title: Comparison of clinical and immunological effects of intravenous and intradermal administration of α-galactosylceramide (KRN7000)-pulsed dendritic cells.
abstract: OBJECTIVE
  Human Vα24+Vβ11+ natural killer T-cells (NKT cells) have antitumor activity via direct cytotoxicity and by induction of antitumor actions of T and NK cells. Activation of NKT cells is crucial for their antitumor activity and is induced by α-galactosylceramide (α-GalCer, KRN7000) presented by CD1d on dendritic cells (DC). We conducted a phase I clinical trial of therapy with α-GalCer-pulsed DC to determine safety, tolerability, immune effects and an optimal dose, and administration route.
  
  
  METHODS
  Twelve subjects (3 cohorts) with metastatic malignancy received 4 treatments of α-GalCer-pulsed DC, 2 treatments intravenously (IV), and 2 treatments intradermally (ID). Each successive cohort received a log higher cell dose. Clinical and immunological outcomes were evaluated, including secondary effects on NK and T cells.
  
  
  RESULTS
  Substantial effects on peripheral blood NKT cells were observed but were greater following IV treatment. Secondary immune effects including activation of T and NK cells, increases in T- and NK-cell cytoplasmic interferon-γ, and increases in serum interferon-γ levels were seen after IV but not after ID treatment. Therapy was well tolerated, but 9 of 12 subjects had tumor flares with clinical findings consistent with transient tumor inflammation. Disease response (minor) or stabilization of disease progressing up to enrollment was observed in 6 of the 12 subjects. Stabilization of previously progressive disease lasted for at least one year in three subjects.
  
  
  CONCLUSIONS
  We conclude that therapy with α-GalCer-pulsed DC induced clinically beneficial immune responses that are highly dependent on cell dose and administration route.
authors.affiliation: Division of Medicine, University of Queensland, Brisbane, Australia. anic9909@bigpond.net.au
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nicol
authors.forename: Andrea
authors.initials: A
authors.lastname: Tazbirkova
authors.forename: Mie
authors.initials: M
authors.lastname: Nieda
mesh_terms: D000328:Adult; D000368:Aged; D003713:Dendritic Cells / Q000637:transplantation*; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007271:Injections, Intradermal; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D005699:Galactosylceramides; C493154:alpha-galactosylceramide