title: Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma.
abstract: OBJECTIVE
  The recent identification of toll-like receptors (TLRs) and respective ligands allows the evaluation of novel dendritic cell (DC) -activating strategies. Stimulation of TLR9 directly activates human plasmacytoid DCs (PDCs) and indirectly induces potent innate immune responses in preclinical tumor models. We performed an open-label, multicenter, single-arm, phase II pilot trial with a TLR9-stimulating oligodeoxynucleotide in melanoma patients.
  
  
  METHODS
  Patients with unresectable stage IIIb/c or stage IV melanoma received 6 mg PF-3512676 weekly by subcutaneous injection for 24 weeks or until disease progression to evaluate safety as well as clinical and immunologic activity. Clinical and laboratory safety assessments were performed weekly; blood samples for immunological measurements were taken every 8 weeks. Tumor measurements were performed according to Response Evaluation Criteria in Solid Tumors.
  
  
  RESULTS
  Twenty patients received PF-3512676 for a mean of 10.9 weeks with a mean of 10.7 injections. Laboratory and nonlaboratory adverse events were limited, transient, and did not result in any withdrawals. Two patients experienced a confirmed partial response; one response is ongoing for 140+ weeks. Three patients experienced stable disease. Immunologic measurements revealed induction of an activated phenotype of PDC, elevation of serum levels of 2',5'-oligoadenylate, a surrogate marker of type I interferon production, and significant stimulation of natural killer cell cytotoxicity (the latter was associated with clinical benefit).
  
  
  CONCLUSIONS
  These results indicate that TLR9-targeted therapy can stimulate innate immune responses in cancer patients, identify biomarkers that may be associated with TLR9-induced tumor regression, and encourage the design of follow-up studies to evaluate the ability of this therapeutic approach to target human cancer.
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pashenkov
authors.forename: Gerda
authors.initials: G
authors.lastname: Goëss
authors.forename: Christine
authors.initials: C
authors.lastname: Wagner
authors.forename: Markus
authors.initials: M
authors.lastname: Hörmann
authors.forename: Tamara
authors.initials: T
authors.lastname: Jandl
authors.forename: Anna
authors.initials: A
authors.lastname: Moser
authors.forename: Cedrik M
authors.initials: CM
authors.lastname: Britten
authors.forename: Josef
authors.initials: J
authors.lastname: Smolle
authors.forename: Silvia
authors.initials: S
authors.lastname: Koller
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.forename: Iliana
authors.initials: I
authors.lastname: Tantcheva-Poor
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.forename: Stefan
authors.initials: S
authors.lastname: Esser
authors.forename: Tom
authors.initials: T
authors.lastname: Franckson
authors.forename: Achim
authors.initials: A
authors.lastname: Schneeberger
authors.forename: Cäcilia
authors.initials: C
authors.lastname: Haarmann
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Wagner
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009841:Oligonucleotides / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D007370:Interferon Type I; D009841:Oligonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9