An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factor-enhanced cancer selectivity and enhanced oncolytic potency.
Oncolytic adenoviruses hold promise as a new treatment platform for cancer, but limitations have been identified, including limited spread and potency. The adenoviral protein E1B-19 kDa is a Bcl-2 homologue that blocks apoptosis induction via the intrinsic and extrinsic pathways, specifically including tumor necrosis factor-mediated cell death. We demonstrate that an E1B-19 kDa gene deletion mutant had tumor necrosis factor-enhanced cancer selectivity, in vitro and in vivo, due to genetic blocks in apoptosis pathways in cancer cells. In addition, this mutant demonstrated significantly enhanced viral spread and antitumoral potency relative to dl1520 (aka Onyx-015) and wild-type adenovirus in vitro. Significant antitumoral efficacy was demonstrated in vivo by intratumoral and intravenous routes of administration. E1B-19 kDa deletion should be considered as a feature of oncolytic adenoviruses to enhance their safety, spread, and efficacy.
Liu
Ta-Chiang
TC
Viral and Genetic Therapy Program, Cancer Research UK, Imperial College Faculty of Medicine, London, UK.
Hallden
Gunnel
G
Wang
Yaohe
Y
Brooks
Gabriel
G
Francis
Jennelle
J
Lemoine
Nick
N
Kirn
David
D
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D017353:Gene Deletion; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D014775:Virus Activation / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D014409:Tumor Necrosis Factor-alpha; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases