Figure 2.

Dual CAR strategies to improve specificity of CAR T-cell MM therapy. (A) Split CAR T-cells, in which activation through CD3ζ and co-stimulation are split over a first generation CAR and a chimeric co-stimulatory CAR (CCR), each targeting distinct tumor antigens. Binding of both CARs is required for full T-cell activation. Split CAR T-cells can be generated using a bicistronic vector (A1) or two separate CAR and CCR vectors (A2). (B) An inhibitory CAR (iCAR) binding a self-antigen inhibits T-cell activation of a second CAR targeting a tumor-associated antigen (TAA). In the absence of a self-antigen it functions as a conventional single CAR T-cell. CAR/iCAR combinations can also be made using a bicistronic vector (B1) or two separate CAR and iCAR vectors (B2).