A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma

Autores
Sangro, B.; Mazzolini Rizzo, Guillermo Daniel; Ruiz, M.; Ruiz, J.; Quiroga, J.; Herrero, I.; Qian, C.; Benito, A.; Larrache, J.; Olagüe, C.; Boan, J.; Peñuelas, I.; Sádaba, B.; Prieto, J.
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10 10 to 2 × 10 12 viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 10 12 vp per patient.
Fil: Sangro, B.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Clinica Universitaria de Navarra; España
Fil: Ruiz, M.. Clinica Universitaria de Navarra; España
Fil: Ruiz, J.. Center For Biomedical Research; España
Fil: Quiroga, J.. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España. Clinica Universitaria de Navarra; España
Fil: Herrero, I.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España
Fil: Qian, C.. Center For Biomedical Research; España
Fil: Benito, A.. Clinica Universitaria de Navarra; España
Fil: Larrache, J.. Clinica Universitaria de Navarra; España
Fil: Olagüe, C.. Center For Biomedical Research; España
Fil: Boan, J.. Center For Biomedical Research; España
Fil: Peñuelas, I.. Clinica Universitaria de Navarra; España
Fil: Sádaba, B.. Clinica Universitaria de Navarra; España
Fil: Prieto, J.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España
Materia
Thymidine kinase
Hepatocellular carcinoma
Gene therapy
Phase I
Adenovirus
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/96178
Acceder
id CONICETDig_28ad0fe42f776221226ac4c18b0b6281
oai_identifier_str oai:ri.conicet.gov.ar:11336/96178
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinomaSangro, B.Mazzolini Rizzo, Guillermo DanielRuiz, M.Ruiz, J.Quiroga, J.Herrero, I.Qian, C.Benito, A.Larrache, J.Olagüe, C.Boan, J.Peñuelas, I.Sádaba, B.Prieto, J.Thymidine kinaseHepatocellular carcinomaGene therapyPhase IAdenovirushttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10 10 to 2 × 10 12 viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 10 12 vp per patient.Fil: Sangro, B.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Clinica Universitaria de Navarra; EspañaFil: Ruiz, M.. Clinica Universitaria de Navarra; EspañaFil: Ruiz, J.. Center For Biomedical Research; EspañaFil: Quiroga, J.. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España. Clinica Universitaria de Navarra; EspañaFil: Herrero, I.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Qian, C.. Center For Biomedical Research; EspañaFil: Benito, A.. Clinica Universitaria de Navarra; EspañaFil: Larrache, J.. Clinica Universitaria de Navarra; EspañaFil: Olagüe, C.. Center For Biomedical Research; EspañaFil: Boan, J.. Center For Biomedical Research; EspañaFil: Peñuelas, I.. Clinica Universitaria de Navarra; EspañaFil: Sádaba, B.. Clinica Universitaria de Navarra; EspañaFil: Prieto, J.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; EspañaNature Publishing Group2010-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/96178Sangro, B.; Mazzolini Rizzo, Guillermo Daniel; Ruiz, M.; Ruiz, J.; Quiroga, J.; et al.; A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma; Nature Publishing Group; Cancer Gene Therapy; 17; 12; 12-2010; 837-8430929-1903CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/cgt.2010.40info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/cgt201040info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-05T10:36:47Zoai:ri.conicet.gov.ar:11336/96178instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-11-05 10:36:47.834CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
title A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
spellingShingle A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
Sangro, B.
Thymidine kinase
Hepatocellular carcinoma
Gene therapy
Phase I
Adenovirus
title_short A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
title_full A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
title_fullStr A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
title_full_unstemmed A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
title_sort A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma
dc.creator.none.fl_str_mv Sangro, B.
Mazzolini Rizzo, Guillermo Daniel
Ruiz, M.
Ruiz, J.
Quiroga, J.
Herrero, I.
Qian, C.
Benito, A.
Larrache, J.
Olagüe, C.
Boan, J.
Peñuelas, I.
Sádaba, B.
Prieto, J.
author Sangro, B.
author_facet Sangro, B.
Mazzolini Rizzo, Guillermo Daniel
Ruiz, M.
Ruiz, J.
Quiroga, J.
Herrero, I.
Qian, C.
Benito, A.
Larrache, J.
Olagüe, C.
Boan, J.
Peñuelas, I.
Sádaba, B.
Prieto, J.
author_role author
author2 Mazzolini Rizzo, Guillermo Daniel
Ruiz, M.
Ruiz, J.
Quiroga, J.
Herrero, I.
Qian, C.
Benito, A.
Larrache, J.
Olagüe, C.
Boan, J.
Peñuelas, I.
Sádaba, B.
Prieto, J.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Thymidine kinase
Hepatocellular carcinoma
Gene therapy
Phase I
Adenovirus
topic Thymidine kinase
Hepatocellular carcinoma
Gene therapy
Phase I
Adenovirus
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10 10 to 2 × 10 12 viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 10 12 vp per patient.
Fil: Sangro, B.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Clinica Universitaria de Navarra; España
Fil: Ruiz, M.. Clinica Universitaria de Navarra; España
Fil: Ruiz, J.. Center For Biomedical Research; España
Fil: Quiroga, J.. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España. Clinica Universitaria de Navarra; España
Fil: Herrero, I.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España
Fil: Qian, C.. Center For Biomedical Research; España
Fil: Benito, A.. Clinica Universitaria de Navarra; España
Fil: Larrache, J.. Clinica Universitaria de Navarra; España
Fil: Olagüe, C.. Center For Biomedical Research; España
Fil: Boan, J.. Center For Biomedical Research; España
Fil: Peñuelas, I.. Clinica Universitaria de Navarra; España
Fil: Sádaba, B.. Clinica Universitaria de Navarra; España
Fil: Prieto, J.. Clinica Universitaria de Navarra; España. Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas; España
description The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10 10 to 2 × 10 12 viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 10 12 vp per patient.
publishDate 2010
dc.date.none.fl_str_mv 2010-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/96178
Sangro, B.; Mazzolini Rizzo, Guillermo Daniel; Ruiz, M.; Ruiz, J.; Quiroga, J.; et al.; A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma; Nature Publishing Group; Cancer Gene Therapy; 17; 12; 12-2010; 837-843
0929-1903
CONICET Digital
CONICET
url http://hdl.handle.net/11336/96178
identifier_str_mv Sangro, B.; Mazzolini Rizzo, Guillermo Daniel; Ruiz, M.; Ruiz, J.; Quiroga, J.; et al.; A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma; Nature Publishing Group; Cancer Gene Therapy; 17; 12; 12-2010; 837-843
0929-1903
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/cgt.2010.40
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/cgt201040
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.087074

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