Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity.
Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. However, the host immune system remains a significant obstacle to effective systemic administration of virus in a clinical setting. Here, we demonstrate the severe negative impact of the adaptive immune response on the systemic delivery of oncolytic vesicular stomatitis virus (VSV) in an immune-competent murine tumor model, an effect mediated primarily by the neutralization of injected virions by circulating antibodies. We show that this obstacle can be overcome by administering virus within carrier cells that conceal viral antigen during delivery. Infected cells were delivered to tumor beds and released virus to infect malignant cells while sparing normal tissues. Repeated administration of VSV in carrier cells to animals bearing metastatic tumors greatly improved therapeutic efficacy when compared with naked virion injection. Whole-body molecular imaging revealed that carrier cells derived from solid tumors accumulate primarily in the lungs following intravenous injection, whereas leukemic carriers disseminate extensively throughout the body. Furthermore, xenogeneic cells were equally effective at delivering virus as syngeneic cells. These findings emphasize the importance of establishing cell-based delivery platforms in order to maximize the efficacy of oncolytic therapeutics.
Power
Anthony T
AT
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa Health Research Institute, Centre for Cancer Therapeutics, Ottawa, Ontario, Canada.
Wang
Jiahu
J
Falls
Theresa J
TJ
Paterson
Jennifer M
JM
Parato
Kelley A
KA
Lichty
Brian D
BD
Stojdl
David F
DF
Forsyth
Peter A J
PA
Atkins
Harry
H
Bell
John C
JC
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy / Q000821:virology; D050504:Oncolytic Viruses / Q000276:immunology*; D015996:Survival Rate; D019076:Transgenes / Q000235:genetics*; D018116:Vesiculovirus / Q000276:immunology
D000914:Antibodies, Viral