title: High-dose recombinant interleukin-18 induces an effective Th1 immune response to murine MOPC-315 plasmacytoma.
abstract: Interleukin (IL)-18 has profound antitumor activity when administered at high doses as a single agent for prolonged periods in BALB/c mice bearing late, well-established MOPC-315 tumors. Management with a qD x 27 schedule resulted in regression of tumors in all animals receiving 5 mg/kg/d. A protracted daily management regimen appears to be necessary to induce regression in this advanced tumor model. Biologic markers were assessed and appear to be potentially useful in evaluating the immunologic and antitumor activity of IL-18. The biomarkers of IL-18's immunologic activity include, but are not limited to, IL-1alpha, IL-2, IL-8, IL-10, IL-12, IL-13, interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor. The profile of these circulating cytokines and their expression levels at baseline, and after IL-18 delivery, can be measured in the serum, as well as from splenocytes of mice or human peripheral blood mononuclear cells derived from either normal subjects or patients with cancer. We compared IL-18 and IL-12 alone or in combination for their ability to induce cytokine production and natural killer cytolytic activity. Our data support the notion that IL-18 induces a predominantly Th1 response, and that the mechanism of IL-18 activity differs from that of IL-12. The biologic activity of IL-18 management revealed by increases in serum levels of cytokines and enhancement of natural killer cytolytic activity will be useful as clinical trials initiate in 2002. Expression of interferon-gamma and granulocyte-macrophage colony-stimulating factor serum levels correlates directly over a broad dose escalation with the level of IL-18. Therefore, this provides a convenient pharmacodynamic reference to the biologic response to IL-18 that may serve to guide the conduct of clinical trials.
authors.affiliation: GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA. Zdenka_L_Jonak@gsk.com
authors.forename: Zdenka L
authors.initials: ZL
authors.lastname: Jonak
authors.forename: Stephen
authors.initials: S
authors.lastname: Trulli
authors.forename: Curtis
authors.initials: C
authors.lastname: Maier
authors.forename: Francis L
authors.initials: FL
authors.lastname: McCabe
authors.forename: Robert
authors.initials: R
authors.lastname: Kirkpatrick
authors.forename: Kyung
authors.initials: K
authors.lastname: Johanson
authors.forename: Yen Sen
authors.initials: YS
authors.lastname: Ho
authors.forename: Louis
authors.initials: L
authors.lastname: Elefante
authors.forename: Yi-Jiun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Danuta
authors.initials: D
authors.lastname: Herzyk
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Randall K
authors.initials: RK
authors.lastname: Johnson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000188:drug therapy*; D011995:Recombination, Genetic; D012016:Reference Values; D012680:Sensitivity and Specificity; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D018664:Interleukin-12