Immune Checkpoint Inhibitors.

Undoubtedly the discovery of immune checkpoints such as CTLA-4 and PD-1 has been crucial to the development of cancer immunotherapy. Although these molecules were originally discovered as molecules playing a role in T cell activation or apoptosis, subsequent preclinical research showed their important role in the maintenance of peripheral immune tolerance. Mice deficient of the immune checkpoints CTLA-4 or PD-1 develop autoimmune-like diseases that occur early after birth and are lethal in the case of CTLA-4 deficiency, or become apparent much later in life in the case of PD-1 deficiency. Blockade of CTLA-4 and PD-1 resulted in the development of antitumor immune responses that were effective as single agents or required additional treatment depending on the preclinical model. Therefore, it was surprising that single-agent anti-CTLA-4 and anti-PD-1 are so effective anticancer treatments in humans. These therapies have revolutionized cancer immunotherapy as they showed for the first time in many years of research in metastatic melanoma, which is considered one of the most immunogenic human cancers, an improvement in overall survival, with an increasing group of patients benefitting long-term from these treatments. In this chapter we discuss the discovery of immune checkpoints, the clinical application of their inhibitors and the future directions of this highly interesting class of molecules.