title: Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy.
abstract: OBJECTIVE
  To detect a pretreatment gene expression signature (GS) predictive of response to MAGE-A3 immunotherapeutic in patients with metastatic melanoma and to investigate its applicability in a different cancer setting (adjuvant therapy of resected early-stage non-small-cell lung cancer [NSCLC]).
  
  
  METHODS
  Patients were participants in two phase II studies of the recombinant MAGE-A3 antigen combined with an immunostimulant (AS15 or AS02B). mRNA from melanoma biopsies was analyzed by microarray analysis and quantitative polymerase chain reaction. These results were used to identify and cross-validate the GS, which was then applied to the NSCLC data.
  
  
  RESULTS
  In the patients with melanoma, 84 genes were identified whose expression was potentially associated with clinical benefit. This effect was strongest when the immunostimulant AS15 was included in the immunotherapy (hazard ratio [HR] for overall survival, 0.37; 95% CI, 0.13 to 1.05; P = .06) and was less strong with the other immunostimulant AS02B (HR, 0.84; 95% CI, 0.36 to 1.97; P = .70). The same GS was then used to predict the outcome for patients with resected NSCLC treated with MAGE-A3 plus AS02B; actively treated GS-positive patients showed a favorable disease-free interval compared with placebo-treated GS-positive patients (HR, 0.42; 95% CI, 0.17 to 1.03; P = .06), whereas among GS-negative patients, no such difference was found (HR, 1.17; 95% CI, 0.59 to 2.31; P = .65). The genes identified were mainly immune related, involving interferon gamma pathways and specific chemokines, suggesting that their pretreatment expression influences the tumor's immune microenvironment and the patient's clinical response.
  
  
  CONCLUSIONS
  An 84-gene GS associated with clinical response for MAGE-A3 immunotherapeutic was identified in metastatic melanoma and confirmed in resected NSCLC.
authors.affiliation: GlaxoSmithKline Vaccines, Rixensart, Belgium.
authors.forename: Fernando
authors.initials: F
authors.lastname: Ulloa-Montoya
authors.forename: Jamila
authors.initials: J
authors.lastname: Louahed
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dizier
authors.forename: Olivier
authors.initials: O
authors.lastname: Gruselle
authors.forename: Bart
authors.initials: B
authors.lastname: Spiessens
authors.forename: Frédéric F
authors.initials: FF
authors.lastname: Lehmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.forename: Wim H J
authors.initials: WH
authors.lastname: Kruit
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Johan
authors.initials: J
authors.lastname: Vansteenkiste
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Brichard
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009363:Neoplasm Proteins / Q000276:immunology*; D016017:Odds Ratio; D011237:Predictive Value of Tests; D040081:Protein Array Analysis; D011994:Recombinant Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins