CRISPR-Cas9-Mediated Glucocorticoid Resistance in Virus-Specific T Cells for Adoptive T Cell Therapy Posttransplantation.
Mol Ther
; 28(9): 1965-1973, 2020 09 02.
Article
em En
| MEDLINE
| ID: mdl-32559432
ABSTRACT
Immunosuppression posttransplantation exposes patients to an increased risk for refractory viral infections as an important cause of morbidity and mortality. Protective T cell immunity can be restored by adoptive T cell transfer, but ongoing immunosuppression limits efficacy of T cell responses. In order to deliver protection against viral pathogens and allow at the same time necessary steroid therapy, we generated glucocorticoid-resistant T cells by CRISPR-Cas9-mediated knockout of the glucocorticoid receptor in primary human virus-specific T cell products. Characterization of the T cell product revealed high efficiency of glucocorticoid receptor knockout and high purity of virus-specific T cells. This tandem T cell engineering preserved protective T cell functionality, such as cytotoxicity, CD107a degranulation, proliferative capacity, and cytokine release patterns. Virus-specific T cells with glucocorticoid receptor knockout were resistant to the suppressive effect of dexamethasone treatment on lymphocyte proliferation and cytokine secretion (tumor necrosis factor alpha [TNF-α], interleukin-4 [IL-4], IL-6, and sFas). Additionally, glucocorticoid receptor knockout cells remained sensitive to cyclosporine A treatment, thereby providing a rescue approach for patients in case of safety issues. This novel approach provides a therapeutic option for the treatment of patients with viral infections after transplantation who are receiving glucocorticoid therapy.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Viroses
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Resistência a Medicamentos
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Linfócitos T
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Transplante de Células-Tronco Hematopoéticas
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Transferência Adotiva
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Engenharia Celular
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Sistemas CRISPR-Cas
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Glucocorticoides
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article