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Biological and Clinical Effects of Intravenous Tumor Necrosis Factor- Administered Three Times Weekly¹

Department of Human Oncology and Clinical Cancer Center, The University of Wisconsin, and William S. Middleton Veterans Administration Hospital Madison, Wisconsin 53792

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 µg/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 µg/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 µg/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 < 0.05 for all) enhanced serum ß²-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, ß²-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 (ß₂-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.

¹ This work was partially supported by NIH Contract NO1 CM57735 and NIH Grants NO1-RR03186 and P30-CA14520 from the Division of Research Grants to the University of Wisconsin Medical School.

² Recipient of an American Cancer Society Clinical Oncology Career Development Award and partially supported by the Veterans Administration. To whom requests for reprints should be addressed, at University of Wisconsin Clinical Cancer Center, Room K4/666 CSC. 600 Highland Avenue, Madison, WI 53792.

³ Supported by a Lutheran Brotherhood Life and Health Insurance Medical Research Fund MD/PhD Training Program.

⁴ Present affiliation: Albany Medical Center, Albany, NY.

⁵ Present affiliation: Medicine Branch, National Cancer Institute, Bethesda, MD.

⁶ American Cancer Society Professor of Clinical Oncology.

⁷ Present affiliation: Duke Comprehensive Cancer Center, Durham, NC.

Received 9/ 7/90. Accepted 1/ 4/91.

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