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Clinical Trials |
-Galactosylceramide (KRN7000) in Patients with Solid Tumors
Departments of Medical Oncology [G. G., R. R., N. N., H. J. J. v.d. V., A. J. M. v. d. E., H. M. P.] and Pathology [B. M. E. v. B., R. J. S.], Vrije Universiteit Medical Center, HV 1081 Amsterdam, the Netherlands; Department of Medical Oncology, University Hospital Nijmegen St. Radboud, the Netherlands [C. J. A. P., M. P.]; Kirin Brewery Co. Ltd., Tokyo, Japan [Y. A., N. N.]; NDDO Oncology, Amsterdam, the Netherlands [M. R.]; Slotervaart Hospital, Amsterdam, the Netherlands [J. B.]; and Innsbruck University, Innsbruck, Austria [H. Z.]
Purpose: 
-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 (50–4800 µg/m2) 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 (50–4800 µg/m2). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+V24+Vß11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels (tumor necrosis factor 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.
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J. Schmieg, G. Yang, R. W. Franck, and M. Tsuji Superior Protection against Malaria and Melanoma Metastases by a C-glycoside Analogue of the Natural Killer T Cell Ligand {alpha}-Galactosylceramide J. Exp. Med., December 1, 2003; 198(11): 1631 - 1641. [Abstract] [Full Text] [PDF]
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M. T. Wilson, C. Johansson, D. Olivares-Villagomez, A. K. Singh, A. K. Stanic, C.-R. Wang, S. Joyce, M. J. Wick, and L. Van Kaer The response of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion PNAS, September 16, 2003; 100(19): 10913 - 10918. [Abstract] [Full Text] [PDF]
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Y. Hayakawa, S. Rovero, G. Forni, and M. J. Smyth {alpha}-Galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis PNAS, August 5, 2003; 100(16): 9464 - 9469. [Abstract] [Full Text] [PDF]
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S.-i. Fujii, K. Shimizu, C. Smith, L. Bonifaz, and R. M. Steinman Activation of Natural Killer T Cells by {alpha}-Galactosylceramide Rapidly Induces the Full Maturation of Dendritic Cells In Vivo and Thereby Acts as an Adjuvant for Combined CD4 and CD8 T Cell Immunity to a Coadministered Protein J. Exp. Med., July 21, 2003; 198(2): 267 - 279. [Abstract] [Full Text] [PDF]
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H. J. J. van der Vliet, J. W. Molling, N. Nishi, A. J. Masterson, W. Kolgen, S. A. Porcelli, A. J. M. van den Eertwegh, B. M. E. von Blomberg, H. M. Pinedo, G. Giaccone, et al. Polarization of V{alpha}24+ V{beta}11+ Natural Killer T Cells of Healthy Volunteers and Cancer Patients Using {alpha}-Galactosylceramide-loaded and Environmentally Instructed Dendritic Cells Cancer Res., July 15, 2003; 63(14): 4101 - 4106. [Abstract] [Full Text] [PDF]
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