Shen Yinan, Bai Xueli, Zhang Qi, Liang Xingmei, Jin Xinyan, Zhao Zeda, Song Wei, Tan Qian, Zhao Ronghua, Jia William, Gu Shanzhi, Shi Guoming, Zheng Ziwei, Wei Guyue, Wang Youlei, Fang Tian, Li Yuwei, Wang Zijun, Yang Zifan, Guo Sida, Lin Danni, Wei Fang, Wang Lei, Sun Xiaoli, Qin Aijun, Xie Longshen, Qiu Yeting, Bao Wenqing, Rahimian Shah, Singh Manu, Murad Yanal, Shang Jianying, Chu Min, Huang Maoliang, Ding Jun, Chen Wei, Ye Yufu, Chen Yiwen, Li Xiang, Liang Tingbo
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.
Nature. 2025 May;641(8062):503-511. doi: 10.1038/s41586-025-08717-5. Epub 2025 Mar 19.
Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments. Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity, 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 protein, 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 .
肝细胞癌仍然是一种危及生命的恶性肿瘤，在二线治疗失败后治疗选择有限。溶瘤病毒在癌细胞中选择性复制并裂解癌细胞，释放新抗原并刺激全身抗肿瘤免疫，提供了一种潜在的治疗选择。在这里，我们展示了一项多中心1期临床试验的结果，该试验评估了VG161，一种表达IL-12、IL-15、IL-15Rα和PD-1-PD-L1阻断融合蛋白的工程化溶瘤单纯疱疹病毒，用于晚期肝癌患者的安全性和疗效。VG161耐受性良好，未观察到剂量限制性毒性，并且通过重塑肿瘤免疫微环境和使先前对全身治疗耐药的肿瘤重新敏感化，显示出有前景的疗效。值得注意的是，我们还发现，先前对检查点抑制剂治疗敏感的患者在接受VG161治疗后疗效增强。此外，我们基于差异表达基因开发了一种疗效预测模型，该模型成功识别了可能从VG161中获益的患者，并预测了总生存期的延长。这些发现将VG161定位为难治性肝细胞癌有前景的三线治疗选择。这为治疗提供了一条新途径，并推动了基于溶瘤病毒的免疫疗法领域的发展。ClinicalTrials.gov注册号：NCT04806464 。
