Fig. 3.

Nuances on CAR-T cell design. (a.) Co-expression of two discrete CARs in one cell is known as a dual CAR. (b. and c.) Tandem CARs express two different scFvs in a single CAR molecule and can be arranged in series as a stack (b.) or in an interrupted looped structure (c). In the case of dual and tandem CAR-T cells, identification of either antigen A or antigen B is sufficient for activation. (d.) Combinatorial CARs are composed of two partners; one incorporates the CD3ζ chain while the other includes the co-stimulatory signalling domain. (e.) Synthetic Notch (synNotch) receptors cause the transcription of a second CAR after antigen identification of their corresponding antigen. Combinatorial and synNotch CARs require both antigens to be recognised for full T cell activation. (f.) ON-Switch CARs require the presence of specific activating molecules to promote fully functional receptor assembly. (g.) Inhibitory CARs (iCARs) include inhibitory signalling motifs such as PD-1 or CTLA-4 that block T cell activation following antigen recognition