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Introduction

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: J.W. has received research funding and honoraria from Bristol-Myers Squibb (ipilimumab) and honoraria from Pfizer (tremelimumab). J.W. also received payment from Imedex, LLC, for writing this article.

One of the recent success stories in translational oncology centers around the newly found ability to manipulate immune responses in patients with cancer by the use of immune-modulating antibodies. The prototypes of an entirely new class of drugs, the cytotoxic T lymphocyte antigen (CTLA)-4–abrogating antibodies, are in the final stages of the registration process and will be presented to the U.S. Food and Drug Administration sometime in 2009. The background preclinical and scientific data are presented that set the stage for the clinical development of these two drugs in an illuminating article by Drs. Jedd Wolchok and Yvonne Saenger of Memorial Sloan-Kettering Cancer Center. The experiments in murine systems, many performed in the late 1990s by their Memorial colleague Dr. Jim Allison, are recapitulated and explained, and the overall mechanisms and pathways by which T-cell stimulation and costimulation occur is masterfully set out by Drs. Wolchok and Saenger.

In the second article in this series, a series of early clinical trials with tremelimumab, an IgG₂ antibody from Pfizer that abrogates the CTLA-4 signal, is described in detail by Dr. Antoni Ribas from the University of California, Los Angeles. He clearly lays out the developmental philosophy for tremelimumab and describes the clinical evidence to justify the designs of trials with extended dosing of that drug in metastatic melanoma. Dr. Ribas also postulates how the drug functions to stimulate immunity and eradicate melanoma.

In the final article, Dr. Jeffrey Weber from the Moffitt Cancer Center describes early trials with ipilimumab, an IgG₁ antibody, and indicates how autoimmune-related adverse events arose in relation to treatment when the drug was used alone, with a vaccine approach, or with other cytokines. He postulates that the autoimmune events are related directly to clinical benefit with the drug, and supports this idea with data from trials of patients with metastatic melanoma and resected high-risk melanoma receiving ipilimumab alone or with a vaccine.

The utility of this new class of drugs will not be confined to melanoma, because trials in kidney cancer and prostate cancer using ipilimumab have shown promise. Development of antibodies and small molecules that bind PD-1, CD137, OX-40, and CD40 are moving ahead rapidly, and may bring the promise of cancer immunotherapy into the realm of clinical reality.

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