 24 established malignant glioma cell lines tested. It caused a dramatic and often complete tumor regression 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 prolongation of survival (compared with control mice treated with dead virus; log-rank test, P<.0001 for both U251N and U87 cell lines). The animals treated 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 primary cultures of brain tumors removed from patients and found that it killed nine (100%) of nine glioma specimens but none of the cultured meningiomas.


CONCLUSIONS
Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.
Wilcox
M E
ME
Departments of Oncology and Clinical Neurosciences, University of Calgary, and Tom Baker Cancer Centre, Alberta, Canada.
Yang
W
W
Senger
D
D
Rewcastle
N B
NB
Morris
D G
DG
Brasher
P M
PM
Shi
Z Q
ZQ
Johnston
R N
RN
Nishikawa
S
S
Lee
P W
PW
Forsyth
P A
PA
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D005260:Female; D005910:Glioma / Q000473:pathology / Q000628:therapy* / Q000821:virology; D006801:Humans; D008297:Male; D012089:Mammalian orthoreovirus 3 / Q000302:isolation & purification / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D015996:Survival Rate; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured