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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, Mayela Mendt, Francia Reyes Silva, Sunil Acharya, Tamara Laskowski, Luis Muniz-Feliciano, Pinaki 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 Champlin, Elizabeth J. Shpall, Katayoun Rezvani
doi: https://doi.org/10.1101/2020.09.15.298547
Rafet Basar
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Nadima Uprety
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Emily Ensley
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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May Daher
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Kimberly Klein
2Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Fernando Martinez
2Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Fleur Aung
2Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Mayra Shanley
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Bingqian Hu
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Elif Gokdemir
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Mayela Mendt
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Francia Reyes Silva
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Sunil Acharya
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Tamara Laskowski
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Luis Muniz-Feliciano
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Pinaki Banerjee
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Ye Li
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Sufang Li
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Luciana Melo Garcia
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Paul Lin
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Hila Shaim
3Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX, USA
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Sean G. Yates
4Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
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David Marin
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Indreshpal Kaur
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Sheetal Rao
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Duncan Mak
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Angelique Lin
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Qi Miao
6Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Jinzhuang Dou
6Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Ken Chen
6Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Richard Champlin
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Elizabeth J. Shpall
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Katayoun Rezvani
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • For correspondence: KRezvani@mdanderson.org
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SUMMARY

Adoptive 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 15, 2020.
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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, Mayela Mendt, Francia Reyes Silva, Sunil Acharya, Tamara Laskowski, Luis Muniz-Feliciano, Pinaki 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 Champlin, Elizabeth J. Shpall, Katayoun Rezvani
bioRxiv 2020.09.15.298547; doi: https://doi.org/10.1101/2020.09.15.298547
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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, Mayela Mendt, Francia Reyes Silva, Sunil Acharya, Tamara Laskowski, Luis Muniz-Feliciano, Pinaki 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 Champlin, Elizabeth J. Shpall, Katayoun Rezvani
bioRxiv 2020.09.15.298547; doi: https://doi.org/10.1101/2020.09.15.298547

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