title: Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4.
abstract: There is a need for novel therapies targeting hypoxic cells in tumors. These cells are associated with tumor resistance to therapy and express hypoxia inducible factor-1 (HIF-1), a transcription factor that mediates metabolic adaptation to hypoxia and activates tumor angiogenesis. We previously developed an oncolytic adenovirus (HYPR-Ad) for the specific killing of hypoxic/HIF-active tumor cells, which we now armed with an interleukin-4 gene (HYPR-Ad-IL4). We designed HYPR-Ad-IL4 by cloning the Ad E1A viral replication and IL-4 genes under the regulation of a bidirectional hypoxia/HIF-responsive promoter. The IL-4 cytokine was chosen for its ability to induce a strong host antitumor immune response and its potential antiangiogenic activity. HYPR-Ad-IL4 induced hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic, but not normoxic cells. The treatment of established human tumor xenografts with HYPR-Ad-IL4 resulted in rapid and maintained tumor regression with the same potency as that of wild-type dl309-Ad. HYPR-Ad-IL4-treated tumors displayed extensive necrosis, fibrosis, and widespread viral replication. Additionally, these tumors contained a distinctive leukocyte infiltrate and prominent hypoxia. The use of an oncolytic Ad that locally delivers IL-4 to tumors is novel, and we expect that HYPR-Ad-IL4 will have broad therapeutic use for all solid tumors that have hypoxia or active HIF, regardless of tissue origin or genetic alterations.
authors.affiliation: Department of Neurosurgery, Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA. postd@upstate.ede
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Post
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sandberg
authors.forename: Michele M
authors.initials: MM
authors.lastname: Kyle
authors.forename: Narra Sarojini
authors.initials: NS
authors.lastname: Devi
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Xu
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003001:Cloning, Molecular; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D015847:Interleukin-4