title: A Safety Checkpoint to Eliminate Cancer Risk of the Immune Evasive Cells Derived from Human Embryonic Stem Cells.
abstract: Human embryonic stem cells (hESCs) hold great promise in the regenerative therapy of many currently untreatable human diseases. One of the key bottlenecks is the immune rejection of hESC-derived allografts by the recipient. To overcome this challenge, we have established new approaches to induce immune protection of hESC-derived allografts through the coexpression of immune suppressive molecules CTLA4-Ig and PD-L1. However, this in turn raises a safety concern of cancer risk because these hESC-derived cells can evade immune surveillance. To address this safety concern, we developed a safety checkpoint so that the immune evasive hESC-derived cells in the graft can be effectively eliminated if any cellular transformation is detected. In this context, we knock-in the suicidal gene herpes simplex virus thymidine kinase (HSVTK) into the constitutive HPRT locus of CP hESCs (knock-in hESCs expressing CTLA4-Ig and PD-L1), denoted CPTK hESCs. Employing humanized mice (Hu-mice) reconstituted with human immune system, we demonstrated that the CPTK hESC-derived cells are protected from immune rejection. In addition, CPTK hESC-derived cells can be efficiently eliminated in vitro and in vivo with FDA approved TK-targeting drug ganciclovir. Therefore, this new safety checkpoint improves the feasibility to use the immune evasive hESC-derived cells for regenerative medicine. Stem Cells 2017;35:1154-1161.
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, China.|Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jingjin
authors.initials: J
authors.lastname: He
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, China.|Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Rong
authors.affiliation: Shenzhen Children's Hospital, Shenzhen, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Fu
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong, China.|Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D002460:Cell Line; D015774:Ganciclovir / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology*; D012307:Risk Factors; D013724:Teratoma / Q000473:pathology
chemical_list: D015774:Ganciclovir
keywords: Cancer risk; Human embryonic stem cells; Humanized mice; Immune protection; Suicidal genes