Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients

Liping Zhong¹, Lu Gan², Bing Wang³, Tao Wu⁴, Fei Yao⁵, Wenlin Gong², Hongmei Peng⁴, Zhiming Deng⁴, Guoyou Xiao⁶, Xiyu Liu², Jintong Na², Desong Xia², Xianjun Yu⁷, Zhikun Zhang², Bangde Xiang⁸, Yu Huo², Dan Yan⁵, Zhixin Dong⁵, Fang Fang⁵, Yun Ma⁹, Guanqiao Jin¹⁰, Danke Su¹⁰, Xiuli Liu², Qiang Li¹⁰, Hai Liao¹⁰, Chao Tang², Jian He², Zhiping Tang¹¹, Shilai Zhang⁶, Bingqing Qiu⁶, Zhi Yang⁶, Lihui Yang¹², Ziqin Chen⁴, Mengsi Zeng⁴, Ronghua Feng⁴, Jiege Jiao¹³, Yuan Liao², Tinghua Wang², Liangliang Wu², Zhengcheng Mi², Ziqun Liu³, Si Shi⁷, Kun Zhang¹⁴, Wei Shi¹⁵, Yongxiang Zhao¹⁶

Affiliations

¹ State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: zhongliping@gxmu.edu.cn.
² State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China.
³ Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
⁴ The First People’s Hospital of Changde City, Changde, Hunan 415000, China.
⁵ Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China.
⁶ Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China.
⁷ Department of Pancreatic Surgery, The Affiliated Tumor Hospital, Fudan University, Shanghai 200032, China.
⁸ Department of Hepatobiliary Surgery, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China.
⁹ Department of Pathology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China.
¹⁰ Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China.
¹¹ Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
¹² Fundamental Nursing Teaching and Research Office, Nursing College of Guangxi Medical University, Nanning, Guangxi 530021, China.
¹³ Yuandan Biotechnology (Hainan) Co., Ltd., Haikou, Hainan 570100, China.
¹⁴ State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: zhang1986kun@tongji.edu.cn.
¹⁵ Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. Electronic address: shiwei1001@csco.org.cn.
¹⁶ State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: zhaoyongxiang@gxmu.edu.cn.

PMID: 39826543
DOI: 10.1016/j.cell.2024.12.010

Free article

Abstract

Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine α1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.

Keywords: CRISPR monkey liver cancer model; clinical trial; efficacy; hyperacute rejection; immunovirotherapy; intravenous NDV; recombinant Newcastle disease virus; refractory cancer; safety; α1,3GT.

Cell. 2025 Feb 20;188(4)(IF:66.850).

Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients

Abstract

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