ICOS and neoplasm: Limitations in the proliferative response following recognition of tumor cells, and in persistence and homing of first-generation CAR-T cells to local tumor cells in vivo have been largely surmounted by second-generation CAR constructs containing co-stimulatory signaling molecules such as CD28 [45], 4-1BB [46], OX40 [47] and ICOS (inducible T-cell co-stimulator; CD278) [48], resulting in upregulation of anti-apoptotic factors and increased secretion of cytokines upon antigen recognition [49,50].