Second-generation HIF-activated oncolytic adenoviruses with improved replication, oncolytic, and antitumor efficacy.
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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Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, Syracuse, NY 13210, USA.
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Tovar-Spinoza
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D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods* / Q000592:standards; D005822:Genetic Vectors / Q000235:genetics / Q000592:standards*; D057809:HEK293 Cells; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000628:therapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D057074:Virus Release; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D015847:Interleukin-4