RESTORATION OF INTERFERON-ALPHA POTENTIATION OF A RECOMBINANT RICIN-ACHAIN IMMUNOTOXIN FOLLOWING CYTOREDUCTION OF XENOGRAFTS OF ADVANCED OVARIAN-TUMORS

Background: We have demonstrated that, in the human ovarian carcinoma cell line (OVCAR-3), recombinant human interferon alpha (rHuIFN-alpha) potentiated in vitro inhibition of protein synthesis by immunotoxins. The antitumor activity of intracavitary immunotoxin administered to n ude mice 5 days after tumor cell injection was enhanced by a nontherap eutic dose of rHuIFN-alpha, as evidenced by increased survival time. P urpose: Our purpose was to determine the outcome of treatment with imm unotoxin and rHuIFN-alpha in xenografts of more advanced tumors. Metho ds: At 10 or 15 days after tumor cell injection, nude mice with perito neal OVCAR-3 xenografts were treated intraperitoneally with immunotoxi n or with 454A12 monoclonal antibody (MAb) recombinant ricin A chain ( rRA), alone or combined with a nontherapeutic dose of rHuIFN-alpha. Th e immunotoxin was composed of rRA covalently bound to an anti-CD71 (tr ansferrin receptor) MAb. In other experiments, mice were treated intra peritoneally with cyclophosphamide and cisplatin to reduce tumor size on days 20 and 27 after tumor cell inoculation and then, beginning on day 40, with immunotoxin alone or combined with rHuIFN-alpha. Results: Initiation of treatment 10 days after OVCAR-3 transplantation signifi cantly increased median survival from 41 to 89 days (10% survivors on day 120) with 454A12 MAb rRA alone and to more than 120 days (70% surv ivors) with 454A12 MAb rRA combined with rHuIFN-alpha. (P<.0001). The increase in survival time between tumor-bearing mice treated with immu notoxin combined with rHuIFN-alpha and those treated with immunotoxin alone was statistically significant (P = .017). In contrast, the 15-da y transplant tumors were not curable with immunotoxin therapy (surviva l, 72 days; 0% survivors) and were refractory to rHuIFN-alpha potentia tion (survival, 75 days; 0% survivors). After the second course of che motherapy to reduce the size of the advanced tumors (day 40), during t he ascites cell count nadir, initiation of treatment with 454A12 MAb r RA alone or combined with rHuIFN-alpha resulted in significantly diffe rent survival times of 129 and 162 days, respectively (P = .0037). Pat hologic examination of surviving mice treated with chemotherapy and 45 4A12 MAb rRA alone or in combination with rHuIFN-alpha revealed that o ne (17%) of six mice and 11 (65%) of 17 were tumor free, respectively. Conclusions: The synergy between immunotoxins and IFN-alpha is depend ent on tumor burden. These agents are less effective against large tum or burdens (i.e., advanced stage disease), but their beneficial effect s re-emerge after cytoreduction by combination chemotherapy. Implicati ons: The ideal setting for testing the efficacy of intracavitary immun otoxin combined with rHuIFN-alpha after front-line chemotherapy is in patients with residual tumor refractory to additional chemotherapy or in those with toxic effects that prevent delivery of effective doses.