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Targeting an Oncolytic Influenza A Virus to Tumor Tissue by Elastase
Irina Kuznetsova1,2, Tobias Arnold1, Thomas Aschacher1
1Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Abstract:
Oncolytic viruses are currently established as a novel type of immunotherapy. The challenge is to safely target oncolytic viruses to tumors. Previously, we have generated influenza A viruses (IAVs) containing deletions in the viral interferon antagonist. Those deletions have attenuated the virus in normal tissue but allowed replication in tumor cells. IAV entry is mediated by hemagglutinin (HA), which needs to be activated by a serine protease, for example, through trypsin. To further target the IAV to tumors, we have changed the trypsin cleavage site to an elastase cleavage site. We chose this cleavage site because elastase is expressed in the tumor microenvironment. Moreover, the exchange of the cleavage site previously has been shown to attenuate viral growth in lungs. Newly generated elastase-activated influenza viruses (AE viruses) grew to similar titers in tumor cells as the trypsin-activated counterparts (AT viruses). Intratumoral injection of AE viruses into syngeneic B16f1 melanoma-derived tumors in mice reduced tumor growth similar to AT viruses and had a better therapeutic effect in heterologous human PANC-1-derived tumors. Therefore, the introduction of the attenuation marker "elastase cleavage site" in viral HA allows for safe, effective oncolytic virus therapy.
Insights
Researchers engineered influenza A viruses (IAVs) for oncolytic immunotherapy. Modifying the hemagglutinin cleavage site to be elastase-dependent enhances tumor targeting and safety for effective cancer treatment.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Viral engineering
Background:
- Oncolytic viruses offer a novel immunotherapy approach.
- Safely targeting oncolytic viruses to tumors remains a challenge.
- Influenza A viruses (IAVs) engineered for tumor cell replication show promise.
Purpose of the Study:
- To enhance the tumor-targeting specificity of oncolytic influenza A viruses (IAVs).
- To investigate the efficacy of elastase-activated IAVs (AE viruses) for oncolytic virotherapy.
- To assess the safety profile of AE viruses compared to trypsin-activated IAVs (AT viruses).
Main Methods:
- Engineering IAVs with a modified hemagglutinin (HA) cleavage site, changing from trypsin-dependent to elastase-dependent activation.
- Evaluating viral replication titers in tumor cells and normal tissues.
- Assessing therapeutic efficacy and tumor growth reduction in mouse models (syngeneic B16f1 melanoma and heterologous human PANC-1 tumors).
Main Results:
- AE viruses replicated effectively in tumor cells, similar to AT viruses.
- Intratumoral injection of AE viruses demonstrated comparable tumor growth reduction to AT viruses in syngeneic models.
- AE viruses exhibited superior therapeutic effects in heterologous human tumor models.
- The elastase cleavage site modification attenuated viral growth in lungs, suggesting improved safety.
Conclusions:
- Modifying the HA cleavage site to be elastase-dependent enhances the tumor-targeting capability of oncolytic IAVs.
- Elastase-activated IAVs represent a safe and effective strategy for oncolytic virotherapy.
- This approach holds potential for improved cancer treatment outcomes.