Overcoming cancer tolerance with immune checkpoint blockade

Cancer immunotherapy has largely been hindered by the ability of tumors to induce tolerance and escape the immune system. By targeting coinhibitory and costimulatory receptors in the immune system, it is possible to counteract the pathways that tumors utilize to avoid immune destruction. Ipilimumab, the first approved drug of this class, blocks the coinhibitory receptor CTLA-4 and has been shown to improve survival in advanced melanoma. Research into expanding the uses of CTLA-4 blockade as well as targeting alternative coinhibitory and costimulatory checkpoints is ongoing. Checkpoint blockade, particularly when combined with conventional therapies and cancer vaccines, has the potential to revolutionize cancer immunotherapy and provide new therapeutic options to a broad range of malignancies. This chapter will review the rationale for targeting immune checkpoints, the pathways of particular interest, and the research being conducted to bring checkpoint blockade to clinical use.