Fig. 5

Different types of “Dual targeting” approaches. a The CD3ζ and costimulatory domains are separated in individual molecules targeting two diverse tumor antigens, an event known as trans-signaling CARs. These proteins will be activated when both antigens are identified [115–117]. b The “ON-switch” CAR T cell requires a small molecule drug to activate an “ON-switch” such that the engaging antigen and intracellular signaling domain will be connected [118]. c The mechanism of “notch CAR” recognizes combinatorial antigens by using a synthetic Notch receptor for one antigen that drives the inducible expression of the CAR target to a second antigen; this system requires a tumor cell to express both antigens before recognition by the CAR T cells [119]. d An inhibitory CAR replaces the CD28- CD3ζ chain with an inhibitory domain, which limits the excess activation signal from other CARs [120, 121]. e “PD1CD28” switch CAR T cells express a switch receptor construct comprising the PD1 extracellular domain and the CD28 costimulatory domain; this allows PD-L1 binding to enhance CAR T cell cytokine secretion and proliferation [122]. f Dual-signaling CAR, T cells are respectively modified by two distinct CAR molecules with two different scFvs and the same intracellular signaling domain [108, 109]. g Tandem CARs comprise two different linked scFvs to allow for targeting of two different antigens using a single construct [112]. h This is a hypothetical strategy to reduce CRS and was inspired by the “PD1CD28” switch CAR T cells