Cloning and expansion of antigen-specific T cells using iPS cell technology: Possible use of regenerated T cells in personalized medicine

Abstract

Recent advances in adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) have demonstrated that CTLs are effective in killing tumor cells in vivo for some tumor types. However, a critical issue that CTLs collected from patients are easily exhausted during expansion culture is yet to be addressed. Therefore, we have been developing a strategy that utilizes induced pluripotent stem cell (iPSC) technology, based on the idea that iPSCs produced from antigen-specific CTLs would regenerate CTLs with the same antigen specificity as the original CTLs. We previously succeeded in regenerating melanoma antigen MART1-specific CTLs, and more recently in producing potent CTLs expressing the CD8αβ heterodimer. We are now developing a novel method by which non-T derived iPSCs are transduced with exogenous T cell receptor (TCR) genes. If this method is applied to the allogeneic transfusion setting wherein HLA haplotype-homozygous iPSC stocks are used as the cell source, it will be possible to prepare “off-the-shelf” T cells. We are also considering incorporation of a personalized medicine approach to this allogeneic setting. In such a scheme, genes encoding TCRs specific for neoantigens will be collected from patients and HLA-homo iPSCs will be transduced with these TCR genes. Using such iPSCs, it will be possible to produce allogeneic CTLs expressing autologous TCRs originating from patients.