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.

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.

• Authors: Daniel S Green, Syed R Husain, Chase L Johnson, Yuki Sato, Jing Han, Bharat Joshi, Stephen M Hewitt, Raj K Puri, Kathryn C Zoon
• Journal: Immunotherapy (Immunotherapy) Vol. 11 Issue 6 Pg. 483-496 (04 2019) ISSN: 1750-7448 [Electronic] England
• PMID: 30860437 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Bacterial Toxins
• Exotoxins
• Interferon-alpha
• Recombinant Fusion Proteins
• Virulence Factors
• Interleukin-4
• Interferon-gamma
• ADP Ribose Transferases

Topics

• ADP Ribose Transferases (genetics)
• Animals
• Apoptosis
• Bacterial Toxins (genetics)
• Cell Line, Tumor
• Combined Modality Therapy
• Disease Models, Animal
• Exotoxins (genetics)
• Female
• Humans
• Immunotherapy (methods)
• Interferon-alpha (therapeutic use)
• Interferon-gamma (therapeutic use)
• Interleukin-4 (genetics)
• Mice
• Mice, Nude
• Ovarian Neoplasms (therapy)
• Recombinant Fusion Proteins (genetics, therapeutic use)
• Signal Transduction
• Virulence Factors (genetics)
• Xenograft Model Antitumor Assays
• Pseudomonas aeruginosa Exotoxin A