Research Overview

We are engaged in research aimed at ensuring the safety of iPS cells and realizing immunotherapy by exploiting the special characteristics of iPS cells. T lymphocytes are a type of white blood cell whose functions are activated by antigen-specific recognition of target cells; the T cell receptors (TCR) which enable recognition of the target antigens are formed by gene rearrangement involving deletion of a genome sequence. However, iPS cells created by reprogramming T lymphocytes (T-iPS cells) retain the TCR gene sequence of the original T lymphocytes. We have established a method of inducing redifferentiation of rejuvenated cytotoxic T cells in large quantities from antigen-specific human T-iPS cells. (Nishimura et al., Cell Stem Cell, 2013, Ito et al., Communication Biology, 2021).

We have progressed with basic research to bring this technology to the clinical stage. By inserting patient-specific T-cell receptor genes into the HLA homozygous donor-derived iPS cells supplied by CiRA, we demonstrated that it is possible to create antigen-specific T lymphocytes that can be used in a number of patients (Minagawa et al., Cell Stem Cell, 2018). We also enhanced the antigen-specific T cell induction process to establish manufacturing and expansion culture processes free of animal-derived substances. By simultaneously inducing chimeric antigen receptor (CAR) genes, we indicated the possibility of supplying iPS cell-derived CAR-T lymphocytes for use in a number of patients (Iriguchi, Yasui, and Kawai et al., Nature Communications, 2021; Kawai et al., Molecular Therapy, 2021 Ueda et al., Nature Biomedical Engineering, 2022). Furthermore, by using a range of techniques to minimize the immunogenicity of iPS cells, we showed that it may be possible to supply T lymphocytes for therapeutic use from just a small number of iPS cells （Xu and Wang et al., Cell Stem Cell, 2019, Wang et al., Nature Biomedical Engineering, 2021). Some of these technologies have been outlicensed to private-sector enterprises for clinical development.

Elsewhere, we are working on the differentiation from iPS cells of some of the large number of other T lymphocyte subsets (Kitayama et al., Stem Cell Report, 2016), as well as other cell types such as natural killer cells and other innate lymphocyte subsets (Ueda et al., Stem Cell Reports, 2018; Ueda et al., Cancer Science, 2020), and macrophages (Higaki and Hirao, Molecular Therapy, 2018; Iwamoto et al., Molecular Therapy Methods & Clinical Development, 2021), and progressing with the development of immunoregenerative therapies emphasizing the particular characteristics of each subset.

These research projects will enable us to contribute to realizing regenerative medicine and to improving treatment outcomes in areas such as cancer, infectious and autoimmune diseases, and transplant surgery.