Second-generation HIF-activated oncolytic adenoviruses with improved replication, oncolytic, and antitumor efficacy

Gene Ther. 2010 Dec;17(12):1430-41. doi: 10.1038/gt.2010.100. Epub 2010 Jul 22.


There is a need to develop more potent oncolytic adenoviruses (Ads) that show increased antitumor activity in patients. The HYPR-Ads are targeted oncolytic Ads that specifically kill tumor cells, which express active hypoxia-inducible factor (HIF). While therapeutically efficacious, the HYPR-Ads showed attenuated replication and oncolytic activity. To overcome these deficiencies and improve antitumor efficacy, we created new HIF-activated oncolytic Ads, HIF-Ad and HIF-Ad-IL4, which have two key changes: (i) a modified HIF-responsive promoter to regulate the E1A replication gene and (ii) insertion of the E3 gene region. The HIF-Ads showed conditional activation of E1A expression under hypoxia. Importantly, the HIF-Ads show hypoxia-dependent replication, oncolytic and cellular release activities, and potent antitumor efficacy, all of which are significantly greater than that of the HYPR-Ads. Notably, HIF-Ad-IL4 treatment led to regressions in tumor size by 70% and extensive tumor infiltration by leukocytes resulting in an antitumor efficacy that is up to six-fold greater than that of the HYPR-Ads, HIF-Ad and wild-type Ad treatment. These studies show that treatment with an HIF-activated oncolytic Ad leads to a measurable therapeutic response. The novel design of the HIF-Ads represents a significant improvement compared with first-generation oncolytic Ads and has great potential to increase the efficacy of this cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / physiology*
  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / metabolism
  • Antineoplastic Agents / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Hypoxia / physiology
  • Gene Expression Regulation*
  • Genetic Therapy / methods*
  • Genetic Therapy / standards
  • Genetic Vectors / genetics
  • Genetic Vectors / standards*
  • HEK293 Cells
  • Humans
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Neoplasms / therapy
  • Oncolytic Viruses / genetics
  • Oncolytic Viruses / physiology
  • Tumor Cells, Cultured
  • Virus Release
  • Virus Replication*


  • Adenovirus E1A Proteins
  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Interleukin-4