Profile of ipilimumab and its role in the treatment of metastatic melanoma

Abstract

Melanoma is an immunogenic cancer. However, the ability of the immune system to eradicate melanoma tumors is affected by intrinsic negative regulatory mechanisms. Multiple immune-modulatory therapies are currently being developed to optimize the immune response to melanoma tumors. Two recent Phase III studies using the monoclonal antibody ipilimumab, which targets the cytotoxic T-lymphocyte antigen (CTLA-4), a negative regulator of T-cell activation, have demonstrated improvement in overall survival of metastatic melanoma patients. This review highlights the clinical trial data that supports the efficacy of ipilimumab, the immune-related response criteria used to evaluate clinical response, and side-effect profile associated with ipilimumab treatment.

Keywords: CTLA-4; T-cells; ipilimumab; melanoma.

Figure 1

Ipilimumab blocks the costimulatory signal required for T-cell activation. Antigen-presenting cells (APCs) present melanoma antigens bound to the major histocompatibility complex (MHC) to T-cells. Costimulation of CD28 receptor on T-cells by CD80 or CD86 ligands on APCs is also required for optimal T-cell activation. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T-cells can bind with greater affinity to CD80 and CD86, and thus disrupt the necessary costimulatory signal provided by APCs. Ipilimumab binds to CTLA-4 and blocks its binding to CD80 or CD86 on APCs allowing for costimulation of CD28 receptors on T-cells by APC CD80/86, and optimal T-cell activation.,