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A recombinant influenza virus with a CTLA4-specific scFv inhibits tumor growth in a mouse model
Guang-Lin Lei1, Li-Peng Wang2,3, Suo-Hua Dong1
1Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
Abstract:
Oncolytic viruses (OV) have shown excellent safety and efficacy in preclinical and clinical studies. Influenza A virus (IAV) is considered a promising oncolytic virus. In this report, we generated a recombinant influenza virus expressing an immune checkpoint blockade agent targeting CTLA4. Using reverse genetics, a recombinant influenza virus, termed rFlu-CTLA4, encoding the heavy chain of a CTLA4 antibody on the PB1 segment and the light chain of the CTLA4 antibody on the PA segment was produced. RFlu-CTLA4 could replicate to high titers, and antibodies were produced in the allantoic fluid of infected eggs. Furthermore, the selective cytotoxicity of the virus was higher in various hepatocellular carcinoma cancer cell lines than in the normal cell line L02 in vitro, as indicated by MTS assays. More importantly, in a subcutaneous H22 mouse hepatocarcinoma model, intratumoral injections of rFlu-CTLA4 inhibited the growth of treated tumors and increased the overall survival of mice compared with injections of the PR8 virus. Taken together, these results warrant further exploration of this novel recombinant influenza virus for its potential use as a single or combination agent for cancer immunotherapy.
Insights
Researchers engineered a novel oncolytic virus, rFlu-CTLA4, based on Influenza A virus. This recombinant virus targets cancer cells, showing promise for effective cancer immunotherapy strategies.
Area of Science:
- Virology
- Immunology
- Oncology
Background:
- Oncolytic viruses (OV) demonstrate significant potential in cancer treatment.
- Influenza A virus (IAV) is a promising candidate for OV development.
- Immune checkpoint blockade is a key strategy in cancer immunotherapy.
Purpose of the Study:
- To generate a recombinant influenza virus expressing a CTLA4-targeting immune checkpoint blockade agent.
- To evaluate the efficacy and safety of the engineered virus in preclinical cancer models.
Main Methods:
- Production of a recombinant influenza virus (rFlu-CTLA4) using reverse genetics, incorporating CTLA4 antibody components.
- Assessment of viral replication and antibody production in vitro.
- Evaluation of selective cytotoxicity against hepatocellular carcinoma cell lines.
- In vivo studies using a hepatocarcinoma mouse model to assess tumor growth inhibition and survival.
Main Results:
- rFlu-CTLA4 replicated efficiently and produced functional antibodies.
- The virus exhibited selective cytotoxicity towards cancer cells compared to normal cells.
- Intratumoral administration of rFlu-CTLA4 significantly inhibited tumor growth and improved survival in mice.
- rFlu-CTLA4 demonstrated superior efficacy compared to the control PR8 virus.
Conclusions:
- The engineered rFlu-CTLA4 is a potent oncolytic virus with potential in cancer immunotherapy.
- Further research is warranted to explore its use as a monotherapy or in combination treatments for cancer.
