Biological and Clinical Effects of Intravenous Tumor Necrosis Factor-a Administered Three Times Weekly

Joan H. Schiller, Barry E. Storcr, Patricia L. Witt, Dona Alberti, Mary Beth Tombes, Rhoda Arzomanian, Richard A. Proctor, Donna McCarthy, Raymond R. Brown, Stephan D. Voss, Scott C. Remick, Jean L. Grcm, Ernest C. Borden, Donald L. Trump

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Tumor necrosis factor (TNK) is a cytokine «¡pIhleiotropic biological and antitumor effects iti ritro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. \Ve conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNK when administered as a 30-min i.v. infusion three times/week. Dose levels of TNK ranged from 5 to 275 Mg/nr; doses of TNK were escalated between patient groups. The most common clinical toxicities of TNK consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. 1our patients treated at the maximally tolerated dose of 225 //g 'm ' received dexamethasone to determine whether the toxicities of TNK could be ameliorated. No significant differences in hypotension or subjective symp tomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it »asnot. One patient with colorectal carcinoma treated with 50 Mg/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maxi mally tolerated dose before therapy and 24 h afterward. INK significantly (/' < 0.05 for all) enhanced serum ^'-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3- dioxygenasc activity was also increased 24 h following the administration of TNK, although this increase was only of borderline statistical signifi cance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLADR. IH.A-DQ, ¿P-microglobulin,and the Kc receptor, and serum interleukin-1 activity also were not significantly increased by the administra tion of TNF. thus, in humans TNF caused biological response modulation with evidence of 11LA Class I (.; -niicroglohii lin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.

Original languageEnglish (US)
Pages (from-to)1651-1658
Number of pages8
JournalCancer Research
Volume51
Issue number6
StatePublished - Mar 1991

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schiller, J. H., Storcr, B. E., Witt, P. L., Alberti, D., Beth Tombes, M., Arzomanian, R., Proctor, R. A., McCarthy, D., Brown, R. R., Voss, S. D., Remick, S. C., Grcm, J. L., Borden, E. C., & Trump, D. L. (1991). Biological and Clinical Effects of Intravenous Tumor Necrosis Factor-a Administered Three Times Weekly. Cancer Research, 51(6), 1651-1658.