Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12

Autores
Barrios, Bibiana Elisabet; Baez, Natalia Soledad; Reynolds, Della; Iribarren, Pablo; Cejas, Hugo; Young, Howard A.; Rodriguez Galan, Maria Cecilia
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
For more than a decade, the cytokine interleukin-12 (IL-12) has been utilized, either alone or in combination with otherdrugs, as a treatment for cancer. The numerous anti-tumor properties of IL-12 still generate interest in the clinical use of thiscytokine, even though it has demonstrated toxicity when administrated systemically. As an approach to overcome thistoxicity, numerous laboratories have attempted to induce IL-12 expression at the site of the tumor. However for tumors thatare difficult to remove surgically or for the treatment of disseminated metastases, systemic expression of this cytokine stillremains as the most efficient method of administration. Nevertheless, finding alternative approaches for the use of IL-12 inthe treatment of cancer and unraveling the basis of IL-12-side effects remain a challenge. In the present work wedemonstrate that systemic expression of IL-12 through hydrodynamic injection of IL-12 cDNA is able to induce differenttypes of liver lesions associated with a toxic pathology. However we report here that hepatic toxicity is diminished andsurvival of mice enhanced in the absence of tumor necrosis factor alpha (TNFa). This observation is in contrast to severalmurine models and clinical trials that postulate interferon gamma (IFNc) as the main cytokine responsible for IL-12 toxicity.Moreover, our work demonstrates that when IL-12 cDNA is co-injected with IL-18 cDNA or when mice are pre-treated with alow dose of IL-12 cDNA prior to receiving a high dose of IL-12 cDNA, systemic levels of TNFaare almost completelyabrogated, resulting in improved survival and less hepatic damage. Importantly, abrogation of TNFasignaling does notaffect the strong anti-tumor activity of IL-12. Thus, neutralizing TNFawith antagonists already approved for human useoffers a promising approach to abrogate IL-12 side effects during the use of this cytokine for the treatment of cancer.
Fil: Barrios, Bibiana Elisabet. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Baez, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Reynolds, Della. National Cancer Institute. Maryland; Estados Unidos
Fil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Cejas, Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Young, Howard A.. National Cancer Institute. Maryland; Estados Unidos
Fil: Rodriguez Galan, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Materia
IL-12
IL-18
TNF-a
GENE THERAPY
CANCER
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:11336/31955
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/31955
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12Barrios, Bibiana ElisabetBaez, Natalia SoledadReynolds, DellaIribarren, PabloCejas, HugoYoung, Howard A.Rodriguez Galan, Maria CeciliaIL-12IL-18TNF-aGENE THERAPYCANCERhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3For more than a decade, the cytokine interleukin-12 (IL-12) has been utilized, either alone or in combination with otherdrugs, as a treatment for cancer. The numerous anti-tumor properties of IL-12 still generate interest in the clinical use of thiscytokine, even though it has demonstrated toxicity when administrated systemically. As an approach to overcome thistoxicity, numerous laboratories have attempted to induce IL-12 expression at the site of the tumor. However for tumors thatare difficult to remove surgically or for the treatment of disseminated metastases, systemic expression of this cytokine stillremains as the most efficient method of administration. Nevertheless, finding alternative approaches for the use of IL-12 inthe treatment of cancer and unraveling the basis of IL-12-side effects remain a challenge. In the present work wedemonstrate that systemic expression of IL-12 through hydrodynamic injection of IL-12 cDNA is able to induce differenttypes of liver lesions associated with a toxic pathology. However we report here that hepatic toxicity is diminished andsurvival of mice enhanced in the absence of tumor necrosis factor alpha (TNFa). This observation is in contrast to severalmurine models and clinical trials that postulate interferon gamma (IFNc) as the main cytokine responsible for IL-12 toxicity.Moreover, our work demonstrates that when IL-12 cDNA is co-injected with IL-18 cDNA or when mice are pre-treated with alow dose of IL-12 cDNA prior to receiving a high dose of IL-12 cDNA, systemic levels of TNFaare almost completelyabrogated, resulting in improved survival and less hepatic damage. Importantly, abrogation of TNFasignaling does notaffect the strong anti-tumor activity of IL-12. Thus, neutralizing TNFawith antagonists already approved for human useoffers a promising approach to abrogate IL-12 side effects during the use of this cytokine for the treatment of cancer.Fil: Barrios, Bibiana Elisabet. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Baez, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Reynolds, Della. National Cancer Institute. Maryland; Estados UnidosFil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Cejas, Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Young, Howard A.. National Cancer Institute. Maryland; Estados UnidosFil: Rodriguez Galan, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaPublic Library of Science2014-02info: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/11336/31955Rodriguez Galan, Maria Cecilia; Young, Howard A.; Cejas, Hugo; Iribarren, Pablo; Reynolds, Della; Baez, Natalia Soledad; et al.; Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12; Public Library of Science; Plos One; 9; 2; 2-2014; 1-111932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0090116info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090116info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:13:22Zoai:ri.conicet.gov.ar:11336/31955instacron: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:34982025-10-22 11:13:22.497CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
title Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
spellingShingle Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
Barrios, Bibiana Elisabet
IL-12
IL-18
TNF-a
GENE THERAPY
CANCER
title_short Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
title_full Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
title_fullStr Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
title_full_unstemmed Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
title_sort Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12
dc.creator.none.fl_str_mv Barrios, Bibiana Elisabet
Baez, Natalia Soledad
Reynolds, Della
Iribarren, Pablo
Cejas, Hugo
Young, Howard A.
Rodriguez Galan, Maria Cecilia
author Barrios, Bibiana Elisabet
author_facet Barrios, Bibiana Elisabet
Baez, Natalia Soledad
Reynolds, Della
Iribarren, Pablo
Cejas, Hugo
Young, Howard A.
Rodriguez Galan, Maria Cecilia
author_role author
author2 Baez, Natalia Soledad
Reynolds, Della
Iribarren, Pablo
Cejas, Hugo
Young, Howard A.
Rodriguez Galan, Maria Cecilia
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv IL-12
IL-18
TNF-a
GENE THERAPY
CANCER
topic IL-12
IL-18
TNF-a
GENE THERAPY
CANCER
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv For more than a decade, the cytokine interleukin-12 (IL-12) has been utilized, either alone or in combination with otherdrugs, as a treatment for cancer. The numerous anti-tumor properties of IL-12 still generate interest in the clinical use of thiscytokine, even though it has demonstrated toxicity when administrated systemically. As an approach to overcome thistoxicity, numerous laboratories have attempted to induce IL-12 expression at the site of the tumor. However for tumors thatare difficult to remove surgically or for the treatment of disseminated metastases, systemic expression of this cytokine stillremains as the most efficient method of administration. Nevertheless, finding alternative approaches for the use of IL-12 inthe treatment of cancer and unraveling the basis of IL-12-side effects remain a challenge. In the present work wedemonstrate that systemic expression of IL-12 through hydrodynamic injection of IL-12 cDNA is able to induce differenttypes of liver lesions associated with a toxic pathology. However we report here that hepatic toxicity is diminished andsurvival of mice enhanced in the absence of tumor necrosis factor alpha (TNFa). This observation is in contrast to severalmurine models and clinical trials that postulate interferon gamma (IFNc) as the main cytokine responsible for IL-12 toxicity.Moreover, our work demonstrates that when IL-12 cDNA is co-injected with IL-18 cDNA or when mice are pre-treated with alow dose of IL-12 cDNA prior to receiving a high dose of IL-12 cDNA, systemic levels of TNFaare almost completelyabrogated, resulting in improved survival and less hepatic damage. Importantly, abrogation of TNFasignaling does notaffect the strong anti-tumor activity of IL-12. Thus, neutralizing TNFawith antagonists already approved for human useoffers a promising approach to abrogate IL-12 side effects during the use of this cytokine for the treatment of cancer.
Fil: Barrios, Bibiana Elisabet. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Baez, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Reynolds, Della. National Cancer Institute. Maryland; Estados Unidos
Fil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Cejas, Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Young, Howard A.. National Cancer Institute. Maryland; Estados Unidos
Fil: Rodriguez Galan, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
description For more than a decade, the cytokine interleukin-12 (IL-12) has been utilized, either alone or in combination with otherdrugs, as a treatment for cancer. The numerous anti-tumor properties of IL-12 still generate interest in the clinical use of thiscytokine, even though it has demonstrated toxicity when administrated systemically. As an approach to overcome thistoxicity, numerous laboratories have attempted to induce IL-12 expression at the site of the tumor. However for tumors thatare difficult to remove surgically or for the treatment of disseminated metastases, systemic expression of this cytokine stillremains as the most efficient method of administration. Nevertheless, finding alternative approaches for the use of IL-12 inthe treatment of cancer and unraveling the basis of IL-12-side effects remain a challenge. In the present work wedemonstrate that systemic expression of IL-12 through hydrodynamic injection of IL-12 cDNA is able to induce differenttypes of liver lesions associated with a toxic pathology. However we report here that hepatic toxicity is diminished andsurvival of mice enhanced in the absence of tumor necrosis factor alpha (TNFa). This observation is in contrast to severalmurine models and clinical trials that postulate interferon gamma (IFNc) as the main cytokine responsible for IL-12 toxicity.Moreover, our work demonstrates that when IL-12 cDNA is co-injected with IL-18 cDNA or when mice are pre-treated with alow dose of IL-12 cDNA prior to receiving a high dose of IL-12 cDNA, systemic levels of TNFaare almost completelyabrogated, resulting in improved survival and less hepatic damage. Importantly, abrogation of TNFasignaling does notaffect the strong anti-tumor activity of IL-12. Thus, neutralizing TNFawith antagonists already approved for human useoffers a promising approach to abrogate IL-12 side effects during the use of this cytokine for the treatment of cancer.
publishDate 2014
dc.date.none.fl_str_mv 2014-02
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/11336/31955
Rodriguez Galan, Maria Cecilia; Young, Howard A.; Cejas, Hugo; Iribarren, Pablo; Reynolds, Della; Baez, Natalia Soledad; et al.; Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12; Public Library of Science; Plos One; 9; 2; 2-2014; 1-11
1932-6203
CONICET Digital
CONICET
url http://hdl.handle.net/11336/31955
identifier_str_mv Rodriguez Galan, Maria Cecilia; Young, Howard A.; Cejas, Hugo; Iribarren, Pablo; Reynolds, Della; Baez, Natalia Soledad; et al.; Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12; Public Library of Science; Plos One; 9; 2; 2-2014; 1-11
1932-6203
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090116
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 Public Library of Science
publisher.none.fl_str_mv Public Library of Science
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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