Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events

Abstract

The immune system is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the antitumor immune response. Ipilimumab (MDX-010) is a fully human, monoclonal antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. Preclinical and early clinical studies of patients with advanced melanoma show that ipilimumab promotes antitumor activity as monotherapy and in combination with treatments such as chemotherapy, vaccines, or cytokines. Emerging data on the kinetics of response to ipilimumab and associated adverse events are increasing our understanding about how to manage patients treated with this therapy. For example, short-term tumor progression prior to delayed regression has been observed in ipilimumab-treated patients, and objective responses may be of prolonged duration. In some patients clinical improvement manifests as stable disease, which may also extend for months or years. Immune-related adverse events (IRAEs) have been observed in patients after CTLA-4 blockade and most likely reflect the drug mechanism of action and corresponding effects on the immune system. Early clinical data suggest a correlation between IRAEs and response to ipilimumab treatment. This paper briefly reviews the results from several ongoing and completed ipilimumab clinical trials, provides a synopsis of current trials, and presents several cases that demonstrate the kinetics of antitumor responses and the relationship to IRAEs in patients receiving ipilimumab.