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Cell Stem Cell. 2018 Dec 6;23(6):850-858.e4. doi: 10.1016/j.stem.2018.10.005. Epub 2018 Nov 15.

Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy.

Author information

1
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Japan.
2
Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.
3
Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan.
4
Department of Life Science Frontiers, CiRA, Kyoto University, Kyoto, Japan.
5
Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Japan; Regenerative Medicine Unit, Takeda Pharmaceutical Company, Fujisawa, Japan.
6
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Japan.
7
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
8
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
9
Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.
10
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan.
11
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
12
Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Japan; Facility for iPS Cell Therapy, CiRA, Kyoto University, Kyoto, Japan. Electronic address: kaneko.shin@cira.kyoto-u.ac.jp.

Abstract

Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8αβ T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) α chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8αβ T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.

KEYWORDS:

CD8 T cell; HLA matched iPS cell; T cell differentiation; T cell-derived iPS cell; TCR gene therapy; TCR rearrangement; antigen-specific T cell regeneration; cancer immunotherapy; cytotoxic T cell; iPS cell bank

PMID:
30449714
DOI:
10.1016/j.stem.2018.10.005
[Indexed for MEDLINE]
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