VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents.
Ideally, an oncolytic virus will replicate preferentially in malignant cells, have the ability to treat disseminated metastases, and ultimately be cleared by the patient. Here we present evidence that the attenuated vesicular stomatitis strains, AV1 and AV2, embody all of these traits. We uncover the mechanism by which these mutants are selectively attenuated in interferon-responsive cells while remaining highly lytic in 80% of human tumor cell lines tested. AV1 and AV2 were tested in a xenograft model of human ovarian cancer and in an immune competent mouse model of metastatic colon cancer. While highly attenuated for growth in normal mice, both AV1 and AV2 effected complete and durable cures in the majority of treated animals when delivered systemically.
Stojdl
David F
DF
Ottawa Regional Cancer Centre Research Laboratories, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
Lichty
Brian D
BD
tenOever
Benjamin R
BR
Paterson
Jennifer M
JM
Power
Anthony T
AT
Knowles
Shane
S
Marius
Ricardo
R
Reynard
Jennifer
J
Poliquin
Laurent
L
Atkins
Harold
H
Brown
Earl G
EG
Durbin
Russell K
RK
Durbin
Joan E
JE
Hiscott
John
J
Bell
John C
JC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D003110:Colonic Neoplasms / Q000628:therapy / Q000821:virology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology / Q000502:physiology*; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000628:therapy / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009374:Neoplasms, Experimental / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000628:therapy / Q000821:virology; D015398:Signal Transduction; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
C094460:M protein, Vesicular stomatitis virus; D014763:Viral Matrix Proteins; D016899:Interferon-beta