title: A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy.
abstract: The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy.
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Miki
authors: M
authors: Ando
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors: Toshinobu
authors: T
authors: Nishimura
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Satoshi
authors: S
authors: Yamazaki
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Tomoyuki
authors: T
authors: Yamaguchi
authors: Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
authors: Ai
authors: A
authors: Kawana-Tachikawa
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Tomonari
authors: T
authors: Hayama
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Yusuke
authors: Y
authors: Nakauchi
authors: Department of Hematology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors: Jun
authors: J
authors: Ando
authors: Department of Pathology, Research Hospital, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Yasunori
authors: Y
authors: Ota
authors: Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors: Satoshi
authors: S
authors: Takahashi
authors: Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors: Ken
authors: K
authors: Nishimura
authors: Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8562, Japan.
authors: Manami
authors: M
authors: Ohtaka
authors: Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8562, Japan.
authors: Mahito
authors: M
authors: Nakanishi
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia.
authors: John J
authors: JJ
authors: Miles
authors: QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia.
authors: Scott R
authors: SR
authors: Burrows
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Feigin Center, 1102 Bates Avenue, Houston, TX 77030, USA.
authors: Malcolm K
authors: MK
authors: Brenner
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Electronic address: nakauchi@ims.u-tokyo.ac.jp.
authors: Hiromitsu
authors: H
authors: Nakauchi
mesh_terms: D000818:Animals; D017209:Apoptosis; D053453:Caspase 9 / Q000235:genetics*; D002454:Cell Differentiation; D002478:Cells, Cultured; D015316:Genetic Therapy; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation*
chemical_list: D053453:Caspase 9