title: Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma.
abstract: BACKGROUND
  The incidence of melanoma continues to rise, and prognosis in patients with metastatic melanoma remains poor. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) serves as one of the primary immune check points and downregulates T-cell activation pathways. Enhancing T-cell activation by antibody blockade of CTLA-4 provides a new approach to overcome tumor-induced immune tolerance. Recently, anti-CTLA-4 therapy demonstrated significant clinical benefits in patients with metastatic melanoma, which led to the approval of ipilimumab by the FDA in early 2011.
  
  
  METHODS
  The fundamental concepts underlying CTLA-4 blockade-potentiated immune activation are presented in this paper, along with the scientific rationale for and the preclinical evidence supporting CTLA-4-targeted cancer immunotherapy. It also provides an update on clinical trials with anti-CTLA-4 inhibitors and discusses the associated autoimmune toxicity.
  
  
  CONCLUSIONS
  Given that overall survival is the only validated end point for anti-CTLA-4 therapy, the clinical implications of the antigen or tumor-specific immunity in patients remain to be clarified. Additional research is necessary to elucidate the prognostic significance of immune-related side effects and significantly optimize the treatment regimens. An improved understanding of the mechanisms of action of CTLA-4 antibodies may also culminate in wide-ranging clinical applications of this new therapy for other tumor types.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. xywang@vcu.edu
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Daming
authors.initials: D
authors.lastname: Zuo
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D008545:Melanoma / Q000628:therapy*; D012878:Skin Neoplasms / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D000074324:Ipilimumab
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