A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells

doi:10.1002/anie.202109550

. 2022 Mar 1;61(10):e202109550.

doi: 10.1002/anie.202109550. Epub 2022 Jan 18.

A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells

Wenyue Cao^{1

2}, Zhi Zachary Geng², Na Wang¹, Quan Pan², Shaodong Guo², Shiqing Xu², Jianfeng Zhou¹, Wenshe Ray Liu^{2

3

4

5}

Affiliations

¹ Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
² The Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, TX, 77843-3255, USA.
³ Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, 77030, USA.
⁴ Department of Biochemistry and Biophysics, Texas A&M University, Houston, TX, 77843, USA.
⁵ Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, Houston, TX, 77843, USA.

PMID: 34783141
DOI: 10.1002/anie.202109550

A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells

Wenyue Cao et al. Angew Chem Int Ed Engl. 2022.

. 2022 Mar 1;61(10):e202109550.

doi: 10.1002/anie.202109550. Epub 2022 Jan 18.

Authors

Wenyue Cao^{1

2}, Zhi Zachary Geng², Na Wang¹, Quan Pan², Shaodong Guo², Shiqing Xu², Jianfeng Zhou¹, Wenshe Ray Liu^{2

3

4

5}

Affiliations

¹ Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
² The Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, TX, 77843-3255, USA.
³ Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, 77030, USA.
⁴ Department of Biochemistry and Biophysics, Texas A&M University, Houston, TX, 77843, USA.
⁵ Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, Houston, TX, 77843, USA.

PMID: 34783141
DOI: 10.1002/anie.202109550

Abstract

As a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR-T cells that is achievable through regulatory display of CARs. By embedding the hepatitis C virus NS3 protease (HCV-NS3) between the single-chain variable fragment (scFv) and the hinge domain, we showed that the display of anti-CD19 scFv on CAR-T cells was positively correlated to the presence of a clinical HCV-NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti-CD19 scFv in the presence of ASV and its removal in the absence of ASV creates a practically reversible chemical switch. We demonstrated that the intact CAR on T cells can be repeatedly turned on and off by controlling the presence of ASV in a dose dependent manner both in vitro and in vivo, which enables delicate modulation of CAR-T activation during cancer treatment.

Keywords: CAR-T therapy; NS3 protease; asunaprevir; chemical switches; chimeric antigen receptors.

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References

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[1] None

[2] None

[3] S. L. Maude, N. Frey, P. A. Shaw, R. Aplenc, D. M. Barrett, N. J. Bunin, A. Chew, V. E. Gonzalez, Z. Zheng, S. F. Lacey, Y. D. Mahnke, J. J. Melenhorst, S. R. Rheingold, A. Shen, D. T. Teachey, B. L. Levine, C. H. June, D. L. Porter, S. A. Grupp, N. Engl. J. Med. 2014, 371, 1507-1517;

[4] S. L. Maude, N. Frey, P. A. Shaw, R. Aplenc, D. M. Barrett, N. J. Bunin, A. Chew, V. E. Gonzalez, Z. Zheng, S. F. Lacey, Y. D. Mahnke, J. J. Melenhorst, S. R. Rheingold, A. Shen, D. T. Teachey, B. L. Levine, C. H. June, D. L. Porter, S. A. Grupp, N. Engl. J. Med. 2014, 371, 1507-1517;

[5] F. L. Locke, S. S. Neelapu, N. L. Bartlett, T. Siddiqi, J. C. Chavez, C. M. Hosing, A. Ghobadi, L. E. Budde, A. Bot, J. M. Rossi, Y. Z. Jiang, A. X. Xue, M. Elias, J. Aycock, J. Wiezorek, W. Y. Go, Mol. Ther. 2017, 25, 285-295.

[6] F. L. Locke, S. S. Neelapu, N. L. Bartlett, T. Siddiqi, J. C. Chavez, C. M. Hosing, A. Ghobadi, L. E. Budde, A. Bot, J. M. Rossi, Y. Z. Jiang, A. X. Xue, M. Elias, J. Aycock, J. Wiezorek, W. Y. Go, Mol. Ther. 2017, 25, 285-295.

[7] P. Vormittag, R. Gunn, S. Ghorashian, F. S. Veraitch, Curr. Opin. Biotechnol. 2018, 53, 164-181.

[8] P. Vormittag, R. Gunn, S. Ghorashian, F. S. Veraitch, Curr. Opin. Biotechnol. 2018, 53, 164-181.

[9] M. Kalos, B. L. Levine, D. L. Porter, S. Katz, S. A. Grupp, A. Bagg, C. H. June, Sci. Transl. Med. 2011, 3, 95ra73.

[10] M. Kalos, B. L. Levine, D. L. Porter, S. Katz, S. A. Grupp, A. Bagg, C. H. June, Sci. Transl. Med. 2011, 3, 95ra73.

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A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells

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A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells

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