Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy

Rafet Basar; Nadima Uprety; Emily Ensley; May Daher; Kimberly Klein; Fernando Martinez; Fleur Aung; Mayra Shanley; Bingqian Hu; Elif Gokdemir; Ana Karen Nunez Cortes; Mayela Mendt; Francia Reyes Silva; Sunil Acharya; Tamara Laskowski; Luis Muniz-Feliciano; Pinaki P. Banerjee; Ye Li; Sufang Li; Luciana Melo Garcia; Paul Lin; Hila Shaim; Sean G. Yates; David Marin; Indreshpal Kaur; Sheetal Rao; Duncan Mak; Angelique Lin; Qi Miao; Jinzhuang Dou; Ken Chen; Richard E. Champlin; Elizabeth J. Shpall; Katayoun Rezvani

doi:10.1016/j.celrep.2021.109432

Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy

Rafet Basar, Nadima Uprety, Emily Ensley, May Daher, Kimberly Klein, Fernando Martinez, Fleur Aung, Mayra Shanley, Bingqian Hu, Elif Gokdemir, Ana Karen Nunez Cortes, Mayela Mendt, Francia Reyes Silva, Sunil Acharya, Tamara Laskowski, Luis Muniz-Feliciano, Pinaki P. Banerjee, Ye Li, Sufang Li, Luciana Melo GarciaPaul Lin, Hila Shaim, Sean G. Yates, David Marin, Indreshpal Kaur, Sheetal Rao, Duncan Mak, Angelique Lin, Qi Miao, Jinzhuang Dou, Ken Chen, Richard E. Champlin, Elizabeth J. Shpall, Katayoun Rezvani

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Article number	109432
Journal	Cell Reports
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109432
State	Published - Jul 20 2021
Externally published	Yes

Keywords

CRISPR-Cas9
CTL expansion
SARS-CoV-2
adoptive cell therapy
convalescent plasma
glucocorticoid receptor

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.109432

Cite this

Basar, R., Uprety, N., Ensley, E., Daher, M., Klein, K., Martinez, F., Aung, F., Shanley, M., Hu, B., Gokdemir, E., Nunez Cortes, A. K., Mendt, M., Reyes Silva, F., Acharya, S., Laskowski, T., Muniz-Feliciano, L., Banerjee, P. P., Li, Y., Li, S., ... Rezvani, K. (2021). Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy. Cell Reports, 36(3), Article 109432. https://doi.org/10.1016/j.celrep.2021.109432

Basar, R, Uprety, N, Ensley, E, Daher, M, Klein, K, Martinez, F, Aung, F, Shanley, M, Hu, B, Gokdemir, E, Nunez Cortes, AK, Mendt, M, Reyes Silva, F, Acharya, S, Laskowski, T, Muniz-Feliciano, L, Banerjee, PP, Li, Y, Li, S, Melo Garcia, L, Lin, P, Shaim, H, Yates, SG, Marin, D, Kaur, I, Rao, S, Mak, D, Lin, A, Miao, Q, Dou, J, Chen, K, Champlin, RE, Shpall, EJ & Rezvani, K 2021, 'Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy', Cell Reports, vol. 36, no. 3, 109432. https://doi.org/10.1016/j.celrep.2021.109432

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title = "Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy",

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.",

keywords = "CRISPR-Cas9, CTL expansion, SARS-CoV-2, adoptive cell therapy, convalescent plasma, glucocorticoid receptor",

author = "Rafet Basar and Nadima Uprety and Emily Ensley and May Daher and Kimberly Klein and Fernando Martinez and Fleur Aung and Mayra Shanley and Bingqian Hu and Elif Gokdemir and {Nunez Cortes}, {Ana Karen} and Mayela Mendt and {Reyes Silva}, Francia and Sunil Acharya and Tamara Laskowski and Luis Muniz-Feliciano and Banerjee, {Pinaki P.} and Ye Li and Sufang Li and {Melo Garcia}, Luciana and Paul Lin and Hila Shaim and Yates, {Sean G.} and David Marin and Indreshpal Kaur and Sheetal Rao and Duncan Mak and Angelique Lin and Qi Miao and Jinzhuang Dou and Ken Chen and Champlin, {Richard E.} and Shpall, {Elizabeth J.} and Katayoun Rezvani",

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year = "2021",

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doi = "10.1016/j.celrep.2021.109432",

language = "English (US)",

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T1 - Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy

AU - Basar, Rafet

AU - Uprety, Nadima

AU - Ensley, Emily

AU - Daher, May

AU - Klein, Kimberly

AU - Martinez, Fernando

AU - Aung, Fleur

AU - Shanley, Mayra

AU - Hu, Bingqian

AU - Gokdemir, Elif

AU - Nunez Cortes, Ana Karen

AU - Mendt, Mayela

AU - Reyes Silva, Francia

AU - Acharya, Sunil

AU - Laskowski, Tamara

AU - Muniz-Feliciano, Luis

AU - Banerjee, Pinaki P.

AU - Li, Ye

AU - Li, Sufang

AU - Melo Garcia, Luciana

AU - Lin, Paul

AU - Shaim, Hila

AU - Yates, Sean G.

AU - Marin, David

AU - Kaur, Indreshpal

AU - Rao, Sheetal

AU - Mak, Duncan

AU - Lin, Angelique

AU - Miao, Qi

AU - Dou, Jinzhuang

AU - Chen, Ken

AU - Champlin, Richard E.

AU - Shpall, Elizabeth J.

AU - Rezvani, Katayoun

PY - 2021/7/20

Y1 - 2021/7/20

N2 - 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.

AB - 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.

KW - CRISPR-Cas9

KW - CTL expansion

KW - SARS-CoV-2

KW - adoptive cell therapy

KW - convalescent plasma

KW - glucocorticoid receptor

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Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy

Abstract

Keywords

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