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Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus
Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic canc...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415321/ https://www.ncbi.nlm.nih.gov/pubmed/28480328 http://dx.doi.org/10.1016/j.omto.2017.03.003 |
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author | Illingworth, Sam Di, Ying Bauzon, Maxine Lei, Janet Duffy, Margaret R. Alvis, Simon Champion, Brian Lieber, André Hermiston, Terry Seymour, Len W. Beadle, John Fisher, Kerry |
author_facet | Illingworth, Sam Di, Ying Bauzon, Maxine Lei, Janet Duffy, Margaret R. Alvis, Simon Champion, Brian Lieber, André Hermiston, Terry Seymour, Len W. Beadle, John Fisher, Kerry |
author_sort | Illingworth, Sam |
collection | PubMed |
description | Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 10(10) virus particles given on days 1, 3, and 5. |
format | Online Article Text |
id | pubmed-5415321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-54153212017-05-05 Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus Illingworth, Sam Di, Ying Bauzon, Maxine Lei, Janet Duffy, Margaret R. Alvis, Simon Champion, Brian Lieber, André Hermiston, Terry Seymour, Len W. Beadle, John Fisher, Kerry Mol Ther Oncolytics Original Article Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 10(10) virus particles given on days 1, 3, and 5. American Society of Gene & Cell Therapy 2017-03-29 /pmc/articles/PMC5415321/ /pubmed/28480328 http://dx.doi.org/10.1016/j.omto.2017.03.003 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Illingworth, Sam Di, Ying Bauzon, Maxine Lei, Janet Duffy, Margaret R. Alvis, Simon Champion, Brian Lieber, André Hermiston, Terry Seymour, Len W. Beadle, John Fisher, Kerry Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus |
title | Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus |
title_full | Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus |
title_fullStr | Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus |
title_full_unstemmed | Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus |
title_short | Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus |
title_sort | preclinical safety studies of enadenotucirev, a chimeric group b human-specific oncolytic adenovirus |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415321/ https://www.ncbi.nlm.nih.gov/pubmed/28480328 http://dx.doi.org/10.1016/j.omto.2017.03.003 |
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