Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells

Abstract

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Wen Zhang1, *, Li Bao3, 9, 10, *, Shaoxing Yang6, *, Zhaoyang Qian3, *, Mei Dong4, *, Liyuan Yin2, 19, Qian Zhao7, Keli Ge1, Zhenling Deng1, Jing Zhang5, Fei Qi8, Zhongxue An3, Yuan Yu3, Qingbo Wang3, Renhua Wu3, Fan Fan3, Lianfeng Zhang16, Xiping Chen17, Yingjian Na17, Lin Feng2, Lingling liu1, Yujie Zhu1, Tiancheng Qin2, Shuren Zhang1, Youhui Zhang1, Xiuqing Zhang3, 11, 12, Jian Wang3, 13, Xin Yi3, Liqun Zou5, Hong-Wu Xin18, Henrik J. Ditzel10, 14, Hongjun Gao6, Kaitai Zhang2, Binlei Liu15, 1, Shujun Cheng2 1Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 2State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 3BGI-Shenzhen, Shenzhen 518083, China 4Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 5Department of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China 6Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, China 7Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 8Department of Respiratory Diseases, Chinese PLA General Hospital, Beijing 100853, China 9Molecular Disease Biology Section, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Danish Cancer Society, DK-2100 Copenhagen, Denmark 10Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark 11The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 518083, China 12Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, 518083 Shenzhen, China 13James D. Watson Institute of Genome Science, 310008 Hangzhou, China 14Department of Oncology, Odense University Hospital, DK-5000 Odense C, Denmark 15Hubei Provincial Cooperative, Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan 30068, China 16Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 10021, China 17Institute of Environmental Health and Related Product Safety, China CDC, Beijing 10021, China 18Laborartory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing 100142, China 19Lung Cancer Center, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China *These authors contributed equally to this work Correspondence to: Binlei Liu, email: liubinlei@cicams.ac.cn Kaitai Zhang, email: zhangkt@cicams.ac.cn Hongjun Gao, email: gaohj6708@hotmail.com Keywords: viable circulating tumor cells, epithelial-marker-independent, telomerase-specific HSV, clinical application Received: October 20, 2015 Accepted: April 24, 2016 Published: May 18, 2016 ABSTRACT Detection of circulating tumor cells remains a significant challenge due to their vast physical and biological heterogeneity. We developed a cell-surface-marker-independent technology based on telomerase-specific, replication-selective oncolytic herpes-simplex-virus-1 that targets telomerase-reverse-transcriptase-positive cancer cells and expresses green-fluorescent-protein that identifies viable CTCs from a broad spectrum of malignancies. Our method recovered 75.5–87.2% of tumor cells spiked into healthy donor blood, as validated by different methods, including single cell sequencing. CTCs were detected in 59–100% of 326 blood samples from patients with 6 different solid organ carcinomas and lymphomas. Significantly, CTC-positive rates increased remarkably with tumor progression from N0M0, N+M0 to M1 in each of 5 tested cancers (lung, colon, liver, gastric and pancreatic cancer, and glioma). Among 21 non-small cell lung cancer cases in which CTC values were consecutively monitored, 81% showed treatment-related decreases, which was also found after treatments in the other solid tumors. Moreover, monitoring CTC values provided an efficient treatment response indicator in hematological malignancies. Compared to CellSearch, our method detected significantly higher positive rates in 40 NSCLC in all stages, including N0M0, N+M0 and M1, and was less affected by chemotherapy. This simple, robust and clinically-applicable technology detects viable CTCs from solid and hematopoietic malignancies in early to late stages, and significantly improves clinical detection and treatment prognostication.