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. (12th March 2019)

• Record Type: Journal Article
• Authors: Green, Daniel S; Husain, Syed R; Johnson, Chase L; Sato, Yuki; Han, Jing; Joshi, Bharat; Hewitt, Stephen M; Puri, Raj K; Zoon, Kathryn C
• Is Part Of: Immunotherapy. Volume 11:Number 6(2019)
• Page Start: 483
• Page End: 496
• Publication Date: 2019-03-12
• Subjects: antitumor -- combination immunotherapy -- IL-4-PE -- interferons -- ovarian cancer; Immunotherapy -- Periodicals; 615.37
• DOI: 10.2217/imt-2018-0158
• Languages: English
• ISSNs: 1750-743X

Abstract

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-α, IFN-γ 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-α and IFN-γ 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-α and IFN-γ, and the combination of all three. Tumor-bearing xenograft mice were treated with the combination of IL-4-PE, IFN-α and IFN-γ 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-α and IFN-γ 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.