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

Abstract

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.

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Abbreviations

HIF:

hypoxia-inducible factor

IL-4:

interleukin-4

MOI:

multiplicity of infection

LDH:

lactate dehydrogenase

CPE:

cytopathic effect

IFUs:

infectious forming units

dpi:

days post infection

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Acknowledgements

We thank Michele Kyle, Amanda Magee and David Padalino for technical assistance with the animal tumor studies, and Ed Shillitoe and Richard Cross for critical reading of the manuscript. Grant support to DEP was provided by NIH (NS49300).

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Correspondence to D E Post.

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Competing interests

Dawn Post is a co-inventor on intellectual property that relates to this work. Title of patent: Viruses targeted to hypoxic cells and tissues. Patent numbers: US 7,285,414, European 1328291, Australian 2001-294793, Canadian 2,423,833, and Japanese 2002-530023.

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Cherry, T., Longo, S., Tovar-Spinoza, Z. et al. Second-generation HIF-activated oncolytic adenoviruses with improved replication, oncolytic, and antitumor efficacy. Gene Ther 17, 1430–1441 (2010). https://doi.org/10.1038/gt.2010.100

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