The development of chimeric antigen receptor (CAR) T cell therapeutics has revolutionized clinical intervention of cancer. Crowned as live drugs, CAR-T cell therapy has demonstrated success in the elimination of hematopoietic tumors including different types of leukemia, lymphoma and myeloma. Several CAR-T therapeutics have been clinically approved. Many others are on clinical trials. Although extremely powerful, CAR-T cell therapy suffers from serious safety concerns including cytokine release syndrome, neurological toxicity, tumor lysis syndrome, on-target/off-tumor toxicity, anaphylaxis, and hematological toxicity. Besides safety concerns, there are other challenges that limit efficacy of...

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The development of chimeric antigen receptor (CAR) T cell therapeutics has revolutionized clinical intervention of cancer. Crowned as live drugs, CAR-T cell therapy has demonstrated success in the elimination of hematopoietic tumors including different types of leukemia, lymphoma and myeloma. Several CAR-T therapeutics have been clinically approved. Many others are on clinical trials. Although extremely powerful, CAR-T cell therapy suffers from serious safety concerns including cytokine release syndrome, neurological toxicity, tumor lysis syndrome, on-target/off-tumor toxicity, anaphylaxis, and hematological toxicity. Besides safety concerns, there are other challenges that limit efficacy of CAR-T cell therapy such as CAR-T cell exhaustion and antigen escape. A method that can potentially alleviate toxicity and/or resolve in part non-safety challenges of CAR-T cell therapy is to build a switch in CAR-T cells for the regulation of their activation. Using a hepatitis C virus nonstructural protein 3 protease (HCV-NS3) and its inhibitory regulation by asunaprevir (ASV), an imbedded reversible chemogenetic switch has been integrated into a proof-of-concept switchable CAR for human CD19 (sCAR19). Preliminary results have shown that sCAR19-T cells can be reversibly turned on and off by ASV and showed ASV-regulated tumor killing effect in a mouse model. Built upon this strong preliminary investigation, the current application proposes to significantly expand the designs and tests of the HCV-NS3-based reversible chemogenetic switch by pursuing two specific aims: 1) Expand the evaluation of the HCV-NS3 switch; 2) Develop dual HCV-NS3 switches to orthogonally control two separate CARs. The ultimate goal is to establish protocols that can be potentially used in clinical investigations of HCV-NS3-based switchable CAR-T cells for better manageable toxicity, better tumor killing efficacy, delayed CAR-T cell exhaustion, and repeated CAR-T cell activation for treating tumor relapse.

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