The current issue of The Oncologist carries two articles on anti-CTLA-4 intervention. The articles are actually downloadable in pdf-format without charge.
URL: theoncologist.alphamedpress.org
Weber's introduction to the two articles:
In this issue of The Oncologist, two articles describe the recent clinical experience with two novel antibodies that abrogate the function of CTLA-4, a molecule expressed on T cells that acts to exert a dampening effect on the immune system. These antibodies were produced using different types of mice with engineered immune systems, and are thus fully human, with long half-lives of 2–4 weeks. Both antibodies, one produced by Pfizer and the other from Bristol-Myers Squibb/Medarex, have been shown to have clinical activity against metastatic melanoma and other histologies. Their use is accompanied by a unique spectrum of autoimmune side effects that in some cases are associated with clinical response and long-term freedom from progression. The kinetics of response in patients receiving either of these antibodies can be unusually prolonged, and in some cases patients with mixed responses or even progressive disease may subsequently achieve an objective response. Their clinical testing has ushered in a new era in immunotherapy, with a new set of side effects to be managed, and encouraging clinical activity that has driven the two companies to conduct four registration trials. If the trials are successful, and if one or both CTLA-4-antibodies are approved by the U.S. Food and Drug Administration, that would mark the first new agents approved for melanoma in over a decade. The initial success with these antibodies has encouraged the rapid development of new agonistic and antagonistic antibodies that alter immune regulation, such as anti-PD-1, anti-4-1BB, anti-CD40, and anti-OX-40. As new members of the co-stimulatory interactions between effector cells and antigen presenting cells are described, exciting new targets for immunotherapeutic intervention in oncology will be defined.
Review: Anti–CTLA-4 Antibody Ipilimumab: Case Studies of Clinical Response and Immune-Related Adverse Events
Jeffrey Weber
Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
Key Words. Cytotoxic T lymphocyte antigen 4 • CTLA-4 • Ipilimumab • Melanoma • Immune-related adverse events
Correspondence: Jeffrey Weber, M.D., Ph.D., Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, SRB 22045, Tampa, Florida 33612, USA. Telephone: 813-745-2691; Fax: 813-745-5838; e-mail; jeffrey.weber@moffitt.org
The immune system is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the antitumor immune response. Ipilimumab (MDX-010) is a fully human, monoclonal antibody that overcomes CTLA-4–mediated T-cell suppression to enhance the immune response against tumors. Preclinical and early clinical studies of patients with advanced melanoma show that ipilimumab promotes antitumor activity as monotherapy and in combination with treatments such as chemotherapy, vaccines, or cytokines. Emerging data on the kinetics of response to ipilimumab and associated adverse events are increasing our understanding about how to manage patients treated with this therapy. For example, short-term tumor progression prior to delayed regression has been observed in ipilimumab-treated patients, and objective responses may be of prolonged duration. In some patients clinical improvement manifests as stable disease, which may also extend for months or years. Immune-related adverse events (IRAEs) have been observed in patients after CTLA-4 blockade and most likely reflect the drug mechanism of action and corresponding effects on the immune system. Early clinical data suggest a correlation between IRAEs and response to ipilimumab treatment. This paper briefly reviews the results from several ongoing and completed ipilimumab clinical trials, provides a synopsis of current trials, and presents several cases that demonstrate the kinetics of antitumor responses and the relationship to IRAEs in patients receiving ipilimumab.
and
Tremelimumab (CP-675,206), a Cytotoxic T Lymphocyte–Associated Antigen 4 Blocking Monoclonal Antibody in Clinical Development for Patients with Cancer
Antoni Ribasa,c, Douglas C. Hansond, Dennis A. Noee, Robert Millhamf, Deborah J. Guyotg, Steven H. Bernsteinh, Paul C. Canniffd, Amarnath Sharmae, Jesus Gomez-Navarrof
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@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.
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