Toxicity and antitumor activity of interferon γ alone and in combinations with TNFα and melphalan in isolated limb perfusion in the BN175 sarcoma tumor model in rats

Isolated limb perfusion (ILP) with TNFα, melphalan (M), and IFNγ results in high tumor response rates in patients with soft tissue sarcomas, melanomas and other tumors. IFN can act synergistically in combination with TNFα but in clinical studies this has not been fully investigated. In the BN175 rat sarcoma limb perfusion model we investigated the role of IFNγ. There were 8 different treatment groups: (I) sham ILP (n=9); (u) IFNγ alone (n=10); (III) TNFα 50 μg (n=9); (IV) TNFα + IFNγ (n=6); (V) melphalan (M) 40 ng (n=11); (VI) M + IFNγ (n=6); (VII) TNFα + M (n=27); (VIII) TNFα + M + IFNγ (n=9). Tumor response and hindlimb function were analyzed. In group I-VI no tumor regressions were observed at 5 days after ILP. ILP with TNFα + M had highly effective response rate (RR) of 73%: complete response (CR) rate 55%), very similar to RR in patients. Addition of IFNγ increased the RR by 16% to 89% and the CR rate by 23% to 78%. This difference was not statistically significant. When IFNγ was added to TNFα or TNFα + M it increased limb toxicity significantly (p<0,05 and p<0.005). Since such regional toxicity has not been observed in patients while similar increases in tumor response rates have been reported with IFNγ it is of importance to define the role of IFNγ in the clinical setting.