The pharmacology of second-generation chimeric antigen receptors

T cell engineering is a novel therapeutic strategy designed to rapidly establish potent tumour immunity. Tumour antigen targeting and enhanced T cell functionality may be achieved through the expression of synthetic receptors for antigen, known as chimeric antigen receptors (CARs).Second-generation CARs, which provide co-stimulatory signals in addition to initiating T cell activation, have shown impressive complete remissions in patients with B cell malignancies, especially acute lymphoblastic leukaemia and B cell lymphomas.Co-stimulation is required for effective proliferation, persistence and function of CAR T cells.CD28 and 4-1BB provide distinct, complementary co-stimulatory support to T cells, although their effect within CAR structures cannot be equated to that of the native receptors.Both 28ζ and BBζ CARs show promising clinical results against B cell malignancies, with different tumour-killing kinetics. Inclusion of CD28 appears to mediate faster tumour reduction, whereas 4-1BB appears to promote T cell persistence.The design and study of CARs is giving rise to the new field of immunopharmacology.