title: Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly.
abstract: Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological and antitumor effects in vitro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. We conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNF when administered as a 30-min i.v. infusion three times/week. Dose levels of TNF ranged from 5 to 275 micrograms/m2; doses of TNF were escalated between patient groups. The most common clinical toxicities of TNF consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. Four patients treated at the maximally tolerated dose of 225 micrograms/m2 received dexamethasone to determine whether the toxicities of TNF could be ameliorated. No significant differences in hypotension or subjective symptomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it was not. One patient with colorectal carcinoma treated with 50 micrograms/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maximally tolerated dose before therapy and 24 h afterward. TNF significantly (P less than 0.05 for all) enhanced serum beta 2-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3-dioxygenase activity was also increased 24 h following the administration of TNF, although this increase was only of borderline statistical significance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLA-DR, HLA-DQ, beta 2-microglobulin, and the Fc receptor, and serum interleukin-1 activity also were not significantly increased by the administration of TNF. Thus, in humans TNF caused biological response modulation with evidence of HLA Class I (beta 2-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.
authors.affiliation: Department of Human Oncology, University of Wisconsin, Madison 53792.
authors.forename: J H
authors.initials: JH
authors.lastname: Schiller
authors.forename: B E
authors.initials: BE
authors.lastname: Storer
authors.forename: P L
authors.initials: PL
authors.lastname: Witt
authors.forename: D
authors.initials: D
authors.lastname: Alberti
authors.forename: M B
authors.initials: MB
authors.lastname: Tombes
authors.forename: R
authors.initials: R
authors.lastname: Arzoomanian
authors.forename: R A
authors.initials: RA
authors.lastname: Proctor
authors.forename: D
authors.initials: D
authors.lastname: McCarthy
authors.forename: R R
authors.initials: RR
authors.lastname: Brown
authors.forename: S D
authors.initials: SD
authors.lastname: Voss
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000032:analysis; D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D014366:Tryptophan Oxygenase / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001613:beta 2-Microglobulin / Q000032:analysis
chemical_list: D006684:HLA-DR Antigens; D007375:Interleukin-1; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; D014366:Tryptophan Oxygenase; D015088:2',5'-Oligoadenylate Synthetase