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

• Published in: Clinical cancer research Vol. 12; no. 14; pp. 4265 - 4273
• Main Authors: ROBERTSON, Michael J, MIER, James W, JEWELL, Roxanne C, BELL, William N, THURMOND, Linda M, WEISENBACH, Jill, ROBERTS, Suzanne, DAR, Mohammed M, LOGAN, Theodore, ATKINS, Michael, KOON, Henry, KOCH, Kevin M, KATHMAN, Steven, PANDITE, Lini N, OEI, Coreen, KIRBY, Lyndon C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2006
• Subjects: Adult; Aged; Antineoplastic agents; Area Under Curve; Biological and medical sciences; biological therapy; Carcinoma, Renal Cell - drug therapy; Cohort Studies; cytokine; Cytokines - metabolism; Dose-Response Relationship, Drug; Female; Hodgkin Disease - drug therapy; Humans; i.v. infusion; IL-12; IL-18; IL-2; immunotherapy; Infusions, Intravenous; Interleukin-18 - administration & dosage; Male; Medical sciences; Melanoma - drug therapy; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Recombinant Proteins - administration & dosage; Human; Intravenous administration; Perfusion; Cytokine; Advanced stage; Biological effect; Recombinant protein; Malignant tumor; Interleukin 18
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0121

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-γ, 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.