Highlights

iPSC-derived rejuvenated CTLs are effective against EBV-induced tumors invivo

Rejuvenated CTLs are implemented with an inducible caspase-9 (iC9)-based suicide system

Upon induction, the iC9 system efficiently leads to apoptosis in rejuvenated CTLs

The iC9-based system provides a safeguard for future iPSC-mediated cell therapy

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 killingactivity. iC9-expressing rejCTLs exert antitumor effects invivo. 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.

Human induced pluripotent stem cells (iPSCs) can unlimitedly self-renew and differentiate into various cell types (Takahashi etal., 2007). Their pluripotency makes iPSCs a promising tool for therapy in a wide range of diseases at present refractory to treatment (Inoue etal., 2014). Recent studies, however, reported the tumorigenic potential of contaminated undifferentiated iPSCs and the malignant transformation of differentiated iPSCs (Lee etal., 2013aandNori etal., 2015). The tumorigenic risks of iPSCs could be reduced by several strategies, such as sorting out undifferentiated cells with antibodies targeting surface-displayed biomarkers (Tang etal., 2011), killing undifferentiated cells with cytotoxic antibodies (Choo etal., 2008), or elimination of remaining undifferentiated pluripotent cells with chemical inhibitors (Ben-David etal., 2013andLee etal., 2013b). However, these strategies may not suffice to lower risk to acceptable levels, because the tumorigenic risk of iPSC-based cell therapy arises not just from contamination with undifferentiated iPSCs but also from other unexpected events associated with long-term culture for reprogramming and redifferentiation. There is always a chance of unexpected issues associated with first-in-human clinical studies.

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