title: An immune-active tumor microenvironment favors clinical response to ipilimumab.
abstract: OBJECTIVE
  Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has been shown to improve overall survival in metastatic melanoma patients. As a consequence of CTLA-4 blockade, ipilimumab treatment is associated with proliferation and activation of peripheral T cells. To better understand various tumor-associated components that may influence the clinical outcome of ipilimumab treatment, gene expression profiles of tumors from patients treated with ipilimumab were characterized.
  
  
  METHODS
  Gene expression profiling was performed on tumor biopsies collected from 45 melanoma patients before and 3 weeks after the start of treatment in a phase II clinical trial.
  
  
  RESULTS
  Analysis of pre-treatment tumors indicated that patients with high baseline expression levels of immune-related genes were more likely to respond favorably to ipilimumab. Furthermore, ipilimumab appeared to induce two major changes in tumors from patients who exhibited clinical activity: genes involved in immune response showed increased expression, whereas expression of genes for melanoma-specific antigens and genes involved in cell proliferation decreased. These changes were associated with the total lymphocyte infiltrate in tumors, and there was a suggestion of association with prolonged overall survival in these patients. Many IFN-γ-inducible genes and Th1-associated markers showed increased expression after ipilimumab treatment, suggesting an accumulation of this particular type of T cell at the tumor sites, which might play an important role in mediating the antitumor activity of ipilimumab.
  
  
  CONCLUSIONS
  These results support the proposed mechanism of action of ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of ipilimumab.
authors.affiliation: Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
authors.forename: Rui-Ru
authors.initials: RR
authors.lastname: Ji
authors.forename: Scott D
authors.initials: SD
authors.lastname: Chasalow
authors.forename: Lisu
authors.initials: L
authors.lastname: Wang
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.forename: Henrik
authors.initials: H
authors.lastname: Schmidt
authors.forename: John
authors.initials: J
authors.lastname: Cogswell
authors.forename: Suresh
authors.initials: S
authors.lastname: Alaparthy
authors.forename: David
authors.initials: D
authors.lastname: Berman
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Siemers
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jackson
authors.forename: Vafa
authors.initials: V
authors.lastname: Shahabi
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D001706:Biopsy; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D000074324:Ipilimumab; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab