title: Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma.
abstract: OBJECTIVE
  To determine safety and feasibility of adjuvant ipilimumab following resection of high-risk melanoma and to identify surrogate markers for benefit.
  
  
  METHODS
  In this phase II trial, 75 patients with resected stage IIIc/IV melanoma received the CTLA-4 antibody ipilimumab every 6 to 8 weeks for 1 year. Eligible patients received further maintenance treatments. The first 25 patients received 3 mg/kg of ipilimumab, and an additional 50 patients received 10 mg/kg. HLA-A*0201+ patients received multipeptide immunizations in combination with ipilimumab. Leukapheresis was performed prior to and 6 months after initiation of treatment.
  
  
  RESULTS
  Median overall and relapse-free survivals were not reached after a median follow-up of 29.5 months. Significant immune-related adverse events were observed in 28 of 75 patients and were positively associated with longer relapse-free survival. Antigen-specific T cell responses to vaccine were variable, and vaccine combination was not associated with additional benefit. No effects on T regulatory cells were observed. Higher changes in Th-17 inducible frequency were a surrogate marker of freedom from relapse (P = 0.047), and higher baseline C-reactive protein (CRP) levels were associated with freedom from relapse (P = 0.035).
  
  
  CONCLUSIONS
  Adjuvant ipilimumab following resection of melanoma at high risk for relapse appeared to be associated with improved outcome compared to historical reports. Significant immune-related adverse events were generally reversible and appeared to be associated with improved relapse-free survival. Although vaccination failed to induce a consistent in vitro measurable response, a higher change in Th-17 inducible cells and higher baseline CRP levels were positively associated with freedom from relapse.
authors.affiliation: Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida 33612, USA.
authors.forename: Amod A
authors.initials: AA
authors.lastname: Sarnaik
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.forename: Dawn
authors.initials: D
authors.lastname: Morelli
authors.forename: Maclean
authors.initials: M
authors.lastname: Hall
authors.forename: Dilip
authors.initials: D
authors.lastname: Bogle
authors.forename: Lulu
authors.initials: L
authors.lastname: Yan
authors.forename: Stephan
authors.initials: S
authors.lastname: Targan
authors.forename: Jolie
authors.initials: J
authors.lastname: Solomon
authors.forename: Geoff
authors.initials: G
authors.lastname: Nichol
authors.forename: Michael
authors.initials: M
authors.lastname: Yellin
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016896:Treatment Outcome; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D000074324:Ipilimumab; D022223:Vaccines, Subunit