Abstract
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. 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. 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. 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
Original language | English |
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Pages (from-to) | 3702-3709 |
Number of pages | 8 |
Journal | Clinical Cancer Research |
Volume | 8 |
Issue number | 12 |
Publication status | Published - Dec 2002 |
Keywords
- Adult
- Aged
- Antigens, CD/metabolism
- Antineoplastic Agents/adverse effects
- Area Under Curve
- Cell Division/drug effects
- Cell Survival/drug effects
- Cytotoxicity, Immunologic
- Female
- Galactosylceramides/adverse effects
- Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
- Humans
- Interferon-gamma/metabolism
- Interleukin-12/metabolism
- Killer Cells, Natural/drug effects
- Ligands
- Lymphocyte Activation/immunology
- Male
- Maximum Tolerated Dose
- Middle Aged
- Neoplasms/drug therapy
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Receptors, Antigen, T-Cell, gamma-delta/analysis
- T-Lymphocytes/immunology