1. Generation of glucocorticoid resistant SARS-CoV-2 T-cells for adoptive cell therapy
- Author
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David Marin, Angelique Lin, Sean G. Yates, Nadima Uprety, Pinaki P. Banerjee, Mayela Mendt, Katayoun Rezvani, Qi Miao, Tamara Laskowski, Bingqian Hu, Sheetal S Rao, Ken Chen, Richard E. Champlin, Kimberly Klein, Duncan Mak, Fleur M. Aung, Elif Gokdemir, Paul Lin, Rafet Basar, Sunil Acharya, Emily Ensley, Indreshpal Kaur, Luis Muniz-Feliciano, Elizabeth J. Shpall, Fernando J. Martinez, Luciana Melo Garcia, May Daher, Jinzhuang Dou, Ye Li, Francia Reyes Silva, Sufang Li, Mayra Shanley, and Hila Shaim
- Subjects
SARS-CoV-2 ,viruses ,CTL expansion ,adoptive cell therapy ,Biology ,Phenotype ,Article ,Cell therapy ,Glucocorticoid receptor ,Genome editing ,Antigen ,Immunology ,convalescent plasma ,medicine ,glucocorticoid receptor ,CRISPR-Cas9 ,Gene ,Function (biology) ,Glucocorticoid ,medicine.drug - Abstract
Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing., Graphical abstract, Basar et al. demonstrate that SARS-CoV-2 T cells can be efficiently generated from COVID19-recovered donors with specificity against multiple structural SARS-CoV-2 proteins, including the Spike protein. Moreover, these cells can be genetically modified to render them resistant to corticosteroids, making their application clinically feasible.
- Published
- 2020