Engineering genetic devices for in vivo control of therapeutic T cell activity triggered by the dietary molecule resveratrol.
Engineering genetic devices for in vivo control of therapeutic T cell activity triggered by the dietary molecule resveratrol.
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DOI：
10.1073/pnas.2106612118
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发表时间：
2021-08-24
影响因子：
11.1
通讯作者：
Ye H
中科院分区：
文献类型：
--
作者：
Yang L;Yin J;Wu J;Qiao L;Zhao EM;Cai F;Ye H
嵌合抗原受体（CAR）工程化T细胞疗法在临床上取得了巨大成功，但过度的细胞毒活性和对工程化T细胞的控制不佳限制了CAR-T疗法的应用。在这里，我们开发了白藜芦醇（RES）触发的调节装置（开/关），可以安装到 CAR-T 细胞中，通过调整 RES 剂量来精确控制 T 细胞活性。我们进一步证明了 RES 诱导/抑制 CAR 表达以及通过 RES 滴定机制对 T 细胞激活的可逆控制。我们的结果表明RESind-CAR T细胞可以被RES剂量依赖性地激活，具有很强的抗癌细胞毒性。我们的 RES 控制系统基于 RES 调节的治疗性免疫细胞的抑制/诱导，为控制癌症免疫疗法的策略建立了概念验证。嵌合抗原受体 (CAR) 工程 T 细胞疗法已被认为是癌症免疫治疗的强大策略；然而，CAR-T的临床应用目前受到细胞毒活性过高和T细胞控制不良造成的严重不良反应的限制。在此，我们利用饮食分子白藜芦醇（RES）响应性反式激活子和反式阻遏物分别开发了抑制性转基因表达（RESrep）装置和诱导性转基因表达（RESind）装置。经过优化后，这些工具能够控制工程化人类细胞中的 CAR 表达和 CAR 介导的抗肿瘤功能。我们证明，在原代 T 细胞和异种移植肿瘤小鼠模型中施用白藜芦醇后，白藜芦醇抑制 CAR 表达 (RESrep-CAR) 装置可以有效抑制 T 细胞活化。此外，我们还展示了白藜芦醇诱导型 CAR 表达 (RESind-CAR) 装置如何通过白藜芦醇滴定机制实现对 T 细胞激活的微调和可逆控制。此外，我们的结果表明，RES 的存在可以激活 RESind-CAR T 细胞，在体外和体内对细胞具有很强的抗癌细胞毒性。我们的研究证明了 RESrep 和 RESind 设备作为转基因表达的有效工具的实用性，并说明了 RESrep-CAR 和 RESind-CAR 设备在提高精准癌症免疫治疗中患者安全性方面的潜力。
Chimeric antigen receptor (CAR)–engineered T cell therapies have shown tremendous success in the clinic, but excessive cytotoxic activity and poor control over engineered T cells limit the application of CAR-T therapies. Here we have developed resveratrol (RES)–triggered regulation devices (on/off) that could be installed into CAR-T cells, which allow precise control over T cell activity through adjustment of RES dosage. We further demonstrated RES-inducible/repressible CAR expression and reversible control over T cell activation via a RES-titratable mechanism. Our results reveal that RESind-CAR T cells can be dose-dependently activated by RES with strong anticancer cytotoxicity. Our RES-controlled systems establish proof of concept for strategies to control cancer immunotherapies based on the RES-regulated repression/induction of therapeutic immune cells. Chimeric antigen receptor (CAR)–engineered T cell therapies have been recognized as powerful strategies in cancer immunotherapy; however, the clinical application of CAR-T is currently constrained by severe adverse effects in patients, caused by excessive cytotoxic activity and poor T cell control. Herein, we harnessed a dietary molecule resveratrol (RES)–responsive transactivator and a transrepressor to develop a repressible transgene expression (RESrep) device and an inducible transgene expression (RESind) device, respectively. After optimization, these tools enabled the control of CAR expression and CAR-mediated antitumor function in engineered human cells. We demonstrated that a resveratrol-repressible CAR expression (RESrep-CAR) device can effectively inhibit T cell activation upon resveratrol administration in primary T cells and a xenograft tumor mouse model. Additionally, we exhibit how a resveratrol-inducible CAR expression (RESind-CAR) device can achieve fine-tuned and reversible control over T cell activation via a resveratrol-titratable mechanism. Furthermore, our results revealed that the presence of RES can activate RESind-CAR T cells with strong anticancer cytotoxicity against cells in vitro and in vivo. Our study demonstrates the utility of RESrep and RESind devices as effective tools for transgene expression and illustrates the potential of RESrep-CAR and RESind-CAR devices to enhance patient safety in precision cancer immunotherapies.
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DOI：
10.1056/nejmoa1707447
发表时间：
2017-12-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Neelapu SS;Locke FL;Bartlett NL;Lekakis LJ;Miklos DB;Jacobson CA;Braunschweig I;Oluwole OO;Siddiqi T;Lin Y;Timmerman JM;Stiff PJ;Friedberg JW;Flinn IW;Goy A;Hill BT;Smith MR;Deol A;Farooq U;McSweeney P;Munoz J;Avivi I;Castro JE;Westin JR;Chavez JC;Ghobadi A;Komanduri KV;Levy R;Jacobsen ED;Witzig TE;Reagan P;Bot A;Rossi J;Navale L;Jiang Y;Aycock J;Elias M;Chang D;Wiezorek J;Go WY
通讯作者：
Go WY
影响因子：
64.5
作者：
Liu Y;Bai P;Woischnig AK;Charpin-El Hamri G;Ye H;Folcher M;Xie M;Khanna N;Fussenegger M
通讯作者：
Fussenegger M
影响因子：
17.1
作者：
Jan M;Scarfò I;Larson RC;Walker A;Schmidts A;Guirguis AA;Gasser JA;Słabicki M;Bouffard AA;Castano AP;Kann MC;Cabral ML;Tepper A;Grinshpun DE;Sperling AS;Kyung T;Sievers QL;Birnbaum ME;Maus MV;Ebert BL
通讯作者：
Ebert BL
影响因子：
28.2
作者：
Gust J;Hay KA;Hanafi LA;Li D;Myerson D;Gonzalez-Cuyar LF;Yeung C;Liles WC;Wurfel M;Lopez JA;Chen J;Chung D;Harju-Baker S;Özpolat T;Fink KR;Riddell SR;Maloney DG;Turtle CJ
通讯作者：
Turtle CJ
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.