[HTML][HTML] A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy

S Iriguchi, Y Yasui, Y Kawai, S Arima… - Nature …, 2021 - nature.com
S Iriguchi, Y Yasui, Y Kawai, S Arima, M Kunitomo, T Sato, T Ueda, A Minagawa, Y Mishima
Nature communications, 2021nature.com
Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have
facilitated further development of T-cell immunotherapy against wide variety of diseases.
One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate
T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and
synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of
current methods may compromise their utilities. Here we show improved differentiation …
Abstract
Clinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.
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