Endothelial injury is a central driver of systemic IFN-β toxicity and is reversible through Jak inhibition

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Oncolytic viruses (OVs) engineered to express interferon-beta (IFN-β) are in clinical trials.
• IFN-β has antiproliferative and immunomodulatory effects, but systemic toxicity from sustained expression is not well understood.

Purpose of the Study:

• To investigate the systemic toxicity of prolonged IFN-β expression from OVs.
• To identify potential strategies for mitigating IFN-β-induced toxicity.

Main Methods:

• Murine models were used to assess toxicity from sustained IFN-β exposure.
• Histopathology, blood counts, and liver function tests were performed.
• Type I interferon receptor knockout mice and inducible caspase-9 systems were utilized.
• Tumor-bearing mice were treated with OVs, and ruxolitinib was co-administered.

Main Results:

• Prolonged IFN-β exposure caused dose-dependent toxicities including elevated transaminases, thrombocytopenia, lymphopenia, and reduced hemoglobin.
• Histopathology revealed sinusoidal endothelial sloughing, microvascular coagulation, hepatocellular damage, and bone marrow toxicity.
• These toxicities were absent in type I interferon receptor knockout mice.
• Reversing IFN-β production ameliorated toxicity.
• In tumor models, OV treatment led to mortality, which was rescued by ruxolitinib co-administration.

Conclusions:

• Sustained systemic IFN-β expression induces significant, dose-dependent toxicity in mice.
• Ruxolitinib effectively dampens IFN-β signaling and mitigates lethal toxicity, suggesting its potential use in managing OV-associated adverse events.