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Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates

Stimulator of interferon genes (STING) is a cytoplasmic dinucleotide sensor used as an immunomodulatory agent for cancer treatment. The efficacy of the STING ligand (STING-L) against various tumors has been evaluated in mouse models; however, its safety and efficacy in non-human primates have not be...

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Autores principales: Takahama, Shokichi, Ishige, Kazuya, Nogimori, Takuto, Yasutomi, Yasuhiro, Appay, Victor, Yamamoto, Takuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813482/
https://www.ncbi.nlm.nih.gov/pubmed/36620070
http://dx.doi.org/10.1016/j.omtm.2022.12.008
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author Takahama, Shokichi
Ishige, Kazuya
Nogimori, Takuto
Yasutomi, Yasuhiro
Appay, Victor
Yamamoto, Takuya
author_facet Takahama, Shokichi
Ishige, Kazuya
Nogimori, Takuto
Yasutomi, Yasuhiro
Appay, Victor
Yamamoto, Takuya
author_sort Takahama, Shokichi
collection PubMed
description Stimulator of interferon genes (STING) is a cytoplasmic dinucleotide sensor used as an immunomodulatory agent for cancer treatment. The efficacy of the STING ligand (STING-L) against various tumors has been evaluated in mouse models; however, its safety and efficacy in non-human primates have not been reported. We examined the effects of escalating doses of cyclic-di-adenosine monophosphate (c-di-AMP) or cyclic [G (3′,5′)pA (3′,5′p] (3′-3′-cGAMP) administered intramuscularly or intravenously to cynomolgus macaques. Both ligands induced transient local and systemic inflammatory responses and systemic immunomodulatory responses, including the upregulation of interferon-α (IFN-α) and IFN-γ expression and the activation of multiple immunocompetent cell subsets. Better immunological responses were observed in animals that received c-di-AMP compared with those that received 3′-3′-cGAMP. Multi-parameter analysis using a dataset obtained before administering the ligands predicted the efficacy outcome partially. Importantly, the efficacy of these ligands was reduced in older macaques. We propose that 0.5 mg/kg c-di-AMP via intramuscular administration should be the optimal starting point for clinical studies. Our study is the first to demonstrate the age-dependent safety and efficacy of STING-L in non-human primates and supports the potential of STING-L use as a direct immunomodulator in vivo.
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spelling pubmed-98134822023-01-05 Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates Takahama, Shokichi Ishige, Kazuya Nogimori, Takuto Yasutomi, Yasuhiro Appay, Victor Yamamoto, Takuya Mol Ther Methods Clin Dev Original Article Stimulator of interferon genes (STING) is a cytoplasmic dinucleotide sensor used as an immunomodulatory agent for cancer treatment. The efficacy of the STING ligand (STING-L) against various tumors has been evaluated in mouse models; however, its safety and efficacy in non-human primates have not been reported. We examined the effects of escalating doses of cyclic-di-adenosine monophosphate (c-di-AMP) or cyclic [G (3′,5′)pA (3′,5′p] (3′-3′-cGAMP) administered intramuscularly or intravenously to cynomolgus macaques. Both ligands induced transient local and systemic inflammatory responses and systemic immunomodulatory responses, including the upregulation of interferon-α (IFN-α) and IFN-γ expression and the activation of multiple immunocompetent cell subsets. Better immunological responses were observed in animals that received c-di-AMP compared with those that received 3′-3′-cGAMP. Multi-parameter analysis using a dataset obtained before administering the ligands predicted the efficacy outcome partially. Importantly, the efficacy of these ligands was reduced in older macaques. We propose that 0.5 mg/kg c-di-AMP via intramuscular administration should be the optimal starting point for clinical studies. Our study is the first to demonstrate the age-dependent safety and efficacy of STING-L in non-human primates and supports the potential of STING-L use as a direct immunomodulator in vivo. American Society of Gene & Cell Therapy 2022-12-14 /pmc/articles/PMC9813482/ /pubmed/36620070 http://dx.doi.org/10.1016/j.omtm.2022.12.008 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Takahama, Shokichi
Ishige, Kazuya
Nogimori, Takuto
Yasutomi, Yasuhiro
Appay, Victor
Yamamoto, Takuya
Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates
title Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates
title_full Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates
title_fullStr Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates
title_full_unstemmed Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates
title_short Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates
title_sort model for predicting age-dependent safety and immunomodulatory effects of sting ligands in non-human primates
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9813482/
https://www.ncbi.nlm.nih.gov/pubmed/36620070
http://dx.doi.org/10.1016/j.omtm.2022.12.008
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