Figure 4. CAR T cell subsets with increased efficacy and Universal CARs with interchangeable targets.

CD26 high chimeric antigen receptor (CAR) T cells have increased cytokine production, a more stem-like phenotype, and increased cell trafficking compared with conventional CAR T cells. CAR T cells with endogenous γδ T cell receptors (TCRs) have decreased exhaustion and increased costimulation compared with conventional CAR T cell products, of which 95% have αβ TCRs. Several versions of universal CARs have been published in recent years. The split, universal and programmable (SUPRA) CAR uses a ‘zipper’ system to interchangeably affect the CAR. The single chain variable fragments (scFvs) can be switched to target new antigens or multiple antigens at once and the zipper binding affinity can be changed to tune the strength of the CAR signal for an appropriate response. Gating strategies can also be used by having the CD3ζ signaling domain and the costimulatory domain on separate molecules so that both corresponding antigens must be present to have full CAR activation. Others have pursued universal CARs through tagging tumour cells with antibodies (which are transient and can be continuously changed) conjugated to tags like fluorescein isothiocyanate (FITC) or biotin and then developing CAR T cells against the tag to activate their cytotoxic function. CCR, CC-chemokine receptor; HLA-DR, human leukocyte antigen-DR; IFNγ, interferon-γ; IL, interleukin; LEF1, lymphoid enhancer-binding factor 1; PD1, programmed cell death protein 1; TIM3, T-cell immunoglobulin mucin receptor 3.Box 1.

This figure is copyrighted by Nature Reviews Cancer and can be found at: https://www.nature.com/articles/s41568-020-00323-z.