Synergistic effects of combination therapy with human recombinant interleukin-2 and tumor necrosis factor in murine tumor models.

Human recombinant interleukin 2 (IL-2) and tumor necrosis factor (TNF) were evaluated individually and in combination for their antitumor efficacy in vivo, using five s.c. murine tumors: L1210 leukemia, P815 mastocytoma, B16 melanoma, EL-4 lymphoma, and the methylcholanthrene-induced sarcoma, Meth A. While only the s.c. methylcholanthrene-induced tumor exhibited regression and/or cures in response to immunomodulatory therapy with either agent alone, the simultaneous administration of a maximally tolerated dose of TNF and IL-2 given daily from within 1 day (B16 melanoma), 3 days (L1210 leukemia and P815 mastocytoma) or 5 and 10 days (EL-4 lymphoma and methylcholanthrene-induced sarcoma) after tumor cell implant resulted in no tumor takes (growth). The TNF dose was apparently rate limiting in that reduction of the amount of TNF in the combination by 50% resulted in the loss of curative effects, while IL-2 doses could be reduced by 90% (depending upon tumor type) and still result in an efficacious combination. The synergy seen in combination IL-2 and TNF therapy appeared to be dependent upon tumor burden, but somewhat independent of tumor location. For example, no tumors were seen in the artificial pulmonary metastasis model of the B16 melanoma, and the percentage of extension of median lifetime (test versus control) greater than 150% was seen in the i.p. B16 melanoma, as well as several other i.p. models of the five tumor types. On the other hand, no significant extension of lifetime (greater than 150%) was seen with either lymphokine alone when administered i.p. at maximally tolerated dose for any of the five tumors tested here. Results are discussed in relation to potential immune modulatory events which may be occurring during combination treatments.