Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models

Improving the antitumor potency of current oncolytic adenoviruses represents one of the major challenges in development of these viruses for clinical use. We have generated an oncolytic adenovirus carrying the safety-enhancing E1A Delta 24 deletion, the potency-enhancing T1 mutation, and the infecti...

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Autores: Dong, Wenliang, van Ginkel, Jan-Willem H., Au, Kam Y., Alemany Bonastre, Ramon, Meulenberg, Janneke J. M., van Beusechem, Victor W.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/126299
Acceso en línea:https://hdl.handle.net/2445/126299
Access Level:acceso abierto
Palabra clave:Adenovirus
Virus oncogènics
Adenoviruses
Oncogenic viruses
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spelling Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical ModelsDong, Wenliangvan Ginkel, Jan-Willem H.Au, Kam Y.Alemany Bonastre, RamonMeulenberg, Janneke J. M.van Beusechem, Victor W.AdenovirusVirus oncogènicsAdenovirusesOncogenic virusesImproving the antitumor potency of current oncolytic adenoviruses represents one of the major challenges in development of these viruses for clinical use. We have generated an oncolytic adenovirus carrying the safety-enhancing E1A Delta 24 deletion, the potency-enhancing T1 mutation, and the infectivity-enhancing fiber RGD modification. The results of in vitro cytotoxicity assays on 15 human cancer cell lines derived from different tumor types demonstrated that ORCA-010 is more potent than Ad5-Delta 24RGD or ONYX-015. As ORCA-010 will initially be developed for the treatment of prostate cancer, selectivity experiments were performed using primary human prostate cells. ORCA-010 killed cancer cells more effectively than these primary human cells. In both primary prostate fibroblasts and epithelial cells, ORCA-010 was as safe as Ad5-Delta 24RGD. Evaluation of ORCA-010 in in vivo xenograft tumor models in nude mice showed that ORCA-010 significantly inhibited growth of prostate, lung, and ovarian tumors and conferred prolonged survival of tumor-bearing animals. Furthermore, we observed a substantial increase in infectious viral particles in tumors injected with ORCA-010. The number of infectious viral particles increased after treatment and infectious particles remained present up to at least 4 weeks posttreatment. Intratumoral virus replication was associated with substantial necrosis and fibrosis. In conclusion, ORCA-010 is more potent than earlier generation oncolytic adenoviruses, without demonstrating increased toxicity. ORCA-010 exerted strong in vivo antitumor activity and is therefore a suitable candidate for clinical evaluation.Mary Ann Liebert, Inc2018201820142018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion8 p.application/pdfhttps://hdl.handle.net/2445/126299Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1089/hum.2013.229Human Gene Therapy, 2014, vol. 25, num. 10, p. 897-904https://doi.org/10.1089/hum.2013.229(c) Mary Ann Liebert, Inc., 2014info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1262992026-05-29T05:05:01Z
dc.title.none.fl_str_mv Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
title Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
spellingShingle Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
Dong, Wenliang
Adenovirus
Virus oncogènics
Adenoviruses
Oncogenic viruses
title_short Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
title_full Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
title_fullStr Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
title_full_unstemmed Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
title_sort Orca-010, a Novel Potency-enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models
dc.creator.none.fl_str_mv Dong, Wenliang
van Ginkel, Jan-Willem H.
Au, Kam Y.
Alemany Bonastre, Ramon
Meulenberg, Janneke J. M.
van Beusechem, Victor W.
author Dong, Wenliang
author_facet Dong, Wenliang
van Ginkel, Jan-Willem H.
Au, Kam Y.
Alemany Bonastre, Ramon
Meulenberg, Janneke J. M.
van Beusechem, Victor W.
author_role author
author2 van Ginkel, Jan-Willem H.
Au, Kam Y.
Alemany Bonastre, Ramon
Meulenberg, Janneke J. M.
van Beusechem, Victor W.
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Adenovirus
Virus oncogènics
Adenoviruses
Oncogenic viruses
topic Adenovirus
Virus oncogènics
Adenoviruses
Oncogenic viruses
description Improving the antitumor potency of current oncolytic adenoviruses represents one of the major challenges in development of these viruses for clinical use. We have generated an oncolytic adenovirus carrying the safety-enhancing E1A Delta 24 deletion, the potency-enhancing T1 mutation, and the infectivity-enhancing fiber RGD modification. The results of in vitro cytotoxicity assays on 15 human cancer cell lines derived from different tumor types demonstrated that ORCA-010 is more potent than Ad5-Delta 24RGD or ONYX-015. As ORCA-010 will initially be developed for the treatment of prostate cancer, selectivity experiments were performed using primary human prostate cells. ORCA-010 killed cancer cells more effectively than these primary human cells. In both primary prostate fibroblasts and epithelial cells, ORCA-010 was as safe as Ad5-Delta 24RGD. Evaluation of ORCA-010 in in vivo xenograft tumor models in nude mice showed that ORCA-010 significantly inhibited growth of prostate, lung, and ovarian tumors and conferred prolonged survival of tumor-bearing animals. Furthermore, we observed a substantial increase in infectious viral particles in tumors injected with ORCA-010. The number of infectious viral particles increased after treatment and infectious particles remained present up to at least 4 weeks posttreatment. Intratumoral virus replication was associated with substantial necrosis and fibrosis. In conclusion, ORCA-010 is more potent than earlier generation oncolytic adenoviruses, without demonstrating increased toxicity. ORCA-010 exerted strong in vivo antitumor activity and is therefore a suitable candidate for clinical evaluation.
publishDate 2014
dc.date.none.fl_str_mv 2014
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/126299
url https://hdl.handle.net/2445/126299
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1089/hum.2013.229
Human Gene Therapy, 2014, vol. 25, num. 10, p. 897-904
https://doi.org/10.1089/hum.2013.229
dc.rights.none.fl_str_mv (c) Mary Ann Liebert, Inc., 2014
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Mary Ann Liebert, Inc., 2014
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 8 p.
application/pdf
dc.publisher.none.fl_str_mv Mary Ann Liebert, Inc
publisher.none.fl_str_mv Mary Ann Liebert, Inc
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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