A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors
| Autor: | Giaccone, B., Punt, C.J.A., Ando, Y., Ruijter, R., Nishi, N., Peters, M., Blomberg, B.M.E. von, Scheper, R.J., Vliet, S. van, Eertwegh, A.J. van den, Roelvink, M., Beijnen, J.H., Zwierzina, H., Pinedo, H.M. |
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| Rok vydání: | 2002 |
| Předmět: | |
| Zdroj: | Clinical Cancer Research, 8, 12, pp. 3702-9 Clinical Cancer Research, 8, 3702-9 |
| ISSN: | 1078-0432 |
| Popis: | Item does not contain fulltext 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. |
| Databáze: | OpenAIRE |
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