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The Mechanism of Anti-CTLA-4 Activity and the Negative Regulation of T-Cell Activation

^aMelanoma/Sarcoma Oncology Service and Ludwig Center for Cancer Immunotherapy, ^bMemorial Sloan-Kettering Cancer Center, New York, New York, USA

Key Words. CTLA-4 • Melanoma • Antibody • T cell

Correspondence: Jedd D. Wolchok, M.D., Ph.D., Melanoma/Sarcoma Oncology Service and Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box #340, New York, New York 10065, USA. Telephone: 646-888-2395; Fax: 646-422-0453: e-mail: wolchokj{at}mskcc.org

Received December 10, 2007; accepted for publication March 3, 2008.

Disclosure: The authors disclose that the article discusses ipilimumab (Medarex/Bristol-Myers Squibb) for cancer therapy. J.D.W. has acted as a consultant for Bristol-Myers Squibb and Medarex. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

The survival rate of patients diagnosed with late-stage melanoma is poor—only 5%–10%. Enlisting the immune system in the fight against cancers such as melanoma could help improve the prognosis of these patients. Data have shown that melanocyte proteins make good targets for immune system–based therapy in this disease. However, self-tolerance, which develops to inhibit autoimmune attack, makes this strategy difficult. Two proteins on the surface of T cells—CD28 and cytotoxic T-lymphocyte antigen 4 (CTLA-4)—play important roles in the regulation of immune activation and tolerance. CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using anti—CTLA-4 monoclonal antibody therapy has great appeal because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Both clinical and preclinical data indicate that CTLA-4 blockade results in direct activation of CD4⁺ and CD8⁺ effector cells, and anti–CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma. Interestingly, the occurrence of adverse events among patients treated with CTLA-4 blockade helps shed light on the mechanism of action of anti–CTLA-4 monoclonal antibodies. Most adverse events involve immune-related toxicity to the skin and gastrointestinal tract. Major gastrointestinal toxicity develops in up to 21% of treated patients, and while an objective response occurs in approximately 36% of melanoma patients who develop enterocolitis with treatment, an objective response is found in only 11% of patients who do not experience this adverse reaction.

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