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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/31955
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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 Técnicas2025-09-29T09:44:32Zoai: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:34982025-09-29 09:44:33.277CONICET 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 |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0090116 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 |
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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 |
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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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13.070432 |