This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Robertson, M. J. Articles by Dar, M. M. Search for Related Content PubMed PubMed Citation Articles by Robertson, M. J. Articles by Dar, M. M.

Clinical and Biological Effects of Recombinant Human Interleukin-18 Administered by Intravenous Infusion to Patients with Advanced Cancer

Authors' Affiliations: ¹ Lymphoma Program and ² Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; ³ Beth Israel Deaconess Medical Center, Boston, Massachusetts; and ⁴ GlaxoSmithKline, Inc., Research Triangle Park, North Carolina

Requests for reprints: Michael J. Robertson, Indiana University Medical Center, 535 Barnhill Drive, Room 473, Indianapolis, IN 46202. Phone: 317-278-6942; Fax: 317-278-4190; E-mail: mjrobert{at}iupui.edu.

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical animal models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 in patients with advanced cancer.

Experimental Design: Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic measurements.

Results: Twenty-eight patients (21 with renal cell cancer, 6 with melanoma, and 1 with Hodgkin's lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 µg/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory abnormalities included transient, asymptomatic grade 1 to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevations in liver transaminases. One patient in the 100 µg/kg cohort experienced transient grade 3 hypotension and grade 2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes and monocytes. Increases in serum concentrations of IFN-, granulocyte macrophage colony-stimulating factor, IL-18 binding protein, and soluble Fas ligand were observed. Two patients experienced unconfirmed partial responses after rhIL-18 treatment.

Conclusions: rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18 was not determined. Further clinical studies of rhIL-18 are warranted.

This article has been cited by other articles:

				M. J. Robertson, J. M. Kirkwood, T. F. Logan, K. M. Koch, S. Kathman, L. C. Kirby, W. N. Bell, L. M. Thurmond, J. Weisenbach, and M. M. Dar A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer Clin. Cancer Res., June 1, 2008; 14(11): 3462 - 3469. [Abstract] [Full Text] [PDF]

				J. A. Thompson, B. D. Curti, B. G. Redman, S. Bhatia, J. S. Weber, S. S. Agarwala, E. L. Sievers, S. D. Hughes, T. A. DeVries, and D. F. Hausman Phase I Study of Recombinant Interleukin-21 in Patients With Metastatic Melanoma and Renal Cell Carcinoma J. Clin. Oncol., April 20, 2008; 26(12): 2034 - 2039. [Abstract] [Full Text] [PDF]

				M. Bachmann, C. Dragoi, M. A. Poleganov, J. Pfeilschifter, and H. Muhl Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-{kappa}B in acute myeloid leukemia-derived predendritic KG-1 cells Mol. Cancer Ther., February 1, 2007; 6(2): 723 - 731. [Abstract] [Full Text] [PDF]