Combination immunotherapy with IL-4 Pseudomonas exotoxin and IFN-α and IFN-γ mediate antitumor effects in vitro and in a mouse model of human ovarian cancer.

Aim: We have shown that IL-4 fused to Pseudomonas exotoxin (IL-4-PE) is cytotoxic to ovarian cancer cell lines. The antineoplastic properties of IFN-alpha, IFN-gamma and IL-4-PE have been studied and showed some promise in the clinical trials. Here, we investigated whether the combination of IL-4-PE, IFN-alpha and IFN-gamma will result in increased ovarian cancer cell death in vitro and in vivo. Materials & Methods: Ovarian cancer cells were tested in vitro to analyze the cytotoxic effects of IL-4-PE, IFN-alpha and IFN-gamma, and the combination of all three. Tumor-bearing xenograft mice were treated with the combination of IL-4-PE, IFN-alpha and IFN-gamma to monitor their overall survival. The JAK/STAT phosphorylation signaling pathways were studied to delineate the mechanism of synergistic antitumor activity. Results: The combination of IL-4-PE with IFN-alpha and IFN-gamma resulted in increased ovarian cancer cell death in vitro and in vivo. Mechanistically, the synergistic antitumor effect was dependent on interferon signaling, but not IL-4-PE signaling as determined by signaling specific chemical inhibitors. The combination therapy induced the activation of critical mediators of apoptosis. Conclusion: The combination of IL-4-PE with interferons increased overall survival of mice with human ovarian cancer xenograft. These data suggest that this novel combination could provide a unique approach to treating ovarian cancer.