Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma

Abstract

Ipilimumab (MDX-010, Yervoy; Bristol-Myers Squibb), a fully human monoclonal antibody against CTL antigen 4 (CTLA-4), was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In both early- and late-phase trials, ipilimumab has shown consistent activity against melanoma. For example, in a randomized phase III trial that enrolled patients with previously treated metastatic disease, ipilimumab, with or without a peptide vaccine, improved overall survival: Median overall survival was 10.1 and 10.0 months in the ipilimumab and ipilimumab plus vaccine arms, respectively, versus 6.4 months in the vaccine-alone group (hazard ratio, 0.68; P ≤ 0.003). Serious (grade 3-5) immune-related adverse events occurred in 10% to 15% of patients. Thus, although it provides a clear survival benefit, ipilimumab administration requires careful patient monitoring and sometimes necessitates treatment with immune-suppressive therapy. Here, we review the mechanism of action, preclinical data, and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma.

Figure 1

A, melanoma cells express proteins, such as gp100, MART-1, and tyrosinase, that may be processed and presented by antigen-presenting cells. T-cell recognition of peptide antigens derived from these proteins can potentially drive an antitumor immune response. For such tumor-directed T cells to become activated, 2 signals are required. The first signal (signal 1) occurs when the peptide antigen is recognized by the T-cell receptor on antigen-specific T cells. This recognition is exquisitely specific. However, for full T-cell activation, proliferation, and effector function, a second signal (signal 2) is needed. This signal is typically mediated by the interaction between costimulatory molecules such as B7.1 and B7.2 on antigen-presenting cells and CD28 on T cells. In reality, the situation is more complex, and signal 2 is derived from the integration of several positive and negative events. B, under certain conditions, T cells upregulate the cell surface molecule CTLA-4, which binds to B7.1 and B7.2 with greater affinity than does CD28. This series of events effectively hijacks signal 2, resulting in a situation in which specific T cells cannot be fully activated. C, ipilimumab (and other anti-CTLA-4 antibodies) bind to CTLA-4 on the cell surface, effectively blocking the interaction between CTLA-4 and B7.1/B7.2. This leads to interruption of the negative signal mediated by CTLA-4, the resumption of signal 2, and a relative restoration of T-cell activation.