Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.
Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.
Stojdl
D F
DF
Ottawa Regional Cancer Centre Research Laboratories, 501, Smyth Road, Ottawa, ON, Canada.
Lichty
B
B
Knowles
S
S
Marius
R
R
Atkins
H
H
Sonenberg
N
N
Bell
J C
JC
D000818:Animals; D001853:Bone Marrow / Q000821:virology; D003588:Cytopathogenic Effect, Viral; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000821:virology; D008546:Melanoma, Experimental / Q000628:therapy / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy* / Q000821:virology*; D014407:Tumor Cells, Cultured / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000472:pathogenicity*