A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy.
A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy.
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DOI：
10.1016/j.stemcr.2015.07.011
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发表时间：
2015-10-13
影响因子：
5.9
通讯作者：
Nakauchi H
中科院分区：
文献类型：
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作者：
Ando M;Nishimura T;Yamazaki S;Yamaguchi T;Kawana-Tachikawa A;Hayama T;Nakauchi Y;Ando J;Ota Y;Takahashi S;Nishimura K;Ohtaka M;Nakanishi M;Miles JJ;Burrows SR;Brenner MK;Nakauchi H
诱导多能干细胞（iPSC）的发现为再生医学治疗开辟了充满希望的新途径。然而，未分化 iPSC 的致瘤潜力是临床转化的主要安全问题。为了解决这个问题，我们通过将诱导型 caspase-9 (iC9) 引入 iPSC 来证明自杀基因治疗的功效。用特定化学二聚化诱导剂 (CID) 激活 iC9 会启动 caspase 级联，消除 iPSC 和源自 iPSC 的肿瘤。我们将此 iC9/CID 保护系统引入先前报道的 iPSC 衍生的再生细胞毒性 T 淋巴细胞 (rejCTL) 治疗模型中，并确认我们可以从表达高水平 iC9 的 iPSC 生成 rejCTL，而不会干扰抗原特异性杀伤活性。表达 iC9 的 rejCTL 在体内发挥抗肿瘤作用。该系统有效且安全地诱导这些 rejCTL 凋亡。这些结果共同表明，iC9/CID 保障系统是未来 iPSC 介导的临床治疗方法的一个有前途的工具。 iPSC 衍生的再生 CTL 可有效对抗 EBV 诱导的体内肿瘤 再生 CTL 是通过基于诱导型 caspase-9 (iC9) 的自杀系统实现的 诱导后，iC9 系统有效导致再生 CTL 凋亡 基于 iC9 的系统为未来 iPSC 介导的细胞治疗提供了保障 Nakauchi 及其同事表明，利用基于诱导型 caspase-9 (iC9) 的自杀系统实现的 iPSC 衍生的再生 CTL (rejCTL) 可有效对抗 EBV 诱导的体内肿瘤。诱导后，基于 iC9 的系统在体外和体内有效、安全地导致这些 rejCTL 凋亡，并为未来 iPSC 介导的细胞治疗提供保障。
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. iPSC-derived rejuvenated CTLs are effective against EBV-induced tumors in vivo 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 In this article, Nakauchi and colleagues show that iPSC-derived rejuvenated CTLs (rejCTLs) implemented with an inducible caspase-9 (iC9)-based suicide system are effective against EBV-induced tumors in vivo. Upon induction, the iC9-based system efficiently and safely leads to apoptosis in these rejCTLs in vitro and in vivo and provides a safeguard for future iPSC-mediated cell therapy.