Combinatorial treatment with oncolytic adenovirus and helper-dependent adenovirus augments adenoviral cancer gene therapy

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http://hdl.handle.net/10138/253104

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Farzad , L , Cerullo , V , Yagyu , S , Bertin , T , Hemminki , A , Rooney , C , Lee , B & Suzuki , M 2014 , ' Combinatorial treatment with oncolytic adenovirus and helper-dependent adenovirus augments adenoviral cancer gene therapy ' , Molecular Therapy - Oncolytics , vol. 1 , 14008 . https://doi.org/10.1038/mto.2014.8

Title: Combinatorial treatment with oncolytic adenovirus and helper-dependent adenovirus augments adenoviral cancer gene therapy
Author: Farzad, Lisa; Cerullo, Vincenzo; Yagyu, Shigeki; Bertin, Terry; Hemminki, Akseli; Rooney, Cliona; Lee, Brendan; Suzuki, Masataka
Contributor organization: Faculty of Pharmacy
ImmunoViroTherapy Lab
Division of Pharmaceutical Biosciences
Medicum
University of Helsinki
Clinicum
Akseli Eetu Hemminki / Principal Investigator
Transplantation Laboratory
Department of Pathology
Department of Oncology
Date: 2014
Language: eng
Number of pages: 9
Belongs to series: Molecular Therapy - Oncolytics
ISSN: 2372-7705
DOI: https://doi.org/10.1038/mto.2014.8
URI: http://hdl.handle.net/10138/253104
Abstract: Oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Investigators have therefore incorporated sequences into these vectors that encode immunomodulatory molecules to enhance antitumor immunity. Successful implementation of this strategy requires multiple tumor immune inhibitory mechanisms to be overcome, and insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. HDAds, however, lack replicative capacity. Since HDAds encode the adenoviral packaging signal, we hypothesized that the coadministration of Onc.Ad with HDAd would allow to be amplified and packaged during replication of Onc.Ad in transduced cancer cells. This combination could provide immunostimulation without losing oncolytic activity. We now show that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy.
Subject: 3122 Cancers
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by_nc_sa
Usage restriction: openAccess
Self-archived version: publishedVersion


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