Expanded anticancer therapeutic window of hexon-modified oncolytic adenovirus.
One of the significant hurdles toward safe and efficacious systemic treatment of cancer with oncolytic adenoviruses (Ads) is dose-limiting hepatotoxicity that prevents the increase of a therapeutic dose. In this study, we expanded the therapeutic window of oncolytic serotype 5 Ad (Ad5) by a genetic modification of hypervariable loop 5 (HVR5) in the capsid protein hexon that prevented infection of hepatocytes due to ablation of binding to blood factors. This oncolytic virus, Ad-GL-HB, had significantly reduced levels of hepatocyte transduction in immunocompetent and immunodeficient mice as compared to parental virus Ad-GL. The hepatocyte detargeting decreased liver damage and increased the maximum tolerated dose of Ad-GL-HB tenfold relative to that of Ad-GL. Intravenous (i.v.) injection of Ad-GL or Ad-GL-HB into tumor-bearing mice produced equally increased survival rates demonstrating that while Ad-GL-HB detargeted hepatocytes, it sustained tumor cell infection after systemic administration. The significantly improved safety of the virus allowed it to be used at increased doses for improved systemic antitumor efficacy. Our results suggest that hexon modifications provide valuable strategies for systemic oncolytic Ad therapy.
Shashkova
Elena V
EV
Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
May
Shannon M
SM
Doronin
Konstantin
K
Barry
Michael A
MA
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics*; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D049449:Luminescence; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D014161:Transduction, Genetic
D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus