Cell 173, 1426–1438 (2018)

A promising approach in cancer immunotherapy is the use of T cells expressing chimeric antigen receptors (CARs), which consist of an antigen-specific single-chain fragment (scFv) linked to an intracellular signaling domain. Interaction of the CAR-expressing T cell with an antigen-specific tumor cell results in T-cell activation. However, the limited flexibility, specificity, and modularity of existing CARs require constant re-engineering of the T cells for new applications. To address some of these limitations, Cho et al. developed a split, universal and programmable (SUPRA) CAR system, zipCAR, composed of an extracellular leucine zipper fused to the intracellular signaling domain, while a zipFv component contained the complementary leucine zipper linked to the scFv. The level of SUPRA-mediated T-cell activation is determined on the basis of the affinity of the leucine zipper pairs, the expression levels of the zipCAR and zipFv, and the interaction between the T cell and the antigen-presenting cell. SUPRA also enables CAR inhibition by using a competitive zipFv containing a high-affinity leucine zipper, preventing zipFv–zipCAR interaction as well as combinatorial targeting of multiple antigens by adding different antigen-specific zipFv constructs. Overall, SUPRA offers improved utility and modality for cancer immunotherapy strategies.