title: Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients.
abstract: OBJECTIVE
  Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. Local administration of PF-3512676 (formerly known as CpG 7909) has shown immunostimulatory effects of both dendritic cell and T-cell subsets in the melanoma SLN. Here, we set out to ascertain whether these PF-3512676-induced immunostimulatory effects translate into higher frequencies of melanoma-specific CD8(+) T cells.
  
  
  METHODS
  Twenty-four stage I to III melanoma patients were randomized to preoperative local administration of either PF-3512676 or saline. CD8(+) T cells from SLN and peripheral blood were tested for reactivity by IFN-gamma ELISPOT assay against several HLA-A1/A2/A3-restricted epitopes derived from various melanoma-associated antigens (MAA) in 21 of 24 enrolled patients. Frequencies of natural killer (NK) cells and frequencies and maturation state of dendritic cell subsets in the SLN were determined by flow cytometry.
  
  
  RESULTS
  Melanoma-specific CD8(+) T-cell response rates against >1 MAA epitope in the SLN were 0 of 11 for the saline group versus 5 of 10 for the PF-3512676-administered group (P = 0.012). Of these 5 responding patients, 4 also had a measurable response to >1 MAA epitope in the blood. Increased frequencies in the SLN of both MAA-specific CD8(+) T cells and NK cells correlated to CpG-induced plasmacytoid dendritic cell maturation.
  
  
  CONCLUSIONS
  These data show an increase in melanoma-specific CD8(+) T-cell frequencies as well as an increased effector NK cell rate after a single dose of PF-3512676 and thus support the utility of local PF-3512676 administration as adjuvant treatment in early-stage melanoma to try and halt metastatic spread.
authors.affiliation: Department of Surgical Oncology, Medical Oncology, and Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Molenkamp
authors.forename: Berbel J R
authors.initials: BJ
authors.lastname: Sluijter
authors.forename: Paul A M
authors.initials: PA
authors.lastname: van Leeuwen
authors.forename: Saskia J A M
authors.initials: SJ
authors.lastname: Santegoets
authors.forename: Sybren
authors.initials: S
authors.lastname: Meijer
authors.forename: Pepijn G J T B
authors.initials: PG
authors.lastname: Wijnands
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017024:Chemotherapy, Adjuvant; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D015552:Injections, Intralesional; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D021701:Sentinel Lymph Node Biopsy; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D009838:Oligodeoxyribonucleotides; C483020:ProMune