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Antitumor properties of influenza virus vectors
H Zheng1, P Palese, A García-Sastre
1Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract:
We are investigating the potential use of influenza virus vectors expressing selected tumor-associated antigens (TAAs) as therapeutic agents in anticancer strategies. Previously, we have shown that recombinant influenza viruses expressing a model TAA mediated the regression of established pulmonary metastases in mice through the induction of cytotoxic T-cell responses (N. P. Restifo et al., Virology, 249: 89-97, 1998). We have now expanded these observations in the mouse model using survival as the end point of the assay. Animals with a high tumor burden showed extended survival times when treated with a recombinant influenza virus expressing a TAA, but they finally succumbed to death. Death was associated with the presence of a small number of large tumors in lungs. Interestingly, these tumors were found to express undetectable levels of the TAAs because of a down-regulation in the TAA-specific mRNA levels. On the other hand, mice with five times lower tumor burden showed complete tumor regression and survival for >6 six months when treated with the recombinant virus. These animals showed protection against a tumor challenge 6 months after treatment. Our results suggest that recombinant influenza viruses may be useful as therapeutic agents for the prevention and treatment of cancers with known TAAs.
Insights
Recombinant influenza viruses expressing tumor-associated antigens show promise in cancer therapy. While some tumors persisted, others regressed completely, suggesting potential for preventing and treating cancers.
Area of Science:
- Oncolytic virology
- Immunotherapy
- Viral vector technology
Background:
- Influenza virus vectors expressing tumor-associated antigens (TAAs) are being explored for cancer treatment.
- Previous studies demonstrated regression of pulmonary metastases using these vectors via cytotoxic T-cell responses.
Purpose of the Study:
- To evaluate the efficacy of recombinant influenza viruses expressing TAAs as therapeutic agents in a mouse model, using survival as the primary endpoint.
- To investigate the mechanisms of tumor response and resistance to this novel cancer therapy.
Main Methods:
- Recombinant influenza viruses engineered to express specific TAAs were administered to mice with varying tumor burdens.
- Survival rates, tumor regression, TAA expression levels, and TAA-specific mRNA were analyzed.
- Post-treatment tumor challenge was performed to assess long-term protection.
Main Results:
- Mice with high tumor burden showed extended survival but ultimately succumbed to large tumors with down-regulated TAA expression.
- Mice with a fivefold lower tumor burden exhibited complete tumor regression and survival beyond six months.
- Treated mice demonstrated protection against subsequent tumor challenge six months post-therapy.
Conclusions:
- Recombinant influenza viruses expressing TAAs can induce significant tumor regression and long-term survival in a mouse model.
- This approach holds potential for the prevention and treatment of cancers expressing known TAAs.
- Further research is warranted to optimize TAA expression and delivery for enhanced therapeutic outcomes.