Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients
Liping Zhong, Lu Gan, Bing Wang, Liang Cao, Fei Yao, Wenlin Gong, Hongmei Peng, Zhiming Deng, Guoyou Xiao, Xiyu Liu, Jintong Na, Desong Xia, Xianjun Yu, Zhikun Zhang, Xiang Bangde, Yu Huo, Dan Yan, Zhixin Dong, Fang Fang, Yun Ma, Guanqiao Jin, Danke Su, Xiuli Liu, Rui Li, H Liao, Chao Tang, Jian He, Zhiping Tang, Shilai Zhang, Bingqing Qiu, Zhi Yang, Lihui Yang, Ziqin Chen, Mengsi Zeng, Ronghua Feng, Jie-ge Jiao, Yuan Liao, Tinghua Wang, Liangliang Wu, Zhengcheng Mi, Ziqun Liu, Si Shi, Kun Zhang, Wei Shi, Yongxiang Zhao
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.