CD28 and neoplasm: CD28 and 4-1BB endo-domains regulating the effector and the memory T cell phenotypes, respectively, appear both critical for CAR T-cell activity and third-generation CAR built with a combination of these two co-stimulatory domains (CD28.4-1BB.CD3ζ) demonstrated superior anti-tumor efficacy in vitro and in vivo preclinical models compared to their respective second generation CARs (CD28, OX40, 4-1BB) and a third generation CAR encoding for CD28.OX40 costimulatory domains [67].