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Updated: Jun 3, 2025
Ex Vivo Infection of Live Tissue with Oncolytic Viruses
Published on: June 25, 2011
4-1BBL-Armed Oncolytic Herpes Simplex Virus Exerts Antitumor Effects in Pancreatic Ductal Adenocarcinoma
Wenrui Gao1, Zhuoqian Zhao2, Ying Bi1
1Beijing Institute of Biological Products Company Limited, Beijing 100176, China.
Abstract:
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a notably poor response to therapy due to its immunosuppressive tumor microenvironment (TME) and intrinsic drug resistance. The oncolytic virus (OV) represents a promising therapeutic strategy capable of transforming the "cold" immunological profile of PDAC tumors to a "hot" one by reshaping the TME. 4-1BB (CD137), a crucial member of the tumor necrosis factor receptor superfamily, plays a significant role in T-cell activation and function. Methods: In this study, we constructed an oncolytic herpes simplex virus armed with 4-1BBL (oHSV-4-1BBL), the ligand for the 4-1BB receptor, and investigated its therapeutic effects in two mouse models of pancreatic cancer, Pan02_HVEM and KPC. Results: We found that oHSV-4-1BBL remarkably inhibited tumor growth and extended the median survival time in both models. To amplify the therapeutic effect, we further combined oHSV-4-1BBL with PD-1 antibody. This combination therapy not only further suppressed tumor growth but also extended the median survival time by an additional 11 days compared to oHSV (armed with GFP as a control) combined with PD-1 antibody treatment, with some mice achieving complete tumor regression. Conclusions: Our findings confirm the potential of combining oncolytic viral therapy with 4-1BB targeting in enhancing the treatment of pancreatic cancer.
Insights
This study shows that an oncolytic virus armed with 4-1BBL (oHSV-4-1BBL) effectively treats pancreatic cancer. Combining it with a PD-1 antibody further enhances tumor suppression and survival in mouse models.
Area of Science:
- Oncology
- Virology
- Immunotherapy
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits poor therapeutic response due to an immunosuppressive tumor microenvironment (TME) and drug resistance.
- Oncolytic viruses (OVs) can convert the "cold" PDAC TME to a "hot" one, enhancing anti-tumor immunity.
- 4-1BB (CD137) is vital for T-cell activation and function.
Purpose of the Study:
- To construct and evaluate an oncolytic herpes simplex virus armed with 4-1BBL (oHSV-4-1BBL) for pancreatic cancer therapy.
- To investigate the synergistic effects of combining oHSV-4-1BBL with PD-1 antibody treatment.
Main Methods:
- Development of oHSV-4-1BBL, an OV engineered to express 4-1BBL.
- Assessment of oHSV-4-1BBL efficacy in Pan02_HVEM and KPC mouse models of pancreatic cancer.
- Evaluation of combination therapy with oHSV-4-1BBL and anti-PD-1 antibody.
Main Results:
- oHSV-4-1BBL significantly inhibited tumor growth and prolonged survival in both pancreatic cancer models.
- Combination therapy with oHSV-4-1BBL and PD-1 antibody demonstrated enhanced tumor suppression.
- The combination therapy extended median survival by 11 days compared to control OV plus PD-1 antibody, with complete tumor regression observed in some mice.
Conclusions:
- oHSV-4-1BBL shows significant therapeutic potential for pancreatic cancer.
- Combining oncolytic viral therapy with 4-1BB targeting offers a promising strategy to enhance pancreatic cancer treatment outcomes.
