Novel immune checkpoint inhibitor FilC/PD-1 recombinant vaccinia virus inhibits hepatocellular carcinoma
Yanxi Luo1, Zhigao Hu2, Guoxiu Du2
1Institute of Materia Medica, Hangzhou Medical College, Hangzhou, China.
Background:
With limited therapeutic options for advanced stages, hepatocellular carcinoma (HCC) continues to be the primary cause of cancer-related deaths globally. Although still less than ideal in HCC, immunotherapy-especially immune checkpoint drugs targeting the PD-1/PD-L1 axis-shows promise. Combining direct tumor lysis with immune modulation provides a new strategy in oncolytic virotherapy using vaccinia virus. Designed to boost anti-tumor immunity through dual checkpoint inhibition and oncolysis, this study assessed the efficacy of the FilC/PD-1 recombinant vaccinia virus.
Materials And Methods:
Homologous recombination was used to develop a recombinant vaccinia virus expressing FilC and PD-1 inhibitors. We evaluated viral infectivity and replication in HCC cell lines (HepG2, Huh7, Hepa1-6, PLC/PRF/5) and in VERO cells-a non-hepatic kidney epithelial cell line from Chlorocebus sabaeus (African green monkey)-commonly used in virology-to assess baseline viral tropism outside the liver. Using BALB/c nude mice (xenograft) and C57BL/6 mice (syngeneic model), in vivo efficacy was assessed in HCC murine models, evaluating tumor volume reduction, immune cell infiltration, survival rates, and systemic toxicity.
Findings:
The FilC/PD-1 recombinant virus displayed high infection efficiency (88.4% in HepG2), robust viral replication, and substantial oncolytic activity in HCC cells. Compared to the PD-1 inhibitor virus alone, the virus greatly lowered tumor volume (84%) and raised CD8+ T cell infiltration (42.8%), thereby prolonging survival (68 days). Histopathological study verified low toxicity in the main organs.
Conclusion:
Combining synergistic immune checkpoint inhibition with oncolytic virotherapy, the FilC/PD-1 recombinant vaccinia virus significantly increases anti-tumor immunity and slows the growth of HCC.
Insights
This study developed a novel recombinant vaccinia virus (FilC/PD-1) that combines oncolytic virotherapy with immune checkpoint inhibition. The FilC/PD-1 virus effectively reduced hepatocellular carcinoma tumor volume and enhanced anti-tumor immunity in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Hepatocellular carcinoma (HCC) research
Background:
- Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality with limited treatment options.
- Immunotherapy, particularly targeting the PD-1/PD-L1 axis, shows promise for HCC.
- Oncolytic virotherapy using vaccinia virus offers a novel strategy by combining direct tumor lysis with immune modulation.
Purpose of the Study:
- To assess the efficacy of a recombinant vaccinia virus (FilC/PD-1) designed for dual checkpoint inhibition and oncolysis.
- To evaluate the virus's potential to boost anti-tumor immunity in hepatocellular carcinoma (HCC).
Main Methods:
- Developed a recombinant vaccinia virus (FilC/PD-1) using homologous recombination.
- Assessed viral infectivity and replication in various HCC cell lines and VERO cells.
- Evaluated in vivo efficacy in murine HCC models, measuring tumor volume, immune cell infiltration, survival, and toxicity.
Main Results:
- The FilC/PD-1 virus demonstrated high infection efficiency (88.4% in HepG2) and significant oncolytic activity in HCC cells.
- Compared to PD-1 inhibitor alone, the FilC/PD-1 virus reduced tumor volume by 84% and increased CD8+ T cell infiltration by 42.8%.
- Treatment with FilC/PD-1 prolonged survival in mice to 68 days with low toxicity observed in major organs.
Conclusions:
- The FilC/PD-1 recombinant vaccinia virus synergistically combines immune checkpoint inhibition with oncolytic virotherapy.
- This novel approach significantly enhances anti-tumor immunity and inhibits HCC growth.
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