1. A Recurring Chemogenetic Switch for Chimeric Antigen Receptor T Cells
- Author
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Quan Pan, Zhi Z. Geng, Wenshe R. Liu, Shiqing Xu, Jianfeng Zhou, Na Wang, Wenyue Cao, and Shaodong Guo
- Subjects
NS3 ,biology ,Chemistry ,Hepatitis C virus ,medicine.medical_treatment ,T cell ,medicine.disease ,medicine.disease_cause ,CD19 ,Chimeric antigen receptor ,Lymphoma ,Cell biology ,Cytokine ,medicine.anatomical_structure ,medicine ,biology.protein ,Cell activation ,human activities - 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 on the T cell surface. By embedding the hepatitis C virus NS3 protease (HCV-NS3) in an anti-CD19 CAR between the anti-CD19 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 on the T cell surface in the presence of ASV and its removal in the absence of ASV effectuates a practically recurring chemical switch for CAR-T cells. We demonstrated that the intact CAR on T cells was repeatedly turn on and off by controlling the presence of ASV. The dose dependent manner of the intact CAR display on T cells with regard to the ASV concentration enables delicate modulation of CAR-T cell activation during cancer treatment. In a mouse model, we showed different treatment prospects when ASV was provided at different doses to mice that were infused with both human CD19+ lymphoma and the switchable CAR-T cells.
- Published
- 2021