Chimeric antigen receptor (CAR) T cells are synthetic hybrid receptors created by recombinant techniques that combine an extracellular domain, usually derived from an antibody single-chain variable fragment (scFv), with intracellular signaling domains from activating co-stimulatory molecules (from endogenous TCRs, CD28, or 4-1BB) that allow for retargeting of T cells to antigens on malignant cells (Fig.1). A CAR T cell targeting the CD19 molecule on malignant B cells provided the first and most promising therapeutic results in the treatment of B-cell malignancies, with complete response rates of 70–90%. CAR T cells targeting the NY-ESO antigen on sarcoma cells have induced remissions in patients with synovial cell sarcoma. CAR T cells targeting B-cell maturation antigen (BCMA) on myeloma cells have also induced clinical responses. The CAR T-cell strategy is being developed for targeting solid tumors and modified as universal CAR T cells to overcome the need for MHC matching with T CAR recipients. One such strategy is to modify T cells to release cytokine, express co stimulatory ligands, or secrete checkpoint-blocking single-chain variable fragment (scFvs). The next generation of CAR T cells are known as T cells redirected for universal cytokine-mediated killing (TRUCKs). Cytokine-secreting tumor-specific T cells could harness the adjuvant effect of recombinant cytokines by local delivery to the tumor to decrease cytokine side effects of excess inflammation, termed cytokine release syndrome, that can be seen with CAR T-cell therapy. Messenger RNAs that encode for tumor antigens are now being combined with CAR T cells with specificity for the same tumor antigens to expand tumor-specific CAR T cells and amplify their therapeutic effect.

Fig1. Platforms for redirecting T cells to cancer. A. T-cell receptors (TCRs; e.g., anti-NY-ESOI) or chimeric antigen receptors (CARs; e.g., anti-CD19 CAR). B. CAR structure includes an extracellular antigen recognition domain fused to intracellular TCR signaling domains (CD3z) and co-stimulatory domains (e.g., CD28 or 4-1BB). (Reproduced with permission from WA Lim, CH June: The principles of engineering immune cells to treat cancer. Cell 168:724, 2017.)

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