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“Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients
Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848034/ https://www.ncbi.nlm.nih.gov/pubmed/33537032 http://dx.doi.org/10.3389/fimmu.2020.608701 |
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author | Koukoulias, Kiriakos Papayanni, Penelope-Georgia Georgakopoulou, Aphrodite Alvanou, Maria Laidou, Stamatia Kouimtzidis, Anastasios Pantazi, Chrysoula Gkoliou, Glykeria Vyzantiadis, Timoleon-Achilleas Spyridonidis, Alexandros Makris, Antonios Chatzidimitriou, Anastasia Psatha, Nikoletta Anagnostopoulos, Achilles Yannaki, Evangelia Papadopoulou, Anastasia |
author_facet | Koukoulias, Kiriakos Papayanni, Penelope-Georgia Georgakopoulou, Aphrodite Alvanou, Maria Laidou, Stamatia Kouimtzidis, Anastasios Pantazi, Chrysoula Gkoliou, Glykeria Vyzantiadis, Timoleon-Achilleas Spyridonidis, Alexandros Makris, Antonios Chatzidimitriou, Anastasia Psatha, Nikoletta Anagnostopoulos, Achilles Yannaki, Evangelia Papadopoulou, Anastasia |
author_sort | Koukoulias, Kiriakos |
collection | PubMed |
description | Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not receiving high-dose steroids, a prerequisite for optimal T-cell function, practically excluding the most susceptible to infections patients from the benefits of AI. To address this issue, we here rapidly generated, clinical doses of a steroid-resistant T-cell product, simultaneously targeting four viruses (adenovirus, cytomegalovirus, Epstein Barr virus, and BK virus) and the fungus Aspergillus fumigatus, by genetic disruption of the glucocorticoid receptor (GR) gene using CRISPR/CAS9 ribonucleoprotein delivery. The product, “Cerberus” T cells (Cb-STs), was called after the monstrous three-headed dog of Greek mythology, due to its triple potential; specificity against viruses, specificity against fungi and resistance to glucocorticoids. Following efficient on-target GR disruption and minimal off-target editing, the generated Cb-STs maintained the characteristics of pentavalent-STs, their unedited counterparts, including polyclonality, memory immunophenotype, specificity, and cytotoxicity while they presented functional resistance to dexamethasone. Cb-STs may become a powerful, one-time treatment for severely immunosuppressed patients under glucocorticoids who suffer from multiple, life-threatening infections post-transplant, and for whom therapeutic choices are limited. |
format | Online Article Text |
id | pubmed-7848034 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78480342021-02-02 “Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients Koukoulias, Kiriakos Papayanni, Penelope-Georgia Georgakopoulou, Aphrodite Alvanou, Maria Laidou, Stamatia Kouimtzidis, Anastasios Pantazi, Chrysoula Gkoliou, Glykeria Vyzantiadis, Timoleon-Achilleas Spyridonidis, Alexandros Makris, Antonios Chatzidimitriou, Anastasia Psatha, Nikoletta Anagnostopoulos, Achilles Yannaki, Evangelia Papadopoulou, Anastasia Front Immunol Immunology Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not receiving high-dose steroids, a prerequisite for optimal T-cell function, practically excluding the most susceptible to infections patients from the benefits of AI. To address this issue, we here rapidly generated, clinical doses of a steroid-resistant T-cell product, simultaneously targeting four viruses (adenovirus, cytomegalovirus, Epstein Barr virus, and BK virus) and the fungus Aspergillus fumigatus, by genetic disruption of the glucocorticoid receptor (GR) gene using CRISPR/CAS9 ribonucleoprotein delivery. The product, “Cerberus” T cells (Cb-STs), was called after the monstrous three-headed dog of Greek mythology, due to its triple potential; specificity against viruses, specificity against fungi and resistance to glucocorticoids. Following efficient on-target GR disruption and minimal off-target editing, the generated Cb-STs maintained the characteristics of pentavalent-STs, their unedited counterparts, including polyclonality, memory immunophenotype, specificity, and cytotoxicity while they presented functional resistance to dexamethasone. Cb-STs may become a powerful, one-time treatment for severely immunosuppressed patients under glucocorticoids who suffer from multiple, life-threatening infections post-transplant, and for whom therapeutic choices are limited. Frontiers Media S.A. 2021-01-18 /pmc/articles/PMC7848034/ /pubmed/33537032 http://dx.doi.org/10.3389/fimmu.2020.608701 Text en Copyright © 2021 Koukoulias, Papayanni, Georgakopoulou, Alvanou, Laidou, Kouimtzidis, Pantazi, Gkoliou, Vyzantiadis, Spyridonidis, Makris, Chatzidimitriou, Psatha, Anagnostopoulos, Yannaki and Papadopoulou http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Koukoulias, Kiriakos Papayanni, Penelope-Georgia Georgakopoulou, Aphrodite Alvanou, Maria Laidou, Stamatia Kouimtzidis, Anastasios Pantazi, Chrysoula Gkoliou, Glykeria Vyzantiadis, Timoleon-Achilleas Spyridonidis, Alexandros Makris, Antonios Chatzidimitriou, Anastasia Psatha, Nikoletta Anagnostopoulos, Achilles Yannaki, Evangelia Papadopoulou, Anastasia “Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients |
title | “Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients |
title_full | “Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients |
title_fullStr | “Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients |
title_full_unstemmed | “Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients |
title_short | “Cerberus” T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients |
title_sort | “cerberus” t cells: a glucocorticoid-resistant, multi-pathogen specific t cell product to fight infections in severely immunocompromised patients |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848034/ https://www.ncbi.nlm.nih.gov/pubmed/33537032 http://dx.doi.org/10.3389/fimmu.2020.608701 |
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