Zhong, Gan, Wang, and Wu et al. developed a recombinant Newcastle disease virus with a 1,3GT gene (NDV-GT) encoding porcine alpha-galactosidase (α-Gal) – an antigen that triggers the rejection of xenografts in primates. In cynomolgus monkeys with primary HCC induced by CRISPR, i.v. delivery of NDV-GT induced hyperacute rejection, altered tumor vasculature, triggered humoral and cellular immune responses, and reduced suppressive features in the TME, leading to regression of primary tumors and prolonged survival. In a clinical trial of 20 patients with diverse refractory cancer types, NDV-GT provided a 90% disease control rate without serious AEs.
Contributed by Lauren Hitchings
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 _1,3GT 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.
Author Info: (1) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China.
Author Info: (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) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (7) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (8) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (9) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (10) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (11) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (12) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (13) Department of Pancreatic Surgery, The Affiliated Tumor Hospital, Fudan University, Shanghai 200032, China. (14) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (15) Department of Hepatobiliary Surgery, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (16) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (17) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. (18) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. (19) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. (20) Department of Pathology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (21) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (22) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (23) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (24) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (25) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (26) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (27) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (28) Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China. (29) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (30) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (31) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (32) Fundamental Nursing Teaching and Research Office, Nursing College of Guangxi Medical University, Nanning, Guangxi 530021, China. (33) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (34) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (35) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (36) Yuandan Biotechnology (Hainan) Co., Ltd., Haikou, Hainan 570100, China. (37) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (38) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (39) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (40) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (41) Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China. (42) Department of Pancreatic Surgery, The Affiliated Tumor Hospital, Fudan University, Shanghai 200032, China. (43) 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. (44) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. Electronic address: shiwei1001@csco.org.cn. (45) 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.
