Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4

• Authors: Dawn E. Post, Emory University; Eric M. Sandberg, Emory University; Michele M. Kyle, State University of New York Upstate Medical University; Narra Sarojini Devi, Emory University; Daniel J Brat, Emory University; Zhiheng Xu, Emory University; Mourad Tighiouart, Emory University; Erwin Van Meir, Emory University
• Journal Title: Cancer Research
• Volume: Volume 67, Number 14
• Publisher: American Association for Cancer Research | 2007-07-15, Pages 6872-6881
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/0008-5472.CAN-06-3244
• Subjects: Health Sciences, Pathology

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.