Improved safety of induced pluripotent stem cell-derived antigen-presenting cell-based cancer immunotherapy.
Improved safety of induced pluripotent stem cell-derived antigen-presenting cell-based cancer immunotherapy.
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DOI：
10.1016/j.omtm.2021.03.002
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发表时间：
2021-06-11
期刊：
影响因子：
--
通讯作者：
Uemura Y
中科院分区：
文献类型：
--
作者：
Mashima H;Zhang R;Kobayashi T;Tsukamoto H;Liu T;Iwama T;Hagiya Y;Yamamoto M;Fukushima S;Okada S;Idiris A;Kaneko S;Nakatsura T;Ohdan H;Uemura Y
诱导性多能干细胞（iPSC）及其衍生物的致瘤性和毒性是其临床应用中的主要安全问题。最近，我们开发了粒细胞-巨噬细胞集落刺激因子（GM-CSF）-生产增殖骨髓细胞（GM-pMCs）从小鼠iPSC作为无限的抗原呈递细胞用于癌症免疫治疗的来源。由于GM-pMCs是通过将c-Myc和Csf 2引入iPSC衍生的MCs中产生的，并且依赖于自身产生的GM-CSF进行增殖，因此应引入在给药后控制其增殖的方法以提高安全性。在这项研究中，我们比较了两个有前途的自杀基因系统，单纯疱疹病毒胸苷激酶（HSV-TK）/更昔洛韦（GCV）和诱导型caspase-9（iCasp 9）/AP 1903，用于保护GM-pMCs在癌症免疫治疗的疗效。HSV-TK或iCasp 9的表达不损害GM-pMCs的基本性质。这两种表达自杀基因的细胞在用相应的凋亡诱导药物处理后选择性地发生凋亡，并且它们在体内被迅速消除。iCasp 9/AP 1903比HSV-TK/GCV更有效地诱导细胞凋亡。此外，高浓度的GCV对不表达HSV-TK的细胞有毒性，而AP 1903是生物惰性的。这些结果表明，当在引发抗肿瘤免疫后控制GM-pMC的命运时，iCasp 9/AP 1903在安全性和功效方面上级HSV-TK/GCV。来自iPSC的产生GM-CSF的增殖骨髓细胞（GM-pMCs）已经被开发为用于癌症免疫疗法的有效抗原呈递细胞。然而，其潜在的致瘤性和毒性是其临床应用的主要安全性问题。Uemura及其同事证明了诱导型caspase-9自杀系统可以有效地控制GM-pMCs的命运。
The tumorigenicity and toxicity of induced pluripotent stem cells (iPSCs) and their derivatives are major safety concerns in their clinical application. Recently, we developed granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing proliferating myeloid cells (GM-pMCs) from mouse iPSCs as a source of unlimited antigen-presenting cells for use in cancer immunotherapy. As GM-pMCs are generated by introducing c-Myc and Csf2 into iPSC-derived MCs and are dependent on self-produced GM-CSF for proliferation, methods to control their proliferation after administration should be introduced to improve safety. In this study, we compared the efficacy of two promising suicide gene systems, herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV) and inducible caspase-9 (iCasp9)/AP1903, for safeguarding GM-pMCs in cancer immunotherapy. The expression of HSV-TK or iCasp9 did not impair the fundamental properties of GM-pMCs. Both of these suicide gene-expressing cells selectively underwent apoptosis after treatment with the corresponding apoptosis-inducing drug, and they were promptly eliminated in vivo. iCasp9/AP1903 induced apoptosis more efficiently than HSV-TK/GCV. Furthermore, high concentrations of GCV were toxic to cells not expressing HSV-TK, whereas AP1903 was bioinert. These results suggest that iCasp9/AP1903 is superior to HSV-TK/GCV in terms of both safety and efficacy when controlling the fate of GM-pMCs after priming antitumor immunity. GM-CSF-producing, proliferating myeloid cells (GM-pMCs) from iPSCs have been developed as potent antigen-presenting cells for cancer immunotherapy. However, their potential tumorigenicity and toxicity are major safety concerns for their clinical applications. Uemura and colleagues demonstrated that the inducible caspase-9 suicide system can efficiently control the fates of GM-pMCs.
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影响因子：
11.5
作者：
Bol, Kalijn F.;Schreibelt, Gerty;Figdor, Carl G.
通讯作者：
Figdor, Carl G.
影响因子：
2.6
作者：
Gu, Lubing;Chiang, Kuang-Yueh;Zhou, Muxiang
通讯作者：
Zhou, Muxiang
DOI：
10.1038/mto.2016.11
发表时间：
2016
期刊：
Molecular therapy oncolytics
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.5
作者：
Mita, Alain C.;Mita, Monica M.;Giles, Francis J.
通讯作者：
Giles, Francis J.
DOI：
10.1056/nejmoa1106152
发表时间：
2011-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Di Stasi A;Tey SK;Dotti G;Fujita Y;Kennedy-Nasser A;Martinez C;Straathof K;Liu E;Durett AG;Grilley B;Liu H;Cruz CR;Savoldo B;Gee AP;Schindler J;Krance RA;Heslop HE;Spencer DM;Rooney CM;Brenner MK
通讯作者：
Brenner MK