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

Departments of ¹ Neurosurgery, ² Pathology, ³ Hematology/Oncology, and ⁴ Biostatistics Research and Informatics, ⁵ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, and Departments of ⁶ Neurosurgery and ⁷ Microbiology & Immunology, State University of New York Upstate Medical University, Syracuse, New York

Requests for reprints: Dawn E. Post or Erwin G. Van Meir, Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Winship Cancer Institute, 1365C Clifton Rd., N.E., Emory University, Atlanta, GA 30322. Phone: 404-778-5563; Fax: 404-778-5550; E-mail: postd{at}upstate.edu or evanmei{at}emory.edu.

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. [Cancer Res 2007;67(14):6872–81]

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				Correction: Oncolytic and Gene Therapy Using HYPR-Ad-IL4 Cancer Res., September 1, 2007; 67(17): 8422 - 8423. [Full Text] [PDF]