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Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein

Immunotherapy was significantly enhanced in a murine tumor model by combining a vaccine with a fusion protein designed to target the glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR) on the surface of T cells. The recombinant poxvirus-based vaccine platform included Mod...

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Autores principales: Morillon, Y. Maurice, Hammond, Scott A., Durham, Nicholas M., Schlom, Jeffrey, Greiner, John W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650275/
https://www.ncbi.nlm.nih.gov/pubmed/29088720
http://dx.doi.org/10.18632/oncotarget.20703
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author Morillon, Y. Maurice
Hammond, Scott A.
Durham, Nicholas M.
Schlom, Jeffrey
Greiner, John W.
author_facet Morillon, Y. Maurice
Hammond, Scott A.
Durham, Nicholas M.
Schlom, Jeffrey
Greiner, John W.
author_sort Morillon, Y. Maurice
collection PubMed
description Immunotherapy was significantly enhanced in a murine tumor model by combining a vaccine with a fusion protein designed to target the glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR) on the surface of T cells. The recombinant poxvirus-based vaccine platform included Modified Vaccinia virus Ankara (rMVA) and fowlpox (rF) vectors as the driver immunogens both engineered to express the human carcinoembryonic antigen (CEA) and three murine costimulatory molecules B7.1, ICAM-1, LFA-3 (designated TRICOM). In previous studies, mice expressing human CEA as a transgene (CEA.Tg mice) vaccinated with rMVA/rF-CEA-TRICOM overcame CEA immune tolerance by inducing anti-CEA‒specific immunity and regression of CEA-expressing tumors. The murine GITR ligand fusion protein (mGITRL-FP) consisted of a mouse IgG2a Fc region, a yeast-derived coiled GCN4 pII and the extracellular GITR-binding domain of murine GITR ligand. The design maximized valency and the potential to agonize the GITR receptor. Combined treatment of the vaccine and mGITRL-FP mediated a more robust tumor regression, leading to sustained improvement in overall survival. The enhanced immunotherapeutic effect was linked to the generation of a strong CD8(+) T cell antitumor immune response. A treatment schedule with mGITRL-FP administered prior to the priming rMVA-CEA-TRICOM vaccination was of paramount importance. The mechanism of action for the enhanced antitumor effects resided in the depletion of immune cells, particularly FoxP3(+) regulatory T cells, that express high GITR levels following activation. The results provide evidence that targeting GITR with mGITRL-FP in concert with a cancer vaccine represents a potential novel approach to more effective immunotherapy.
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spelling pubmed-56502752017-10-30 Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein Morillon, Y. Maurice Hammond, Scott A. Durham, Nicholas M. Schlom, Jeffrey Greiner, John W. Oncotarget Priority Research Paper Immunotherapy was significantly enhanced in a murine tumor model by combining a vaccine with a fusion protein designed to target the glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR) on the surface of T cells. The recombinant poxvirus-based vaccine platform included Modified Vaccinia virus Ankara (rMVA) and fowlpox (rF) vectors as the driver immunogens both engineered to express the human carcinoembryonic antigen (CEA) and three murine costimulatory molecules B7.1, ICAM-1, LFA-3 (designated TRICOM). In previous studies, mice expressing human CEA as a transgene (CEA.Tg mice) vaccinated with rMVA/rF-CEA-TRICOM overcame CEA immune tolerance by inducing anti-CEA‒specific immunity and regression of CEA-expressing tumors. The murine GITR ligand fusion protein (mGITRL-FP) consisted of a mouse IgG2a Fc region, a yeast-derived coiled GCN4 pII and the extracellular GITR-binding domain of murine GITR ligand. The design maximized valency and the potential to agonize the GITR receptor. Combined treatment of the vaccine and mGITRL-FP mediated a more robust tumor regression, leading to sustained improvement in overall survival. The enhanced immunotherapeutic effect was linked to the generation of a strong CD8(+) T cell antitumor immune response. A treatment schedule with mGITRL-FP administered prior to the priming rMVA-CEA-TRICOM vaccination was of paramount importance. The mechanism of action for the enhanced antitumor effects resided in the depletion of immune cells, particularly FoxP3(+) regulatory T cells, that express high GITR levels following activation. The results provide evidence that targeting GITR with mGITRL-FP in concert with a cancer vaccine represents a potential novel approach to more effective immunotherapy. Impact Journals LLC 2017-09-07 /pmc/articles/PMC5650275/ /pubmed/29088720 http://dx.doi.org/10.18632/oncotarget.20703 Text en Copyright: © 2017 Morillon et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper
Morillon, Y. Maurice
Hammond, Scott A.
Durham, Nicholas M.
Schlom, Jeffrey
Greiner, John W.
Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein
title Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein
title_full Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein
title_fullStr Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein
title_full_unstemmed Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein
title_short Enhanced immunotherapy by combining a vaccine with a novel murine GITR ligand fusion protein
title_sort enhanced immunotherapy by combining a vaccine with a novel murine gitr ligand fusion protein
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650275/
https://www.ncbi.nlm.nih.gov/pubmed/29088720
http://dx.doi.org/10.18632/oncotarget.20703
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