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

The antitumor activity of combination therapy with recombinant tumor necrosis-a (rhTNF-α) and recombinant interleukin-2 (rhIL-2) was assessed against established immunogenic (MCA-106) and nonimmuno-genic (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-α (2, 4, 6, or 8 μg) followed by rhlL-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-α plus rhIL-2 compared to rhTNF-α alone or rhIL-2 alone in the treatment of the immunogenic sarcoma MCA-106. No significant antitumor effects were observed against the nonimmuno-genic 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-α administration (concurrent, 2, 4, or 6 days post single rhTNF-α 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-α administration. No antitumor response was noted with the combination compared to rhTNF-α alone when rhIL-2 was delayed for greater than 4 days. No increase in lethal toxicity during treatment course of the combination of rhTNF-α and rhIL-2 was noted at any schedule compared to single agent rhTNF-α therapy. A possible role of rhTNF-α in regulation of IL-2-dependent antitumor activity in vivo is discussed.