Immunomodulatory therapy for melanoma: ipilimumab and beyond

Abstract

In 2011, the U.S. Food and Drug Administration approved the first new therapy for melanoma in more than a decade, ipilimumab (Yervoy). Ipilimumab is a novel antibody that blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a regulatory molecule expressed on activated T cells. Blockade of this important immune checkpoint can lead to durable tumor regression, and phase III studies show an overall survival benefit for patients with advanced melanoma. During the clinical development of ipilimumab, several unique features of this immunotherapy were identified, including the remarkable durability of responses and a distinct side-effects profile. We review the preclinical and clinical development of CTLA-4-blocking antibodies and describe current practices using ipilimumab for the treatment of advanced melanoma. Unique clinical issues related to ipilimumab will be summarized. Lastly, we will briefly preview combination therapies that incorporate ipilimumab and new checkpoint-targeting antibodies currently in clinical development.

Figure 1

Pre-Clinical and Clinical Development of CTLA-4 blocking Antibodies.

Figure 2. Co-stimulatory and Co-inhibitory Molecules Regulate T cell Activation

A diversity of activating and inhibitory signals are integrated to modulate the process of T cell activation. CTLA-4 is one of many inhibitory checkpoint molecules that regulate T cell activation.