TY - JOUR
T1 - Regeneration of Tumor-Antigen-Specific Cytotoxic T Lymphocytes from iPSCs Transduced with Exogenous TCR Genes
AU - Maeda, Takuya
AU - Nagano, Seiji
AU - Kashima, Soki
AU - Terada, Koji
AU - Agata, Yasutoshi
AU - Ichise, Hiroshi
AU - Ohtaka, Manami
AU - Nakanishi, Mahito
AU - Fujiki, Fumihiro
AU - Sugiyama, Haruo
AU - Kitawaki, Toshio
AU - Kadowaki, Norimitsu
AU - Takaori-Kondo, Akifumi
AU - Masuda, Kyoko
AU - Kawamoto, Hiroshi
N1 - Publisher Copyright:
© 2020
PY - 2020/12/11
Y1 - 2020/12/11
N2 - In the current adoptive T cell therapy, T cells from a patient are given back to that patient after ex vivo activation, expansion, or genetic manipulation. However, such strategy depends on the quality of the patient's T cells, sometimes leading to treatment failure. It would therefore be ideal to use allogeneic T cells as “off-the-shelf” T cells. To this aim, we have been developing a strategy where potent tumor-antigen-specific cytotoxic T lymphocytes (CTLs) are regenerated from T-cell-derived induced pluripotent stem cells (T-iPSCs). However, certain issues still remain that make it difficult to establish highly potent T-iPSCs: poor reprogramming efficiency of T cells into iPSCs and high variability in the differentiation capability of each T-iPSC clone. To expand the versatility of this approach, we thought of a method to produce iPSCs equivalent to T-iPSCs, namely, iPSCs transduced with exogenous T cell receptor (TCR) genes (TCR-iPSCs). To test this idea, we first cloned TCR genes from WT1-specific CTLs regenerated from T-iPSCs and then established WT1-TCR-iPSCs. We show that the regenerated CTLs from TCR-iPSCs exerted cytotoxic activity comparable to those from T-iPSCs against WT1 peptide-loaded cell line in in vitro model. These results collectively demonstrate the feasibility of the TCR-iPSC strategy.
AB - In the current adoptive T cell therapy, T cells from a patient are given back to that patient after ex vivo activation, expansion, or genetic manipulation. However, such strategy depends on the quality of the patient's T cells, sometimes leading to treatment failure. It would therefore be ideal to use allogeneic T cells as “off-the-shelf” T cells. To this aim, we have been developing a strategy where potent tumor-antigen-specific cytotoxic T lymphocytes (CTLs) are regenerated from T-cell-derived induced pluripotent stem cells (T-iPSCs). However, certain issues still remain that make it difficult to establish highly potent T-iPSCs: poor reprogramming efficiency of T cells into iPSCs and high variability in the differentiation capability of each T-iPSC clone. To expand the versatility of this approach, we thought of a method to produce iPSCs equivalent to T-iPSCs, namely, iPSCs transduced with exogenous T cell receptor (TCR) genes (TCR-iPSCs). To test this idea, we first cloned TCR genes from WT1-specific CTLs regenerated from T-iPSCs and then established WT1-TCR-iPSCs. We show that the regenerated CTLs from TCR-iPSCs exerted cytotoxic activity comparable to those from T-iPSCs against WT1 peptide-loaded cell line in in vitro model. These results collectively demonstrate the feasibility of the TCR-iPSC strategy.
KW - CD8αβT cells
KW - TCR
KW - WT1
KW - adoptive T cell therapy
KW - iPSCs
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U2 - 10.1016/j.omtm.2020.09.011
DO - 10.1016/j.omtm.2020.09.011
M3 - Article
AN - SCOPUS:85092525092
SN - 2329-0501
VL - 19
SP - 250
EP - 260
JO - Molecular Therapy Methods and Clinical Development
JF - Molecular Therapy Methods and Clinical Development
ER -