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...
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Gespeichert in:

Autor*in:	Sam Illingworth [verfasserIn] Ying Di [verfasserIn] Maxine Bauzon [verfasserIn] Janet Lei [verfasserIn] Margaret R. Duffy [verfasserIn] Simon Alvis [verfasserIn] Brian Champion [verfasserIn] André Lieber [verfasserIn] Terry Hermiston [verfasserIn] Len W. Seymour [verfasserIn] John Beadle [verfasserIn] Kerry Fisher [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model

Übergeordnetes Werk:	In: Molecular Therapy: Oncolytics - Elsevier, 2016, 5(2017), C, Seite 62-74
Übergeordnetes Werk:	volume:5 ; year:2017 ; number:C ; pages:62-74

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.omto.2017.03.003

Katalog-ID:	DOAJ049842471

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520			\|a 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 × 1010 virus particles given on days 1, 3, and 5.
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allfields	10.1016/j.omto.2017.03.003 doi (DE-627)DOAJ049842471 (DE-599)DOAJa7c13d435d3b499f8c2068ee8f9375b9 DE-627 ger DE-627 rakwb eng RC254-282 Sam Illingworth verfasserin aut Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 × 1010 virus particles given on days 1, 3, and 5. enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ying Di verfasserin aut Maxine Bauzon verfasserin aut Janet Lei verfasserin aut Margaret R. Duffy verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut André Lieber verfasserin aut Terry Hermiston verfasserin aut Len W. Seymour verfasserin aut John Beadle verfasserin aut Kerry Fisher verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 5(2017), C, Seite 62-74 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:5 year:2017 number:C pages:62-74 https://doi.org/10.1016/j.omto.2017.03.003 kostenfrei https://doaj.org/article/a7c13d435d3b499f8c2068ee8f9375b9 kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770517300177 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2017 C 62-74
spelling	10.1016/j.omto.2017.03.003 doi (DE-627)DOAJ049842471 (DE-599)DOAJa7c13d435d3b499f8c2068ee8f9375b9 DE-627 ger DE-627 rakwb eng RC254-282 Sam Illingworth verfasserin aut Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 × 1010 virus particles given on days 1, 3, and 5. enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ying Di verfasserin aut Maxine Bauzon verfasserin aut Janet Lei verfasserin aut Margaret R. Duffy verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut André Lieber verfasserin aut Terry Hermiston verfasserin aut Len W. Seymour verfasserin aut John Beadle verfasserin aut Kerry Fisher verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 5(2017), C, Seite 62-74 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:5 year:2017 number:C pages:62-74 https://doi.org/10.1016/j.omto.2017.03.003 kostenfrei https://doaj.org/article/a7c13d435d3b499f8c2068ee8f9375b9 kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770517300177 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2017 C 62-74
allfields_unstemmed	10.1016/j.omto.2017.03.003 doi (DE-627)DOAJ049842471 (DE-599)DOAJa7c13d435d3b499f8c2068ee8f9375b9 DE-627 ger DE-627 rakwb eng RC254-282 Sam Illingworth verfasserin aut Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 × 1010 virus particles given on days 1, 3, and 5. enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ying Di verfasserin aut Maxine Bauzon verfasserin aut Janet Lei verfasserin aut Margaret R. Duffy verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut André Lieber verfasserin aut Terry Hermiston verfasserin aut Len W. Seymour verfasserin aut John Beadle verfasserin aut Kerry Fisher verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 5(2017), C, Seite 62-74 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:5 year:2017 number:C pages:62-74 https://doi.org/10.1016/j.omto.2017.03.003 kostenfrei https://doaj.org/article/a7c13d435d3b499f8c2068ee8f9375b9 kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770517300177 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2017 C 62-74
allfieldsGer	10.1016/j.omto.2017.03.003 doi (DE-627)DOAJ049842471 (DE-599)DOAJa7c13d435d3b499f8c2068ee8f9375b9 DE-627 ger DE-627 rakwb eng RC254-282 Sam Illingworth verfasserin aut Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 × 1010 virus particles given on days 1, 3, and 5. enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ying Di verfasserin aut Maxine Bauzon verfasserin aut Janet Lei verfasserin aut Margaret R. Duffy verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut André Lieber verfasserin aut Terry Hermiston verfasserin aut Len W. Seymour verfasserin aut John Beadle verfasserin aut Kerry Fisher verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 5(2017), C, Seite 62-74 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:5 year:2017 number:C pages:62-74 https://doi.org/10.1016/j.omto.2017.03.003 kostenfrei https://doaj.org/article/a7c13d435d3b499f8c2068ee8f9375b9 kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770517300177 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2017 C 62-74
allfieldsSound	10.1016/j.omto.2017.03.003 doi (DE-627)DOAJ049842471 (DE-599)DOAJa7c13d435d3b499f8c2068ee8f9375b9 DE-627 ger DE-627 rakwb eng RC254-282 Sam Illingworth verfasserin aut Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 × 1010 virus particles given on days 1, 3, and 5. enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ying Di verfasserin aut Maxine Bauzon verfasserin aut Janet Lei verfasserin aut Margaret R. Duffy verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut André Lieber verfasserin aut Terry Hermiston verfasserin aut Len W. Seymour verfasserin aut John Beadle verfasserin aut Kerry Fisher verfasserin aut In Molecular Therapy: Oncolytics Elsevier, 2016 5(2017), C, Seite 62-74 (DE-627)843857420 (DE-600)2842549-2 23727705 nnns volume:5 year:2017 number:C pages:62-74 https://doi.org/10.1016/j.omto.2017.03.003 kostenfrei https://doaj.org/article/a7c13d435d3b499f8c2068ee8f9375b9 kostenfrei http://www.sciencedirect.com/science/article/pii/S2372770517300177 kostenfrei https://doaj.org/toc/2372-7705 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 5 2017 C 62-74
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source	In Molecular Therapy: Oncolytics 5(2017), C, Seite 62-74 volume:5 year:2017 number:C pages:62-74
sourceStr	In Molecular Therapy: Oncolytics 5(2017), C, Seite 62-74 volume:5 year:2017 number:C pages:62-74
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topic_facet	enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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container_title	Molecular Therapy: Oncolytics
authorswithroles_txt_mv	Sam Illingworth @@aut@@ Ying Di @@aut@@ Maxine Bauzon @@aut@@ Janet Lei @@aut@@ Margaret R. Duffy @@aut@@ Simon Alvis @@aut@@ Brian Champion @@aut@@ André Lieber @@aut@@ Terry Hermiston @@aut@@ Len W. Seymour @@aut@@ John Beadle @@aut@@ Kerry Fisher @@aut@@
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callnumber-first	R - Medicine
author	Sam Illingworth
spellingShingle	Sam Illingworth misc RC254-282 misc enadenotucirev misc adenovirus misc oncolytic virotherapy misc preclinical model misc mouse model misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus
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topic_title	RC254-282 Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus enadenotucirev adenovirus oncolytic virotherapy preclinical model mouse model
topic	misc RC254-282 misc enadenotucirev misc adenovirus misc oncolytic virotherapy misc preclinical model misc mouse model misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc enadenotucirev misc adenovirus misc oncolytic virotherapy misc preclinical model misc mouse model misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus
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title_full	Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus
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title_sort	preclinical safety studies of enadenotucirev, a chimeric group b human-specific oncolytic adenovirus
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title_auth	Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus
abstract	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 × 1010 virus particles given on days 1, 3, and 5.
abstractGer	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 × 1010 virus particles given on days 1, 3, and 5.
abstract_unstemmed	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 × 1010 virus particles given on days 1, 3, and 5.
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title_short	Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus
url	https://doi.org/10.1016/j.omto.2017.03.003 https://doaj.org/article/a7c13d435d3b499f8c2068ee8f9375b9 http://www.sciencedirect.com/science/article/pii/S2372770517300177 https://doaj.org/toc/2372-7705
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