In addition to the TCR downstream modulators described above, CBL-B, an E2 ubiquitin ligase that negatively regulates T cells activation downstream the TCR and CD28 co-stimulatory protein has also being down-regulated in pre-clinical models [21,109,110], where transient down-regulation of this protein resulted in enhanced anti-tumor efficacy and bypassed the requirement for exogenous IL-2 administration for tumor eradication. The gene discussed is CD28; the disease is neoplasm.