Synergistic antitumor effects of immunotherapy with recombinant interleukin-2 and recombinant tumor necrosis factor-alpha.
The antitumor activity of combination therapy with recombinant tumor necrosis-alpha (rhTNF-alpha) 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-alpha (2, 4, 6, or 8 micrograms) 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-alpha plus rhIL-2 compared to rhTNF-alpha 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-alpha administration (concurrent, 2, 4, or 6 days post single rhTNF-alpha 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-alpha administration. No antitumor response was noted with the combination compared to rhTNF-alpha alone when rhIL-2 was delayed for greater than 4 days. No increase in lethal toxicity during treatment course of the combination of rhTNF-alpha and rhIL-2 was noted at any schedule compared to single agent rhTNF-alpha therapy. A possible role of rhTNF-alpha in regulation of IL-2-dependent antitumor activity in vivo is discussed.
McIntosh
J K
JK
Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892.
Mulé
J J
JJ
Merino
M J
MJ
Rosenberg
S A
SA
D000818:Animals; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D007376:Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha