Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models

Autores
Candolfi, Marianela; Yagiz, Kader; Wibowo, Mia; Ahlzadeh, Gabrielle E; Puntel, Mariana; Ghiasi, Homayon; Kamran, Neha; Paran, Christopher; Lowenstein, Pedro R; Castro, Maria G
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
PURPOSE: Glioblastoma multiforme is the most common primary brain cancer in adults. Chemotherapy with temozolomide (TMZ) significantly prolongs the survival of patients with glioblastoma multiforme. However, the three-year survival is still approximately 5%. Herein, we combined intratumoral administration of an adenoviral vector expressing Flt3L (Ad-Flt3L) with systemic temozolomide to assess its impact on therapeutic efficacy. EXPERIMENTAL DESIGN: Wild-type or immunodeficient mice bearing intracranial glioblastoma multiforme or metastatic melanoma were treated with an intratumoral injection of Ad-Flt3L alone or in combination with the conditionally cytotoxic enzyme thymidine kinase (Ad-TK), followed by systemic administration of ganciclovir and temozolomide. We monitored survival and measured the tumor-infiltrating immune cells. RESULTS: Although treatment with temozolomide alone led to a small improvement in median survival, when used in combination with gene therapy-mediated immunotherapy, it significantly increased the survival of tumor-bearing mice. The antitumor effect was further enhanced by concomitant intratumoral administration of Ad-TK, leading to 50% to 70% long-term survival in all tumor models. Although temozolomide reduced the content of T cells in the tumor, this did not affect the therapeutic efficacy. The antitumor effect of Ad-Flt3L+Ad-TK+TMZ required an intact immune system because the treatment failed when administered to knock out mice that lacked lymphocytes or dendritic cells. CONCLUSIONS: Our results challenge the notion that chemotherapy leads to a state of immune-suppression which impairs the ability of the immune system to mount an effective antitumor response. Our work indicates that temozolomide does not inhibit antitumor immunity and supports its clinical implementation in combination with immune-mediated therapies.
Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Yagiz, Kader. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Wibowo, Mia. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Ahlzadeh, Gabrielle E. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Puntel, Mariana. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Ghiasi, Homayon. Cedars-Sinai Medical Center. Viral Immunology and Vaccine Development Center; Estados Unidos
Fil: Kamran, Neha. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Paran, Christopher. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Lowenstein, Pedro R. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Castro, Maria G. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Materia
Temozolomide
Gene Therapy
Adtk
Adflt3l
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:11336/8341
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/8341
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor ModelsCandolfi, MarianelaYagiz, KaderWibowo, MiaAhlzadeh, Gabrielle EPuntel, MarianaGhiasi, HomayonKamran, NehaParan, ChristopherLowenstein, Pedro RCastro, Maria GTemozolomideGene TherapyAdtkAdflt3lhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3PURPOSE: Glioblastoma multiforme is the most common primary brain cancer in adults. Chemotherapy with temozolomide (TMZ) significantly prolongs the survival of patients with glioblastoma multiforme. However, the three-year survival is still approximately 5%. Herein, we combined intratumoral administration of an adenoviral vector expressing Flt3L (Ad-Flt3L) with systemic temozolomide to assess its impact on therapeutic efficacy. EXPERIMENTAL DESIGN: Wild-type or immunodeficient mice bearing intracranial glioblastoma multiforme or metastatic melanoma were treated with an intratumoral injection of Ad-Flt3L alone or in combination with the conditionally cytotoxic enzyme thymidine kinase (Ad-TK), followed by systemic administration of ganciclovir and temozolomide. We monitored survival and measured the tumor-infiltrating immune cells. RESULTS: Although treatment with temozolomide alone led to a small improvement in median survival, when used in combination with gene therapy-mediated immunotherapy, it significantly increased the survival of tumor-bearing mice. The antitumor effect was further enhanced by concomitant intratumoral administration of Ad-TK, leading to 50% to 70% long-term survival in all tumor models. Although temozolomide reduced the content of T cells in the tumor, this did not affect the therapeutic efficacy. The antitumor effect of Ad-Flt3L+Ad-TK+TMZ required an intact immune system because the treatment failed when administered to knock out mice that lacked lymphocytes or dendritic cells. CONCLUSIONS: Our results challenge the notion that chemotherapy leads to a state of immune-suppression which impairs the ability of the immune system to mount an effective antitumor response. Our work indicates that temozolomide does not inhibit antitumor immunity and supports its clinical implementation in combination with immune-mediated therapies.Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados UnidosFil: Yagiz, Kader. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados UnidosFil: Wibowo, Mia. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados UnidosFil: Ahlzadeh, Gabrielle E. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados UnidosFil: Puntel, Mariana. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados UnidosFil: Ghiasi, Homayon. Cedars-Sinai Medical Center. Viral Immunology and Vaccine Development Center; Estados UnidosFil: Kamran, Neha. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados UnidosFil: Paran, Christopher. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados UnidosFil: Lowenstein, Pedro R. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados UnidosFil: Castro, Maria G. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados UnidosAmerican Association For Cancer Research2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8341Candolfi, Marianela; Yagiz, Kader; Wibowo, Mia; Ahlzadeh, Gabrielle E; Puntel, Mariana; et al.; Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models; American Association For Cancer Research; Clinical Cancer Research; 20; 6; 2014; 1555-15651078-0432enginfo:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/20/6/1555info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-13-2140info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959570/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:14:32Zoai:ri.conicet.gov.ar:11336/8341instacron: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:34982025-10-15 15:14:33.029CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
title Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
spellingShingle Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
Candolfi, Marianela
Temozolomide
Gene Therapy
Adtk
Adflt3l
title_short Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
title_full Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
title_fullStr Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
title_full_unstemmed Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
title_sort Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models
dc.creator.none.fl_str_mv Candolfi, Marianela
Yagiz, Kader
Wibowo, Mia
Ahlzadeh, Gabrielle E
Puntel, Mariana
Ghiasi, Homayon
Kamran, Neha
Paran, Christopher
Lowenstein, Pedro R
Castro, Maria G
author Candolfi, Marianela
author_facet Candolfi, Marianela
Yagiz, Kader
Wibowo, Mia
Ahlzadeh, Gabrielle E
Puntel, Mariana
Ghiasi, Homayon
Kamran, Neha
Paran, Christopher
Lowenstein, Pedro R
Castro, Maria G
author_role author
author2 Yagiz, Kader
Wibowo, Mia
Ahlzadeh, Gabrielle E
Puntel, Mariana
Ghiasi, Homayon
Kamran, Neha
Paran, Christopher
Lowenstein, Pedro R
Castro, Maria G
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Temozolomide
Gene Therapy
Adtk
Adflt3l
topic Temozolomide
Gene Therapy
Adtk
Adflt3l
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv PURPOSE: Glioblastoma multiforme is the most common primary brain cancer in adults. Chemotherapy with temozolomide (TMZ) significantly prolongs the survival of patients with glioblastoma multiforme. However, the three-year survival is still approximately 5%. Herein, we combined intratumoral administration of an adenoviral vector expressing Flt3L (Ad-Flt3L) with systemic temozolomide to assess its impact on therapeutic efficacy. EXPERIMENTAL DESIGN: Wild-type or immunodeficient mice bearing intracranial glioblastoma multiforme or metastatic melanoma were treated with an intratumoral injection of Ad-Flt3L alone or in combination with the conditionally cytotoxic enzyme thymidine kinase (Ad-TK), followed by systemic administration of ganciclovir and temozolomide. We monitored survival and measured the tumor-infiltrating immune cells. RESULTS: Although treatment with temozolomide alone led to a small improvement in median survival, when used in combination with gene therapy-mediated immunotherapy, it significantly increased the survival of tumor-bearing mice. The antitumor effect was further enhanced by concomitant intratumoral administration of Ad-TK, leading to 50% to 70% long-term survival in all tumor models. Although temozolomide reduced the content of T cells in the tumor, this did not affect the therapeutic efficacy. The antitumor effect of Ad-Flt3L+Ad-TK+TMZ required an intact immune system because the treatment failed when administered to knock out mice that lacked lymphocytes or dendritic cells. CONCLUSIONS: Our results challenge the notion that chemotherapy leads to a state of immune-suppression which impairs the ability of the immune system to mount an effective antitumor response. Our work indicates that temozolomide does not inhibit antitumor immunity and supports its clinical implementation in combination with immune-mediated therapies.
Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Yagiz, Kader. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Wibowo, Mia. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Ahlzadeh, Gabrielle E. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Puntel, Mariana. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos. University of Michigan. Department of Neurosurgery; Estados Unidos
Fil: Ghiasi, Homayon. Cedars-Sinai Medical Center. Viral Immunology and Vaccine Development Center; Estados Unidos
Fil: Kamran, Neha. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Paran, Christopher. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Lowenstein, Pedro R. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
Fil: Castro, Maria G. University of Michigan. Department of Neurosurgery; Estados Unidos. University of Michigan. Department of Cell and Developmental Biology; Estados Unidos
description PURPOSE: Glioblastoma multiforme is the most common primary brain cancer in adults. Chemotherapy with temozolomide (TMZ) significantly prolongs the survival of patients with glioblastoma multiforme. However, the three-year survival is still approximately 5%. Herein, we combined intratumoral administration of an adenoviral vector expressing Flt3L (Ad-Flt3L) with systemic temozolomide to assess its impact on therapeutic efficacy. EXPERIMENTAL DESIGN: Wild-type or immunodeficient mice bearing intracranial glioblastoma multiforme or metastatic melanoma were treated with an intratumoral injection of Ad-Flt3L alone or in combination with the conditionally cytotoxic enzyme thymidine kinase (Ad-TK), followed by systemic administration of ganciclovir and temozolomide. We monitored survival and measured the tumor-infiltrating immune cells. RESULTS: Although treatment with temozolomide alone led to a small improvement in median survival, when used in combination with gene therapy-mediated immunotherapy, it significantly increased the survival of tumor-bearing mice. The antitumor effect was further enhanced by concomitant intratumoral administration of Ad-TK, leading to 50% to 70% long-term survival in all tumor models. Although temozolomide reduced the content of T cells in the tumor, this did not affect the therapeutic efficacy. The antitumor effect of Ad-Flt3L+Ad-TK+TMZ required an intact immune system because the treatment failed when administered to knock out mice that lacked lymphocytes or dendritic cells. CONCLUSIONS: Our results challenge the notion that chemotherapy leads to a state of immune-suppression which impairs the ability of the immune system to mount an effective antitumor response. Our work indicates that temozolomide does not inhibit antitumor immunity and supports its clinical implementation in combination with immune-mediated therapies.
publishDate 2014
dc.date.none.fl_str_mv 2014
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/11336/8341
Candolfi, Marianela; Yagiz, Kader; Wibowo, Mia; Ahlzadeh, Gabrielle E; Puntel, Mariana; et al.; Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models; American Association For Cancer Research; Clinical Cancer Research; 20; 6; 2014; 1555-1565
1078-0432
url http://hdl.handle.net/11336/8341
identifier_str_mv Candolfi, Marianela; Yagiz, Kader; Wibowo, Mia; Ahlzadeh, Gabrielle E; Puntel, Mariana; et al.; Temozolomide Does Not Impair Gene Therapy-Mediated Antitumor Immunity In Syngeneic Brain Tumor Models; American Association For Cancer Research; Clinical Cancer Research; 20; 6; 2014; 1555-1565
1078-0432
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/20/6/1555
info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-13-2140
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959570/
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
application/pdf
dc.publisher.none.fl_str_mv American Association For Cancer Research
publisher.none.fl_str_mv American Association For Cancer Research
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 13.22299

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