Anticancer agent - ticilimumab
One way of treating cancer is to boost the body's immune system so it can fight the disease off on its own. One mechanism is to target CTLA-4, a Type I transmembrane protein that is expressed by activated T-lymphocytes and monocytes.
One way of treating cancer is to boost the body's immune system so it can fight the disease off on its own. One mechanism is to target CTLA-4, a Type I transmembrane protein that is expressed by activated T-lymphocytes and monocytes.
This is essential in maintaining immunological tolerance as it inhibits T-cell responses and the immune response. CTLA-4 knock-out mice have been shown to develop lymphoproliferative disease, while blockade of CTLA-4 increases T-cell responses and rejection of tumour tissue.
Ticilimumab is being developed by Pfizer as an agent to enhance T-cell activation and is in clinical trials for several types of cancer, including advanced melanoma, and kidney, colorectal and non-small cell lung cancers.1 It is a fully human IgG2 monoclonal antibody that specifically targets CTLA-4.
In a Phase I trial, 39 patients with solid tumours, mostly melanoma, were given single intravenous infusion doses of between 0.01 and 15mg/kg of the antibody.2 Two melanoma patients achieved a complete response and two further subjects a partial response, while four had stable disease and five extended progression-free survival after the treatment of metastases. The maximum tolerated dose was determined at 10 mg/kg.
A Phase I/II trial was carried out in 30 patients with metastatic melanoma. Twenty of the subjects were given 10mg/kg every month, and the remainder 15mg/kg every three months.3 They were assessed every two weeks, and four of the 12 patients with immune-related adverse events achieved an objective response, compared with only one of the 18 who did not. These responses were found to correlate to reductions in T-regulatory cells and the secretion of IL-10, and an increase in IL-2. Further trials are in progress.