Synthetic Biology in Cancer Cellular Immunotherapy

The transfer of tumor-targeting T cells to patients is a promising approach for cancer immunotherapy. In particular, chimeric antigen receptors (CARs) modified T cells had demonstrated phenomenal efficacy against lymphoid leukemia, with more than 90% complete remission being observed. Despite these encouraging results, many challenges remain to be addressed before T cell therapy can be widely adopted for other cancers. Limiting the toxicity without comprising their efficacy are some of the key hurdles that need to be overcome. Here I will describe our recent efforts in using synthetic biology to develop drug-controllable genetic circuits and signaling switches for temporally modulating T cell activation. Specifically, I will highlight a set of multi-state memory switches for regulating multiple CARs expression, which enable the tuning of CAR expression level and ligand specificity. In addition, I will also discuss our novel dual small-molecule-gated signaling switches for ON/OFF control (one drug for ON switch, one drug for OFF switch) of T cell activation originated from T cell receptors and CARs. These genetic tools will provide a flexible tool kit for managing or preventing the toxicity associated with T cell therapy.