A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Academic Article uri icon

Overview

abstract

  • PURPOSE: 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. EXPERIMENTAL DESIGN: 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. CONCLUSION: 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

  • Giaccone, Giuseppe
  • Punt, Cornelis J A
  • Ando, Yoshitaka
  • Ruijter, Rita
  • Nishi, Nobusuke
  • Peters, Marlies
  • von Blomberg, B Mary E
  • Scheper, Rik J
  • van der Vliet, Hans J J
  • van den Eertwegh, Alfons J M
  • Roelvink, Marja
  • Beijnen, Jos
  • Zwierzina, Heinz
  • Pinedo, Herbert M

publication date

  • December 1, 2002

Research

keywords

  • Antineoplastic Agents
  • Galactosylceramides
  • Killer Cells, Natural
  • Neoplasms
  • T-Lymphocytes

Identity

Scopus Document Identifier

  • 0036896332

PubMed ID

  • 12473579

Additional Document Info

volume

  • 8

issue

  • 12