Ando, Miki, Nishimura, Toshinobu, Yamazaki, Satoshi, Yamaguchi, Tomoyuki, Kawana-Tachikawa, Ai, Hayama, Tomonari, Nakauchi, Yusuke, Ando, Jun, Ota, Yasunori, Takahashi, Satoshi, Nishimura, Ken, Ohtaka, Manami, Nakanishi, Mahito, Miles, John J., Burrows, Scott R., Brenner, Malcolm K., and Nakauchi, Hiromitsu (2015) A safeguard system for induced pluripotent stem cell-derived rejuvenated T cell therapy. Stem Cell Reports, 5 (4). pp. 597-608.

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Abstract

The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy.

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