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Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer

BACKGROUND: Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fa...

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Autores principales: Kuhn, Irene, Harden, Paul, Bauzon, Maxine, Chartier, Cecile, Nye, Julie, Thorne, Steve, Reid, Tony, Ni, Shaoheng, Lieber, Andre, Fisher, Kerry, Seymour, Len, Rubanyi, Gabor M., Harkins, Richard N., Hermiston, Terry W.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423470/
https://www.ncbi.nlm.nih.gov/pubmed/18560559
http://dx.doi.org/10.1371/journal.pone.0002409
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author Kuhn, Irene
Harden, Paul
Bauzon, Maxine
Chartier, Cecile
Nye, Julie
Thorne, Steve
Reid, Tony
Ni, Shaoheng
Lieber, Andre
Fisher, Kerry
Seymour, Len
Rubanyi, Gabor M.
Harkins, Richard N.
Hermiston, Terry W.
author_facet Kuhn, Irene
Harden, Paul
Bauzon, Maxine
Chartier, Cecile
Nye, Julie
Thorne, Steve
Reid, Tony
Ni, Shaoheng
Lieber, Andre
Fisher, Kerry
Seymour, Len
Rubanyi, Gabor M.
Harkins, Richard N.
Hermiston, Terry W.
author_sort Kuhn, Irene
collection PubMed
description BACKGROUND: Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term “Directed Evolution” for creating highly potent oncolytic viruses. METHODOLOGY/PRINCIPAL FINDINGS: Taking the “Directed Evolution” approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2–3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. CONCLUSIONS/SIGNIFICANCE: Using the “Directed Evolution” methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a >2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies.
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spelling pubmed-24234702008-06-18 Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer Kuhn, Irene Harden, Paul Bauzon, Maxine Chartier, Cecile Nye, Julie Thorne, Steve Reid, Tony Ni, Shaoheng Lieber, Andre Fisher, Kerry Seymour, Len Rubanyi, Gabor M. Harkins, Richard N. Hermiston, Terry W. PLoS One Research Article BACKGROUND: Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term “Directed Evolution” for creating highly potent oncolytic viruses. METHODOLOGY/PRINCIPAL FINDINGS: Taking the “Directed Evolution” approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2–3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. CONCLUSIONS/SIGNIFICANCE: Using the “Directed Evolution” methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a >2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies. Public Library of Science 2008-06-18 /pmc/articles/PMC2423470/ /pubmed/18560559 http://dx.doi.org/10.1371/journal.pone.0002409 Text en Kuhn et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kuhn, Irene
Harden, Paul
Bauzon, Maxine
Chartier, Cecile
Nye, Julie
Thorne, Steve
Reid, Tony
Ni, Shaoheng
Lieber, Andre
Fisher, Kerry
Seymour, Len
Rubanyi, Gabor M.
Harkins, Richard N.
Hermiston, Terry W.
Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer
title Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer
title_full Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer
title_fullStr Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer
title_full_unstemmed Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer
title_short Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer
title_sort directed evolution generates a novel oncolytic virus for the treatment of colon cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423470/
https://www.ncbi.nlm.nih.gov/pubmed/18560559
http://dx.doi.org/10.1371/journal.pone.0002409
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