title: A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma.
abstract: BACKGROUND
  Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in two phase III trials of patients with advanced melanoma. The primary objective of the current trial was to prospectively explore candidate biomarkers from the tumor microenvironment for associations with clinical response to ipilimumab.
  
  
  METHODS
  In this randomized, double-blind, phase II biomarker study (ClinicalTrials.gov NCT00261365), 82 pretreated or treatment-naïve patients with unresectable stage III/IV melanoma were induced with 3 or 10 mg/kg ipilimumab every 3 weeks for 4 doses; at Week 24, patients could receive maintenance doses every 12 weeks. Efficacy was evaluated per modified World Health Organization response criteria and safety was assessed continuously. Candidate biomarkers were evaluated in tumor biopsies collected pretreatment and 24 to 72 hours after the second ipilimumab dose. Polymorphisms in immune-related genes were also evaluated.
  
  
  RESULTS
  Objective response rate, response patterns, and safety were consistent with previous trials of ipilimumab in melanoma. No associations between genetic polymorphisms and clinical activity were observed. Immunohistochemistry and histology on tumor biopsies revealed significant associations between clinical activity and high baseline expression of FoxP3 (p = 0.014) and indoleamine 2,3-dioxygenase (p = 0.012), and between clinical activity and increase in tumor-infiltrating lymphocytes (TILs) between baseline and 3 weeks after start of treatment (p = 0.005). Microarray analysis of mRNA from tumor samples taken pretreatment and post-treatment demonstrated significant increases in expression of several immune-related genes, and decreases in expression of genes implicated in cancer and melanoma.
  
  
  CONCLUSIONS
  Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity. The observed pharmacodynamic changes in gene expression warrant further analysis to determine whether treatment-emergent changes in gene expression may be associated with clinical efficacy. Further studies are required to determine the predictive value of these and other potential biomarkers associated with clinical response to ipilimumab.
authors: The Angeles Clinic and Research Institute, Santa Monica, USA. ohamid@theangelesclinic.org
authors: Omid
authors: O
authors: Hamid
authors: Henrik
authors: H
authors: Schmidt
authors: Aviram
authors: A
authors: Nissan
authors: Laura
authors: L
authors: Ridolfi
authors: Steinar
authors: S
authors: Aamdal
authors: Johan
authors: J
authors: Hansson
authors: Michele
authors: M
authors: Guida
authors: David M
authors: DM
authors: Hyams
authors: Henry
authors: H
authors: Gómez
authors: Lars
authors: L
authors: Bastholt
authors: Scott D
authors: SD
authors: Chasalow
authors: David
authors: D
authors: Berman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000074324:Ipilimumab; D012333:RNA, Messenger