Generation of glucocorticoid resistant SARS-CoV-2 T-cells for adoptive cell therapy
Author:
Basar Rafet,Uprety Nadima,Ensley Emily,Daher May,Klein Kimberly,Martinez Fernando,Aung Fleur,Shanley Mayra,Hu Bingqian,Gokdemir Elif,Mendt Mayela,Silva Francia Reyes,Acharya Sunil,Laskowski Tamara,Muniz-Feliciano Luis,Banerjee Pinaki,Li Ye,Li Sufang,Garcia Luciana Melo,Lin Paul,Shaim Hila,Yates Sean G.,Marin David,Kaur Indreshpal,Rao Sheetal,Mak Duncan,Lin Angelique,Miao Qi,Dou Jinzhuang,Chen Ken,Champlin Richard,Shpall Elizabeth J.,Rezvani Katayoun
Abstract
SUMMARYAdoptive cell therapy with viral-specific T cells has been successfully used to treat life-threatening viral infections, supporting the application of this approach against COVID-19. We expanded SARS-CoV-2 T-cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observed that the choice of cytokines modulates the expansion, phenotype and hierarchy of antigenic recognition by SARS-CoV-2 T-cells. Culture with IL-2/4/7 but not other cytokine-driven conditions resulted in >1000 fold expansion in SARS-CoV-2 T-cells with a retained phenotype, function and hierarchy of antigenic recognition when compared to baseline (pre-expansion) samples. Expanded CTLs were directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T-cells could not be efficiently expanded from the peripheral blood of non-exposed controls. Since corticosteroids are used for the management of severe COVID-19, we developed an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.
Publisher
Cold Spring Harbor Laboratory
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2 articles.
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