title: Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4.
abstract: OBJECTIVE
  Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known.
  
  
  METHODS
  We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated.
  
  
  RESULTS
  Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells.
  
  
  CONCLUSIONS
  Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Heidelberg, Victoria, Australia.
authors.forename: Oliver
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authors.lastname: Klein
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ebert
authors.forename: Theo
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authors.lastname: Nicholaou
authors.forename: Judy
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authors.lastname: Browning
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Russell
authors.forename: Marina
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authors.lastname: Zuber
authors.forename: Heather M
authors.initials: HM
authors.lastname: Jackson
authors.forename: Nektaria
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authors.lastname: Dimopoulos
authors.forename: Bee Shin
authors.initials: BS
authors.lastname: Tan
authors.forename: Axel
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authors.lastname: Hoos
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon