title: A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors.
abstract: OBJECTIVE
  alpha-galactosylceramide (KRN7000) is a glycosphingolipid that has been shown to inhibit tumor growth and to prolong survival in inoculated mice through activation of natural killer (NK) T cells. We performed a dose escalation study of KRN7000 in advanced cancer patients.
  
  
  METHODS
  Patients with solid tumors received i.v. KRN7000 (50-4,800 micro g/m(2)) on days 1, 8, and 15 of a 4-weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting toxicity or progression, treatment was continued. Pharmacokinetics (PK) and immunomonitoring were performed in all patients.
  
  
  RESULTS
  Twenty-four patients were entered into this study. No dose-limiting toxicity was observed over a wide range of doses (50-4,800 micro g/m(2)). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+Valpha24+Vbeta11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels (tumor necrosis factor alpha and granulocyte macrophage colony-stimulating factor) in 5 of 24 patients and a transient decrease in peripheral blood NK cell numbers and cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000. Pretreatment NKT-cell numbers were significantly lower in patients compared with healthy controls (P = 0.0001). No clinical responses were recorded and seven patients experienced stable disease for a median duration of 123 days.
  
  
  CONCLUSIONS
  i.v. KRN7000 is well tolerated in cancer patients over a wide range of doses. Biological effects were observed in several patients with relatively high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at reconstitution of the deficient NKT-cell population in cancer patients may be warranted.
authors.affiliation: Department of Medical Oncology, Vrije Universiteit Medical Center, HV 1081 Amsterdam, The Netherlands. G.Giaccone@vumc.nl
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ando
authors.forename: Rita
authors.initials: R
authors.lastname: Ruijter
authors.forename: Nobusuke
authors.initials: N
authors.lastname: Nishi
authors.forename: Marlies
authors.initials: M
authors.lastname: Peters
authors.forename: B Mary E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Hans J J
authors.initials: HJ
authors.lastname: van der Vliet
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: Marja
authors.initials: M
authors.lastname: Roelvink
authors.forename: Jos
authors.initials: J
authors.lastname: Beijnen
authors.forename: Heinz
authors.initials: H
authors.lastname: Zwierzina
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D005260:Female; D005699:Galactosylceramides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D005699:Galactosylceramides; D008024:Ligands; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C103873:KRN 7000