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Updated: Mar 17, 2026
Pancreatic Duct Infusion: An Effective and Selective Method of Drug and Viral Delivery
Published on: September 30, 2021
An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy
Matteo Samuele Pizzuto1, Micol Silic-Benussi2, Vincenzo Ciminale2
1Imperial College London, Faculty of Medicine, Division of Infectious Disease, 8 Norfolk Place, London W2 1PG, UK.
Abstract:
Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths worldwide and the development of new treatment strategies for PDA patients is of crucial importance. Virotherapy uses natural or engineered oncolytic viruses (OVs) to selectively kill tumour cells. Due to their genetic heterogeneity, PDA cells are highly variable in their permissiveness to various OVs. The avian influenza A virus (IAV) H7N3 A/turkey/Italy/2962/03 is a potent inducer of apoptosis in PDA cells previously shown to be resistant to other OVs (Kasloff et al., 2014), suggesting that it might be effective against specific subclasses of pancreatic cancer. To improve the selectivity of the avian influenza isolate for PDA cells, here confirmed deficient for IFN response, we engineered a truncation in the NS1 gene that is the major virus-encoded IFN antagonist. The recombinant virus (NS1-77) replicated efficiently in PDA cells, but was attenuated in non-malignant pancreatic ductal cells, in which it induced a potent IFN response that acted upon bystander uninfected cancer cells, triggering their death. The engineered virus displayed an enhanced ability to debulk a PDA-derived tumour in xenograft mouse model. Our results highlight the possibility of selecting an IAV strain from the diverse natural avian reservoir on the basis of its inherent oncolytic potency in specific PDA subclasses and, through engineering, improve its safety, selectivity and debulking activity for cancer treatment.
Insights
Engineered avian influenza virus selectively targets pancreatic cancer cells. This virotherapy approach enhances tumor debulking and offers a safer, more effective pancreatic cancer treatment strategy.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer with limited treatment options.
- Virotherapy using oncolytic viruses (OVs) shows promise but faces challenges with cancer cell selectivity.
- Avian influenza A virus (IAV) H7N3 demonstrates oncolytic activity against some PDA cells resistant to other OVs.
Purpose of the Study:
- To engineer an avian influenza virus for improved selectivity and efficacy against pancreatic ductal adenocarcinoma.
- To enhance the safety and tumor debulking capabilities of oncolytic virotherapy for pancreatic cancer.
Main Methods:
- Engineered a recombinant avian influenza virus (NS1-77) by truncating the NS1 gene, a viral interferon antagonist.
- Tested the virus's replication and selectivity in pancreatic cancer cells and non-malignant pancreatic ductal cells.
- Evaluated the engineered virus's efficacy in reducing tumor size in a PDA xenograft mouse model.
Main Results:
- The engineered NS1-77 virus replicated effectively in PDA cells.
- NS1-77 showed attenuation in non-malignant cells, inducing an interferon response that killed bystander cancer cells.
- The recombinant virus significantly enhanced tumor debulking in a preclinical mouse model.
Conclusions:
- Engineering the NS1 gene of avian influenza virus improves its selectivity for pancreatic cancer cells.
- This modified virotherapy approach offers enhanced safety and efficacy for pancreatic cancer treatment.
- Selecting and engineering naturally occurring viruses presents a viable strategy for developing novel pancreatic cancer therapies.
