title: Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade.
abstract: OBJECTIVE
  CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and helps maintain peripheral self-tolerance. Previously, we showed immune-related adverse events (IRAE) and objective, durable clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade. We have now treated 139 patients in two trials and have sufficient follow-up to examine factors associated with clinical response.
  
  
  METHODS
  A total of 139 patients with metastatic melanoma were treated: 54 patients received ipilimumab in conjunction with peptide vaccinations and 85 patients were treated with intra-patient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201 status.
  
  
  RESULTS
  Three patients achieved complete responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients achieved partial responses (PR) for an overall objective response rate of 17%. The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. Prior therapy with IFNalpha-2b was a negative prognostic factor, whereas prior high-dose interleukin-2 did not significantly affect the probability of response. There were no significant differences in the rate of clinical response or development of IRAEs between the two trials. The duration of tumor response was not affected by the use of high-dose steroids for abrogation of treatment-related toxicities (P = 0.23). There were no treatment-related deaths.
  
  
  CONCLUSIONS
  In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of IRAEs.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Downey
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Klapper
authors.forename: Franz O
authors.initials: FO
authors.lastname: Smith
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.forename: Tamika E
authors.initials: TE
authors.lastname: Allen
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Levy
authors.forename: Michael
authors.initials: M
authors.lastname: Yellin
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Nichol
authors.forename: Donald E
authors.initials: DE
authors.lastname: White
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000187:drug effects*; D000943:Antigens, Differentiation / Q000187:drug effects*; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D011379:Prognosis; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab