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Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors

Targeting immune checkpoint receptors expressed in the T cell synapse induces active and long-lasting antitumor immunity in preclinical tumor models and oncology patients. However, traditional nonhuman primate (NHP) studies in healthy animals have thus far demonstrated little to no pharmacological a...

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Autores principales: Graveline, Richard, Haida, Morad, Dumont, Carolyne, Poulin, Dominic, Poitout-Belissent, Florence, Samadfam, Rana, Kronenberg, Sven, Regenass-Lechner, Franziska, Prell, Rodney, Piche, Marie-Soleil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726661/
https://www.ncbi.nlm.nih.gov/pubmed/34923919
http://dx.doi.org/10.1080/19420862.2021.1979447
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author Graveline, Richard
Haida, Morad
Dumont, Carolyne
Poulin, Dominic
Poitout-Belissent, Florence
Samadfam, Rana
Kronenberg, Sven
Regenass-Lechner, Franziska
Prell, Rodney
Piche, Marie-Soleil
author_facet Graveline, Richard
Haida, Morad
Dumont, Carolyne
Poulin, Dominic
Poitout-Belissent, Florence
Samadfam, Rana
Kronenberg, Sven
Regenass-Lechner, Franziska
Prell, Rodney
Piche, Marie-Soleil
author_sort Graveline, Richard
collection PubMed
description Targeting immune checkpoint receptors expressed in the T cell synapse induces active and long-lasting antitumor immunity in preclinical tumor models and oncology patients. However, traditional nonhuman primate (NHP) studies in healthy animals have thus far demonstrated little to no pharmacological activity or toxicity for checkpoint inhibitors (CPIs), likely due to a quiescent immune system. We developed a NHP vaccine challenge model in Mauritius cynomolgus monkey (MCMs) that elicits a strong CD8(+) T cell response to assess both pharmacology and safety within the same animal. MHC I-genotyped MCMs were immunized with three replication incompetent adenovirus serotype 5 (Adv5) encoding Gag, Nef and Pol simian immunodeficiency virus (SIV) proteins administered 4 weeks apart. Immunized animals received the anti-PD-L1 atezolizumab or an immune checkpoint-targeting bispecific antibody (mAbX) in early development. After a single immunization, Adv5-SIVs induced T-cell activation as assessed by the expression of several co-stimulatory and co-inhibitory molecules, proliferation, and antigen-specific T-cell response as measured by a Nef-dependent interferon-γ ELIspot and tetramer analysis. Administration of atezolizumab increased the number of Ki67(+) CD8(+) T cells, CD8(+) T cells co-expressing TIM3 and LAG3 and the number of CD4(+) T cells co-expressing 4–1BB, BTLA, and TIM3 two weeks after vaccination. Both atezolizumab and mAbX extended the cytolytic activity of the SIV antigen-specific CD8(+) T cell up to 8 weeks. Taken together, this vaccine challenge model allowed the combined study of pharmacology and safety parameters for a new immunomodulatory protein-based therapeutic targeting CD8(+) T cells in an NHP model.
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spelling pubmed-87266612022-01-05 Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors Graveline, Richard Haida, Morad Dumont, Carolyne Poulin, Dominic Poitout-Belissent, Florence Samadfam, Rana Kronenberg, Sven Regenass-Lechner, Franziska Prell, Rodney Piche, Marie-Soleil MAbs Report Targeting immune checkpoint receptors expressed in the T cell synapse induces active and long-lasting antitumor immunity in preclinical tumor models and oncology patients. However, traditional nonhuman primate (NHP) studies in healthy animals have thus far demonstrated little to no pharmacological activity or toxicity for checkpoint inhibitors (CPIs), likely due to a quiescent immune system. We developed a NHP vaccine challenge model in Mauritius cynomolgus monkey (MCMs) that elicits a strong CD8(+) T cell response to assess both pharmacology and safety within the same animal. MHC I-genotyped MCMs were immunized with three replication incompetent adenovirus serotype 5 (Adv5) encoding Gag, Nef and Pol simian immunodeficiency virus (SIV) proteins administered 4 weeks apart. Immunized animals received the anti-PD-L1 atezolizumab or an immune checkpoint-targeting bispecific antibody (mAbX) in early development. After a single immunization, Adv5-SIVs induced T-cell activation as assessed by the expression of several co-stimulatory and co-inhibitory molecules, proliferation, and antigen-specific T-cell response as measured by a Nef-dependent interferon-γ ELIspot and tetramer analysis. Administration of atezolizumab increased the number of Ki67(+) CD8(+) T cells, CD8(+) T cells co-expressing TIM3 and LAG3 and the number of CD4(+) T cells co-expressing 4–1BB, BTLA, and TIM3 two weeks after vaccination. Both atezolizumab and mAbX extended the cytolytic activity of the SIV antigen-specific CD8(+) T cell up to 8 weeks. Taken together, this vaccine challenge model allowed the combined study of pharmacology and safety parameters for a new immunomodulatory protein-based therapeutic targeting CD8(+) T cells in an NHP model. Taylor & Francis 2021-12-20 /pmc/articles/PMC8726661/ /pubmed/34923919 http://dx.doi.org/10.1080/19420862.2021.1979447 Text en © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Report
Graveline, Richard
Haida, Morad
Dumont, Carolyne
Poulin, Dominic
Poitout-Belissent, Florence
Samadfam, Rana
Kronenberg, Sven
Regenass-Lechner, Franziska
Prell, Rodney
Piche, Marie-Soleil
Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors
title Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors
title_full Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors
title_fullStr Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors
title_full_unstemmed Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors
title_short Development of a nonhuman primate challenge model to evaluate CD8(+) T cell responses to an adenovirus-based vaccine expressing SIV proteins upon repeat-dose treatment with checkpoint inhibitors
title_sort development of a nonhuman primate challenge model to evaluate cd8(+) t cell responses to an adenovirus-based vaccine expressing siv proteins upon repeat-dose treatment with checkpoint inhibitors
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726661/
https://www.ncbi.nlm.nih.gov/pubmed/34923919
http://dx.doi.org/10.1080/19420862.2021.1979447
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