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Overcoming Immunologic Tolerance to Melanoma: Targeting CTLA-4 with Ipilimumab (MDX-010)

Department of Interdisciplinary Oncology, Donald A. Adam Comprehensive Melanoma Research Center, and H. Lee Moffi tt Cancer Center and Research Institute, Tampa, Florida, USA

Key Words. CTLA-4 • Melanoma • T cell • Antibody • Ipilimumab • MDX-010

Correspondence: Jeffrey Weber, M.D., Ph.D., H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, SRB-2, Tampa, Florida 33612, USA. Telephone: 813-745-2007; Fax: 813-745-4384: e-mail: Jeffrey.Weber{at}moffitt.org

Received February 7, 2008; accepted for publication July 8, 2008.

Disclosure: The author discloses that the article discusses ipilimumab (Medarex/Bristol-Myers Squibb) and tremelimumab (Pfizer) as anticancer treatments. J.W. has received research funding and honoraria from Bristol-Myers Squibb and honoraria from Pfizer. He also received payment from Imedex, LLC, for writing this article. 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 author, planners, independent peer reviewers, or staff managers.

Targeted biologic therapies such as anti–cytotoxic T lymphocyte antigen (CTLA-4) monoclonal antibodies, either as monotherapy or in combination with chemotherapy or vaccines, have shown great promise in late-stage melanoma, which has a very poor prognosis. Melanoma is relatively resistant to both chemotherapy and radiotherapy. Blockade of CTLA-4, which inhibits T-cell proliferation, promotes stimulation of adaptive immunity and T-cell activation, resulting in eradication of tumor cells. Two human monoclonal antibodies are under investigation in melanoma. Phase II and III clinical trials are currently evaluating the efficacy and safety of ipilimumab (MDX-010, Medarex, Inc., Princeton, NJ, and Bristol-Myers Squibb, Princeton, NJ) and tremelimumab (CP-675,206; Pfizer Pharmaceuticals, New York) in melanoma. Data are available on ipilimumab, which has been explored as monotherapy and in combination with vaccines, other immunotherapies such as interleukin-2, and chemotherapies such as dacarbazine. Overall response rates range from 13% with ipilimumab plus vaccine in patients with stage IV disease to 17% and 22% with ipilimumab plus dacarbazine or interleukin-2, respectively, in patients with metastatic disease. Responses have been durable, and among those experiencing grade 3 or 4 autoimmune toxicities, even higher response rates have been seen—up to 36%. While the optimal dose of ipilimumab has yet to be established, studies also indicate that higher doses may be more effective. Importantly, the lack of an initial clinical response may not predict ultimate treatment failure, because the onset of a response may follow progressive disease or stable disease. Pending results from registration studies with ipilimumab and lessons learned from registration studies conducted with tremelimumab will help to define the role of anti–CTLA-4 blockade in the treatment of metastatic melanoma.