A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy.

Adoptive T-cell immunotherapy is a potential therapeutic strategy for combating various types of cancer. However, highly expanded T cells have not proven particularly effective. This is in part explained by exhaustion and losses of function that occur during the ex vivo expansion of T cells. For an effective adoptive immunotherapy, what we need is not the "exhausted" T cells, but large numbers of "young and active" T cells that can kill tumors. To address this issue, we have recently developed a novel system in which antigen-specific killer T cells (CTLs) can be rejuvenated by reprogramming them to induced pluripotent stem cells (iPSCs) and redifferentiating them while expanding their numbers, yielding abundant rejuvenated T cells (rejT cells). We confirmed the in vivo efficacy of these rejT cell against EBV-induced tumors inoculated in immunedeficient mice. To increase the safety of this novel rejT cell therapy, we inserted a drug inducible suicide system to T cell-derived iPSCs. Both the iPSCs and rejT cells derived from them induced cell death after administration of the inducing drug in vivo thereby demonstarting efficacy of this safety system. The results facilitate clinical application of the rejT cell therapy and other branches of iPSC-derived regenerative medicine.