Targeting interferon-alpha increases antitumor efficacy and reduces hepatotoxicity of E1A-mutated spread-enhanced oncolytic adenovirus.
Novel approaches are needed to improve the antitumor potency and to increase the cancer specificity of oncolytic adenoviruses (Ad). We hypothesized that the combination of interferon-alpha (IFN-alpha) expression with a specific mutation in the e1a gene of Ad could target vector replication to genetic defects in the IFN-alpha pathway resulting in both improved antitumor efficacy and reduced toxicity. The conditionally replicative Ad vector KD3-IFN carries the dl1101/1107 mutation in the e1a gene that eliminates binding of E1A proteins to p300/CBP and pRb. KD3-IFN expresses human IFN-alpha in concurrence with vector replication and overexpresses the adenovirus death protein (ADP; E3-11.6K). The antitumor activity of KD3-IFN was significantly higher than that of a control vector in established human hepatocellular carcinoma tumors in immunodeficient mice and in hamster kidney cancer tumors in immunocompetent Syrian hamsters. The dl1101/1107 mutation rendered Ad replication sensitive to the antiviral effect of IFN-alpha in normal as opposed to cancer cells. These results translated to reduced vector toxicity upon systemic administration to C57BL/6 mice. The combination of Ad oncolysis, ADP overexpression, and IFN-alpha-mediated immunotherapy represents a three-pronged approach for increasing the anticancer efficacy of replicative Ads. Exploiting the dl1101/1107 mutation provides a mechanism for additional selectivity of IFN-alpha-expressing replication-competent Ads.
Shashkova
Elena V
EV
VirRx Inc., St. Louis, Missouri, USA.
Spencer
Jacqueline F
JF
Wold
William S M
WS
Doronin
Konstantin
K
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D016679:Genome, Viral / Q000235:genetics; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D050504:Oncolytic Viruses / Q000235:genetics*; D015996:Survival Rate; D013997:Time Factors; D019076:Transgenes / Q000235:genetics; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D016898:Interferon-alpha