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Cytotoxic T-Lymphocyte–Associated Antigen-4

Author's Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

Requests for reprints: F. Stephen Hodi, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-5053; Fax: 617-582-7992; E-mail: stephen_hodi{at}dfci.harvard.edu.

Previously, the development of immune-based therapies has primarily focused on vaccines and cytokines, yielding benefit in a small percentage of patients. Recent advances in our understanding of the function of costimulatory molecules have revitalized enthusiasm in the development of immune therapies for cancer. This family of proteins possesses properties involved in both lymphocyte activation and immune-inhibitory functions. The costimulatory molecule with the greatest translation into the clinic thus far is CTL-associated antigen-4 (CTLA-4). CTLA-4 engagement leads to T-cell inhibition by two principle mechanisms. The first involves competitive binding with CD28 for B7 on the antigen-presenting cell. The second is direct intracellular inhibitory signals mediated by the CTLA-4 cytoplasmic tail. Numerous clinical trials testing the blockade of CTLA-4 signaling with fully human monoclonal antibodies have treated a variety of cancers, with the most experience in the treatment of metastatic melanoma. Significant antitumor activity as well as potential autoimmune-related toxicities have been observed. Further clinical investigation with CTLA-4 blockade, planned clinical trials testing manipulation of other costimulatory molecules, and continued improvement in understanding of costimulatory pathways present a new era of immune therapies for cancer patients.

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