Science 350, aab4077 (2015)

Credit: SCIENCE

A patient's T cells can be modified to produce chimeric antigen receptors (CARs) that specifically recognize and target tumors that express a particular antigen. However, this approach is less successful in modulating immune activity in the temporal and spatial manner needed to prevent targeting of non-tumor cells and minimize the release of excess cytokines. To address these limitations, Wu et al. have developed a new system called “ON-switch” CARs that activates T cells only in the presence of both the antigen and a small-molecule dimerizer. They attached the FK506 binding protein (FKBP) domain to the extracellular antigen-recognition domain and fused a mutant version of the FKBP-rapamycin binding domain (FRB) to the intracellular immunoreceptor tyrosine–based activation motifs (ITAMs). The introduction of the rapamycin analog AP21967 promoted the heterodimerization of the antigen-recognition and ITAM domains, which triggered antigen-mediated T cell activation. Although the authors detected colocalization of both components in T cells, high-resolution single-molecule imaging revealed that a physical interaction between components was only observable with AP21967 treatment. When these components were expressed in CD4+ helper T cells, the authors detected increased cytokine secretion and T cell proliferation only in the presence of both antigen-expressing target cells and AP21967. These cellular effects could be modulated by adjusting the concentration of the dimerizer. The use of the ON-switch CAR to modify CD8+ cells in culture and in a mouse xenograft model to target CD19+ cells resulted in decreased numbers of CD19+ cells in the presence of AP21967, while non-CD19+ cells were spared. Finally, the ability of the ON-switch CAR to utilize alternative modules, such as the gibberellin-induced dimerization system, provides increased flexibility for modulating T cell activity in a refined manner.