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Overcoming Immunologic Tolerance to Melanoma: Targeting CTLA-4 with Tremelimumab (CP-675,206)

Divisions of Hematology-Oncology and Surgical-Oncology, University of California at Los Angeles, Los Angeles, California, USA

Key Words. CTLA-4 • Melanoma • T cell • Antibody • Tremelimumab • CP-675,206

Correspondence: Antoni Ribas, M.D., Division of Hematology-Oncology, 11-934 Factor Building. UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, California 90095-1782, USA. Telephone: 310-206-3928; Fax: 310-206-0914: e-mail: aribas{at}mednet.ucla.edu

Received December 10, 2007; accepted for publication February 11, 2008.

Disclosure: The author discloses that this article discusses experimental use of tremelimumab (Pfizer) and ipilimumab (Medarex/Bristol-Myers Squibb). A.R. has received research funding and honoraria from Pfizer. 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.

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade therapies have been evaluated in clinical trials and have shown promise as possible options for treating patients with cancer. One agent under investigation is tremelimumab (CP-675,206), a monoclonal antibody that has been demonstrated to be a safe and efficacious treatment in patients with malignant melanoma. Results of a phase I clinical trial suggested that a dose of 15 mg/kg of tremelimumab would be the maximum-tolerated dose, with the most common grade 3–4 toxicities being diarrhea and rash. Pharmacokinetic studies showed that the postinfusion plasma concentration and area under the plasma disposition curve both increased in an approximately proportional manner with dose. Studies also showed that tremelimumab has a low clearance (0.132 ml/h·kg), a small volume of distribution (81.2 ml/kg), and a long terminal-phase half-life (22.1 days). A pivotal phase II clinical trial assessing single-agent tremelimumab as second-line therapy in metastatic melanoma has completed accrual, with response rate as the primary endpoint. A pivotal phase III trial has also completed accrual; that study compared the overall survival of previously untreated patients receiving single-agent tremelimumab versus dacarbazine or temozolomide.