ROLE OF TUMOR-NECROSIS-FACTOR SPECIES IN THE SEQUENCE-DEPENDENT EFFECTS OF INTERLEUKIN-2-TUMOR NECROSIS FACTOR IMMUNOTHERAPY IN MICE - IMPLICATIONS FOR PRECLINICAL CYTOKINE TESTING

We previously demonstrated that recombinant human tumor necrosis facto r (hTNF) is synergistic with human interleukin-2 (hIL-2) for in vivo r egression of murine tumors. In mice, the timing of cytokine administra tion is critical in achieving synergy. Because hTNF exhibits negligibl e binding to the type II murine TNF receptor (TNF-R), we questioned wh ether murine TNF (mTNF) would have therapeutic benefits, scheduling re quirements, and toxic effects similar to those of the hIL-2-hTNF combi nation. To evaluate the biological effects of TNF-R types I and II int eraction, we directly compared the effects of mTNF and hTNF in combina tion with hIL-2 on in vivo tumor regression and in vitro activation of murine splenocytes. Our results demonstrate for the first time that ( a) the cytokine combination hTNF-hIL-2 is consistently more efficaciou s than mTNF-hIL-2 in in vivo murine immunotherapy models; (b) the in v ivo antitumor effects of hTNF-hIL-2 and not mTNF-hIL-2 are critically dependent upon cytokine scheduling; and (c) in vitro culture of spleno cytes with mTNF-hIL-2 enhances cellular proliferation, Lyt 2, and TNF- RI expression compared with hTNF-hIL-2. Collectively, these studies ex tend the previous findings of species-specific mTNF-R responses and re veal that optimal scheduling and efficacy of TNF-hIL-2 combination the rapy in murine tumor models is critically dependent upon the TNF speci es employed.