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immune response against cancer cells. Blocking CTLA-4 induces an antitumor immune response by promoting the activation and proliferation of tumor specific T-cells. This blockade is also thought to promote the generation of memory T-cells which provides a long term antitumor response.

The mechanism of action behind this effect is explained by the fact that CTLA-4 is a CD28 homolog that binds with higher affinity to CD80 (B7.1) and CD86 (B7.2). The relative amount of CD28:B7 binding versus CTLA-4:B7 binding determines whether a T-cell will undergo activation. When CTLA-4 and its ligands bind, no stimulatory signal is produced. This competitive binding can prevent the stimulatory signal normally provided by CD28/B7 binding. Some evidence suggests that CTLA-4 binding to B7 may also produce inhibitory signals that counteracts the stimulatory signals from CD28:B7 binding.

Ipilimumab is an FDA approved CTLA-4 inhibitor which is a selective human IgG1 mAB used for the treatment of melanoma. It is currently undergoing clinical trials for the treatment of non-small cell lung carcinoma, small cell lung cancer, bladder cancer and metastatic prostate cancer. Like all immune checkpoint inhibitors, CTLA-4 inhibitors are associated with immune mediated toxicities, most of which can be managed successfully with corticosteroids. Commonly reported immune mediated adverse reactions include rash, itching and gastrointestinal disorders.

The CTLA-4 and PD-1/PD-L1 pathways have a similar negative effect on T-cell activity however the timing, signaling mechanism and location of immune inhibition by these two checkpoints dif