antigen-presenting cells . Think of it like the alarm system of your house — it alerts you to a burglar trying to get into the house , but burglars learn how and where to cut the wire to the various alarm systems . Similarly , through evolution , the tumor cells acquire the ability to turn off the checkpoint warning system alerting the dispatch ( dendritic cells ). Examples for approved treatments that target PD-1 and disable the off switch of the immune system are Pembrolizumab ( Keytruda ®) and Nivolumab ( Opdivo ®), and the first PD- L1 antibody is in pivotal trials , hopefully headed for FDA approval ( Table 1 ). We can look at them as placing the disabled alarm system of your house on a back-up battery system — now the immune system will again recognize the malignant cells and alert the dispatch station ( antigen-presenting cells , dendritic cells ), resulting in a police response ( activated T-cells ).
Figure 2 . Abnormal expression of receptors on malignant cells can occur
Treatments that Target the Immune Checkpoint CTLA-4 Another immune checkpoint , cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4 ), can be abnormally expressed , allowing the malignant cells to go unnoticed by T cells — it functions as a system controlling cell motility and invasion . CTLA-4 is also a negative regulator of T-cell activity that limits the lifespan and activity of activated T-cells and disables their normal function . Look at CTLA-expressing tumor cells as the burglars with the hacksaw that cut the iron bars on the windows — they can move freely inside your house .
Ipilimumab ( Yervoy ®) is a monoclonal antibody that attaches to CTLA-4 and stops it from working . This can boost the body ’ s immune response against cancer cells . Ipilimumab ( anti-human CTLA-4 ) was approved for the treatment of metastatic melanoma by the FDA in 2010 1 ( Table 1 ).
Consider ipilimumab as the German Shepherd that pins the burglars in the corner until the police arrive — hopefully alerted by the dendritic cells . In a way , this explains why anti-PD-1 and anti-CTLA-4 work so well together .
Therefore , the use of immune checkpoint inhibitors tips the balance from tolerance of the tumor by T cells to targeting of the tumor . For example , blocking the PD-1 protein ( on the surface of T cells ) or the PD-L1 protein ( on the surface of cancer cells ) can increase cancer antigen recognition by preventing PD-1 / PD-L1 interaction on cancer cells . 2 These blockades appear particularly useful for potentiating the antitumor immune response , which has helped to transform cancer therapy . This is also being recognized by investors , with $ 125 million donated to Johns Hopkins University for a new institute focused solely on immunotherapy . 3
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