title: Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells.
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.
authors.affiliation: Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|Molecular Disease Biology Section, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Danish Cancer Society, DK-2100 Copenhagen, Denmark.|Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark.
authors.forename: Li
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, China.
authors.forename: Shaoxing
authors.initials: S
authors.lastname: Yang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.|Lung Cancer Center, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Keli
authors.initials: K
authors.lastname: Ge
authors.affiliation: Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Diseases, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Qi
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Zhongxue
authors.initials: Z
authors.lastname: An
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Renhua
authors.initials: R
authors.lastname: Wu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 10021, China.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Environmental Health and Related Product Safety, China CDC, Beijing 10021, China.
authors.forename: Xiping
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Environmental Health and Related Product Safety, China CDC, Beijing 10021, China.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Na
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Tiancheng
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Shuren
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Youhui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 518083, China.|Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, 518083 Shenzhen, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.|James D. Watson Institute of Genome Science, 310008 Hangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.affiliation: Department of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Zou
authors.affiliation: Laborartory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Xin
authors.affiliation: Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense C, Denmark.|Department of Oncology, Odense University Hospital, DK-5000 Odense C, Denmark.
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Ditzel
authors.affiliation: Department of Pulmonary Oncology, Affiliated Hospital, Academy of Military Medical Science, Beijing 100071, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Kaitai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Hubei Provincial Cooperative, Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan 30068, China.|Department of Immunology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Binlei
authors.initials: B
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D001932:Brain Neoplasms / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D016022:Case-Control Studies; D002452:Cell Count; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D011379:Prognosis; D018139:Simplexvirus; D019098:Telomerase / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D049452:Green Fluorescent Proteins; D019098:Telomerase
keywords: clinical application; epithelial-marker-independent; telomerase-specific HSV; viable circulating tumor cells