Additionally, since both B7 ligands and CD28/CTLA-4 receptors are expressed broadly without tumor specificity and that they play essential roles in the control of general immune homeostasis, targeting this pathway could be met with severe autoimmune toxicities, which was shown to be the case in the clinical trials of TGN1412, an anti-CD28 super agonist antibody [39], and the anti-CTLA-4 antibodies, ipilimumab and tremelimumab [40–42]. This evidence concerns the gene CD28 and neoplasm.