Gated chimeric antigen receptor T-cells: the next logical step in reducing toxicity?

Over recent years, interest in the use of autologous T-cells as a therapeutic strategy for cancer has increased substantially. Studies using ex vivo expanded tumor-infiltrating lymphocytes (TILs) demonstrated that adoptive T-cell therapy could achieve dramatic reductions in tumor burden (1). However such an approach is limited to those patients from whom tumor-specific T-cells can be isolated. Genetic engineering bestows tumor-specificity into an otherwise polyclonal T-cell population through engraftment of a new T-cell receptor (TCR), or a chimeric antigen receptor (CAR). As a result, T-cells from any patient can theoretically be re-directed against a chosen antigen on malignant cells, thus broadening the application of adoptive T-cell therapy. However, a key hurdle in the widespread use of adoptive T-cell therapy is the paucity of antigens exclusively expressed by tumors. In a recent article published in Cell, Roybal et al. (2) have detailed a novel CAR-based ‘antigen recognition circuit’ that aims to overcome this hurdle by uncoupling efficient tumor eradication from the ‘on-target, off tumor’ toxicity associated with concomitant targeting of healthy tissue.