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Melanoma and Cutaneous Malignancies

Tremelimumab (CP-675,206), a Cytotoxic T Lymphocyte–Associated Antigen 4 Blocking Monoclonal Antibody in Clinical Development for Patients with Cancer

^aDepartment of Medicine, Division of Hematology/Oncology, ^bDepartment of Surgery, Division of Surgical Oncology, and ^cJonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California, USA; Departments of ^dImmunology, ^eClinical PK/PD, ^gDrug Safety R&D, and ^fClinical Oncology, Pfizer Global Research & Development, Groton-New London, Connecticut, USA; ^hUniversity of Rochester School of Medicine and Dentistry, Rochester, New York, USA

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

Correspondence: Jesus Gomez-Navarro, M.D., Pfizer Global Research & Development, Groton-New London, Connecticut 06340, USA. Telephone: 860-732-2079; Fax: 860-732-7127; e-mail: jesus.gomez-navarro{at}pfizer.com

Tremelimumab (CP-675,206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte–associated antigen 4 (CTLA-4, CD152) in clinical development for patients with cancer. Blocking the CTLA-4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions. Its IgG₂ isotype minimizes the possibility of cytotoxic effects on activated T lymphocytes and cytokine release syndrome. Preclinical testing in vitro and in large animal models predicted the target concentrations of circulating antibody in humans necessary for a pharmacodynamic effect. Phase I clinical trials provided evidence of dose- or exposure-related effects consistent with the anticipated mechanism of action. Further clinical development has led to two ongoing registration trials in patients with metastatic melanoma: a phase III randomized trial of tremelimumab versus dacarbazine or temozolomide in previously untreated patients with advanced melanoma and a phase II trial of tremelimumab in previously treated patients with advanced melanoma.

Disclosure of potential conflicts of interest is found at the end of this article.

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