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1.  Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4 
Cancer research  2007;67(14):6872-6881.
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.
PMCID: PMC2262867  PMID: 17638898
2.  Development of an oncolytic Herpes Simplex Virus using a tumor-specific HIF-responsive promoter 
Cancer gene therapy  2010;18(2):123-134.
We exploited the differential activation of hypoxia-inducible factor (HIF)-dependent gene expression in tumors versus normal tissue for the design of a targeted oncolytic Herpes simplex virus type-1 (HSV-1). A gene that is essential for viral replication, ICP4, was placed under the regulation of a HIF-responsive promoter and then introduced into the thymidine kinase locus (UL23) of HSV d120 which contains partial deletions in the two endogenous ICP4 genes. Recombinant HIF-HSV were isolated and their derivation from d120 was verified by expression of a truncated, nonfunctional form of ICP4 protein. Disruption of the UL23 locus was confirmed by loss of thymidine kinase expression and resistance to acyclovir. Unexpectedly, HIF-HSV expressed ICP4 and induced tumor cell lysis at similar levels under normoxia and hypoxia. The lack of HIF-dependent ICP4 transgene expression by HIF-HSV was due to two factors that have not previously been reported- reversion of the ICP4 gene region to its wild-type configuration and increased HIF-transcriptional activity under normoxia when cells were infected with any strain of HSV-1. The findings that an oncolytic HSV-1 is genetically unstable and can activate a tumor-related promoter in a non-specific manner have important implications for any proposed use of this virus in cancer therapy.
PMCID: PMC3021095  PMID: 20930860
hypoxia; hypoxia-inducible factor (HIF); herpes simplex virus; HSV; oncolytic; ICP4
3.  Second-generation HIF-activated oncolytic adenoviruses with improved replication, oncolytic, and anti-tumor efficacy 
Gene therapy  2010;17(12):1430-1441.
There is a need to develop more potent oncolytic adenoviruses that exhibit increased anti-tumor activity in patients. The HYPR-Ads are targeted oncolytic adenoviruses that specifically kill tumor cells which express active hypoxia-inducible factor (HIF). While therapeutically efficacious, the HYPR-Ads exhibited attenuated replication and oncolytic activity. To overcome these deficiencies and improve anti-tumor 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 demonstrated conditional activation of E1A expression under hypoxia. Importantly, the HIF-Ads exhibit hypoxia-dependent replication, oncolytic, and cellular release activities and potent anti-tumor efficacy, all of which are significantly greater than 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 anti-tumor efficacy that is up to 6-fold greater than the HYPR-Ads, HIF-Ad, and wild-type adenovirus treatment. These studies demonstrate that treatment with a HIF-activated oncolytic adenovirus leads to a measurable therapeutic response. The novel design of the HIF-Ads represents a significant improvement compared to first-generation oncolytic Ads and has great potential to increase the efficacy of this cancer therapy.
PMCID: PMC2978277  PMID: 20664541
hypoxia; hypoxia-inducible factor (HIF); adenovirus; tumor; oncolytic; virotherapy; interleukin-4

Results 1-3 (3)