title: In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.
abstract: Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.
authors.affiliation: Pittsburgh Cancer Institute, Division of Medical Oncology, PA 15213.
authors.forename: J M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: M S
authors.initials: MS
authors.lastname: Ernstoff
authors.forename: T
authors.initials: T
authors.lastname: Trautman
authors.forename: G
authors.initials: G
authors.lastname: Hebert
authors.forename: Y
authors.initials: Y
authors.lastname: Nishida
authors.forename: C A
authors.initials: CA
authors.lastname: Davis
authors.forename: J
authors.initials: J
authors.lastname: Balzer
authors.forename: S
authors.initials: S
authors.lastname: Reich
authors.forename: J
authors.initials: J
authors.lastname: Schindler
authors.forename: S A
authors.initials: SA
authors.lastname: Rudnick
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis / Q000097:blood; D000943:Antigens, Differentiation / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D006683:HLA-DQ Antigens / Q000032:analysis / Q000235:genetics; D006684:HLA-DR Antigens / Q000032:analysis / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D007371:Interferon-gamma / Q000008:administration & dosage / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology; D008545:Melanoma / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000556:secondary*; D010641:Phenotype; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D000943:Antigens, Differentiation; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D011994:Recombinant Proteins; D007371:Interferon-gamma; D015088:2',5'-Oligoadenylate Synthetase