| Abstract: |
The discovery of checkpoint proteins which regulate T cell activation and proliferation through inhibitory or stimulatory receptors has led to a new class of anti-tumor therapies. The goal of modulating these checkpoints is to overcome pathologic inhibition of T-cell activity which develops during tumorigenesis. The monoclonal antibody mediated blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a co-inhibitory molecule present on the surface of an activated T cell, has been a prototype for demonstration that augmentation of T cell activity can effectively treat malignant melanoma. In this review, we first describe the proposed mechanism of action and preclinical data for CTLA-4 blockade which led to its clinical development. Subsequently, we review the pivotal clinical trials which led to the characterization of inflammatory side effects and also the novel kinetics of anti-tumor response associated with CTLA-4 blockade. Finally, we discuss a panel of potential biomarkers for response to anti-CTLA-4 therapy. CTLA-4 monoclonal antibody blockade has demonstrated the ability to provide durable clinical benefit. With increasing knowledge of how to effectively manipulate this and other T cell checkpoints, cancer immunotherapies are emerging as an attractive therapeutic option in the treatment of melanoma and other malignancies. © Springer Science+Business Media, LLC 2012. All rights reserved. |
