We have proposed a strategy to use the iPSC technology for expansion of tumor antigen specific CTLs; iPSCs produced from T cells (T-iPSCs) inherit rearranged TCR genes, and thus all regenerated T cells from T-iPSCs express the same TCR. Based on this idea, we have succeeded in regenerating MART1-specific CTLs from a melanoma patient (Vizcardo et al, Cell Stem Cell, 2013). Recently we have developed a culture method by which CTLs expressing CD8ab heterodimer with high antigen specific cytotoxicity can be regenerated (Maeda et al, Cancer Research, 2016).
Currently, we are trying to apply this strategy to allogeneic setting. To this end, we thought of a method in which non-T cell derived iPSCs are transduced with exogenous TCR genes (TCR-iPSCs). As a source of such iPSCs, we are going to use HLA-haplotype homo iPSCs established by iPSC stock project conducted by Shinya Yamanaka. In this project, HLA-homo iPSCs will be transplanted to HLA-haplotype heterozygous recipients, expecting that allo-reaction could be reduced. At present, top two frequent HLA-homo iPSC are available, covering 24% of the Japanese population. To test the idea of TCR-iPSCs, we lentivirally transduced non-T cell derived iPSCs with WT1-specific TCR gene cloned by our group. Regenerated CTLs from TCR-iPSCs were found to exhibit cytotoxicity comparable to those from T-iPSCs carrying the same WT1-TCR, indicating that this strategy works well. We are planning to apply this method clinically for acute myeloid leukemia by targeting WT1 antigen. In the future, we plan to establish “TCR-iPSC bank” that covers various tumor antigens and HLA haplotypes, aiming to realize “off-the-shelf T cell therapy” against cancer.