Ipilimumab

Developmental History, Clinical Considerations, and Future Perspectives

Michael A. Postow, MD; Jedd D. Wolchok, MD, PhD

Disclosures

The Melanoma Letter. 2012;30(1):1-4. 

In This Article

Development of a Novel Immune-modulating Therapy

Ipilimumab (commercial name Yervoy™, Bristol-Myers Squibb, Princeton, NJ) was approved on March 25, 2011 by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma. Its approval was a landmark event in the history of melanoma treatment, as it was the first therapy ever to demonstrate improved overall survival in a randomized phase III trial for patients with metastatic melanoma.[1] Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4). Since CTLA-4 is normally expressed on the surface of T-cells as a negative regulator of T-cell function, ipilimumab releases T-cells from this inhibitory mechanism, enabling the uninhibited T-cells to exert their full potential in creating antitumor immunity (Figure 1).

Figure 1.

Panel "A" shows that T-cell activation involves binding of the T-Cell Receptor (TCR) to a peptide antigen bound to the major histocompatibility complex (MHC) on the surface of an antigen-presenting cell (APC). This process also involves the interaction of CD28 on T-cells with the B7 molecules on APC. Following T-cell activation, panel "B" shows that CTLA-4 is up-regulated and expressed on the cell surface of effector T-cells and functions as an inhibitory molecule, outcompeting CD28 in the binding to B7, and causing inhibition of T-cell activation and function. Ipilimumab binds to and inhibits the function of CTLA-4, thus enhancing T-cell function as shown in panel "C".

Over 15 years of research have established the foundations for the therapeutic potential of ipilimumab. Preclinical development was led by Dr. James Allison, who initially demonstrated that antibodies directed at CTLA-4 could result in tumor regressions in mice.[2] Pilot clinical studies of ipilimumab followed, with the first human phase I study of ipilimumab reported in 2002, demonstrating tolerability with early hints of clinical activity.[3] Subsequent phase II studies focused on establishing appropriate dosing (0.3mg/kg vs. 3mg/kg vs. 10mg/kg) and schedule, suggesting that the dose of ipilimumab was relevant. The highest administered dose, 10mg/kg, resulted in a higher response rate compared to the 3mg/kg dose, albeit with increased side effects.[4]

Ultimately, FDA approval at the 3mg/kg dose was based upon an overall survival benefit seen in a randomized phase III trial comparing ipilimumab (3mg/kg) with or without the gp100 peptide vaccine compared to gp100 alone for patients with previously treated, unresectable stage III or stage IV melanoma.[1] More recently, the benefit of ipilimumab was also established for treatment-naïve patients through a second randomized phase III trial.[5] Patients who received a higher dose of ipilimumab (10mg/kg) with dacarbazine had improved overall survival compared to those receiving dacarbazine alone.

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