The intracellular domains of the second and third-generation CARs usually include, in addition to CD3ζ, one or two costimulatory signaling molecules, such as 4-1BB (CD137), CD28, CD27, OX40 (CD134), inducible T cell co-stimulator (ICOS) or regulatory subunit I anchoring disruptor (RIAD) that extend the strength of signal afforded by the CAR, enhance survival, cell activation, proliferation, cytokine secretion and cytotoxicity against tumor cells that express the CAR-specific antigen [69]. This evidence concerns the gene ICOS and neoplasm.