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Synergistic Antitumor Effects of Immunotherapy with Recombinant Interleukin-2 and Recombinant Tumor Necrosis Factor-

Surgery Branch [J. K. M., J. J. M., S. A. R.] and Department of Surgical Pathology [M. J. M.], National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

The antitumor activity of combination therapy with recombinant tumor necrosis- (rhTNF-) and recombinant interleukin-2 (rhIL-2) was assessed against established immunogenic (MCA-106) and nonimmunogenic (MCA-102) sarcomas at both S.C. and visceral (hepatic) sites. C57BL/6 (B6) mice were treated with a single i.v. dose of rhTNF- (2, 4, 6, or 8 µg) followed by rhIL-2 (25,000 U) i.p. thrice daily for 5 consecutive days. Synergistic effects as measured by regression of tumor, prolongation of survival, and improved cure rates were found using the combination of rhTNF- plus rhIL-2 compared to rhTNF- alone or rhIL-2 alone in the treatment of the immunogenic sarcoma MCA-106. No significant antitumor effects were observed against the nonimmunogenic MCA-102 sarcoma. These findings were similar for both S.C. and large single hepatic tumor models. The effect of the timing of rhIL-2 injections in relation to rhTNF- administration (concurrent, 2, 4, or 6 days post single rhTNF- dose) was also evaluated. Substantial tumor regression and increased survival times were seen in mice with S.C. tumors when rhIL-2 therapy was delayed as much as 48 h after rhTNF- administration. No antitumor response was noted with the combination compared to rhTNF- alone when rhIL-2 was delayed for greater than 4 days. No increase in lethal toxicity during treatment course of the combination of rhTNF- and rhIL-2 was noted at any schedule compared to single agent rhTNF- therapy. A possible role of rhTNF- in regulation of IL-2-dependent antitumor activity in vivo is discussed.

¹ To whom requests for reprints should be addressed, at Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 2B42, Bethesda, MD 20892.

Received 1/25/88. Revised 4/14/88. Accepted 4/18/88.

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