Oncolytic virus VG161 in refractory hepatocellular carcinoma

Yinan Shen, Xueli Bai, Qi Zhang, Xingmei Liang, Xinyan Jin, Zeda Zhao, Wei Song, Qian Tan, Ronghua Zhao, William Jia, Shanzhi Gu, Guoming Shi, Ziwei Zheng, Guyue Wei, Youlei Wang, Tian Fang, Yuwei Li, Zijun Wang, Zifan Yang, Sida Guo, Danni Lin, Fang Wei, Lei Wang, Xiaoli Sun, Aijun Qin, Longshen Xie, Yeting Qiu, Wenqing Bao, Shah Rahimian, Manu Singh, Yanal Murad, Jianying Shang, Min Chu, Maoliang Huang, Jun Ding, Wei Chen, Yufu Ye, Yiwen Chen, Xiang Li and Tingbo Liang ()
Additional contact information
Yinan Shen: Zhejiang University School of Medicine
Xueli Bai: Zhejiang University School of Medicine
Qi Zhang: Zhejiang University School of Medicine
Xingmei Liang: Zhejiang University School of Medicine
Xinyan Jin: Zhejiang University School of Medicine
Zeda Zhao: Zhejiang Provincial Key Laboratory of Pancreatic Disease
Wei Song: Zhejiang Provincial Key Laboratory of Pancreatic Disease
Qian Tan: Shanghai Virogin Biotech
Ronghua Zhao: Shanghai Virogin Biotech
William Jia: Shanghai Virogin Biotech
Shanzhi Gu: Hunan Cancer Hospital
Guoming Shi: Fudan University
Ziwei Zheng: Shanghai Virogin Biotech
Guyue Wei: Zhejiang University School of Medicine
Youlei Wang: Zhejiang University School of Medicine
Tian Fang: Zhejiang University School of Medicine
Yuwei Li: Zhejiang University School of Medicine
Zijun Wang: Zhejiang Provincial Key Laboratory of Pancreatic Disease
Zifan Yang: Zhejiang Provincial Key Laboratory of Pancreatic Disease
Sida Guo: Zhejiang Provincial Key Laboratory of Pancreatic Disease
Danni Lin: Zhejiang University School of Medicine
Fang Wei: Zhejiang Provincial Key Laboratory of Pancreatic Disease
Lei Wang: Zhejiang University School of Medicine
Xiaoli Sun: Zhejiang University School of Medicine
Aijun Qin: Shanghai Virogin Biotech
Longshen Xie: CNBG-Virogin Biotech (Shanghai)
Yeting Qiu: Shanghai Virogin Biotech
Wenqing Bao: Shanghai Virogin Biotech
Shah Rahimian: Virogin Biotech Canada
Manu Singh: Virogin Biotech Canada
Yanal Murad: Virogin Biotech Canada
Jianying Shang: Shanghai Virogin Biotech
Min Chu: Shanghai Virogin Biotech
Maoliang Huang: CNBG-Virogin Biotech (Shanghai)
Jun Ding: Shanghai Virogin Biotech
Wei Chen: Zhejiang University School of Medicine
Yufu Ye: Zhejiang University School of Medicine
Yiwen Chen: Zhejiang University School of Medicine
Xiang Li: Zhejiang University School of Medicine
Tingbo Liang: Zhejiang University School of Medicine

Nature, 2025, vol. 641, issue 8062, 503-511

Abstract: Abstract Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments1,2. Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity3, offering a potential therapeutic option. Here we present the results of a multicentre phase 1 clinical trial evaluating VG161, an engineered oncolytic herpes simplex virus that expresses IL-12, IL-15, IL-15Rα and a PD-1–PD-L1-blocking fusion protein4, for safety and efficacy in patients with advanced liver cancer. VG161 was well tolerated, with no dose-limiting toxicities observed, and it demonstrated promising efficacy by reshaping the tumour immune microenvironment and re-sensitizing tumours that were previously resistant to systemic treatments. Notably, we also found that patients who had previously been sensitive to checkpoint inhibitor therapy showed enhanced efficacy with VG161 treatment. Furthermore, we developed an efficacy-prediction model based on differentially expressed genes, which successfully identified patients who were likely to benefit from VG161 and predicted prolonged overall survival. These findings position VG161 as a promising third-line therapeutic option for refractory hepatocellular carcinoma. This provides a new avenue for treatment and advances the field of oncolytic virus-based immunotherapies. ClinicalTrials.gov registration: NCT04806464 .

Date: 2025
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DOI: 10.1038/s41586-025-08717-5

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