CD28 and neoplasm: This effect was at least partly attributed to the 4-1BB-mediated activation of non-canonical nuclear factor κB (ncNF-κB) signaling in CAR-T cells [37]; however, as CARs with a CD28 domain exhibit more rapid tumor elimination [38], attempts to improve their in vivo performance have led to a generation of mutant CD28 endodomain [39], or third generation CARs containing both CD28 and 4-1BB sequences [40].