The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.
The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.
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DOI：
10.1038/s41467-018-05395-y
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发表时间：
2018-08-03
影响因子：
16.6
通讯作者：
Bramson JL
中科院分区：
文献类型：
--
作者：
Helsen CW;Hammill JA;Lau VWC;Mwawasi KA;Afsahi A;Bezverbnaya K;Newhook L;Hayes DL;Aarts C;Bojovic B;Denisova GF;Kwiecien JM;Brain I;Derocher H;Milne K;Nelson BH;Bramson JL
利用嵌合抗原受体(CARS)设计T细胞是引导T细胞攻击肿瘤的有效方法，但可能会引起副作用，如潜在的致命性细胞因子释放综合征。作者指出，与上一代CARS相比，T细胞抗原偶联剂(TAC)是一种与内源性TCR共生的嵌合受体，可诱导更有效的抗肿瘤反应并降低毒性。TAC基因工程的T细胞在体外诱导强大的、抗原特异性的细胞因子产生和细胞毒作用，并在包括实体瘤和液体瘤在内的各种异种移植模型中具有强大的抗肿瘤活性。在实体肿瘤模型中，TAC-T细胞比基于CD28的CAR-T细胞具有更高的抗肿瘤效果、更低的毒性和更快的肿瘤侵袭速度。瘤内TAC-T细胞富含Ki-67+CD8+T细胞，表现为局部扩张。这些结果表明，相对于CAR-T细胞，TAC-T细胞可能具有更好的治疗指标。嵌合抗原受体(CARS)是指导T细胞杀伤肿瘤的有效工具，但可能会产生不良反应。在这里，作者表明，与目前的CARS相比，抗原识别和CD3结合的模块化形式可以诱导更有效的抗肿瘤反应，但毒性更低。
Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67+ CD8+ T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells. Chimeric antigen receptors (CARs) are effective tools for directing T cell killing of tumors, but may cause adverse side effects. Here the authors show that coupling of antigen-recognition and CD3-binding in a modular format induces more efficient anti-tumour responses but reduced toxicity when compared with current CARs.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
8.8
作者：
Fitzgerald JC;Weiss SL;Maude SL;Barrett DM;Lacey SF;Melenhorst JJ;Shaw P;Berg RA;June CH;Porter DL;Frey NV;Grupp SA;Teachey DT
通讯作者：
Teachey DT
影响因子：
10.1
作者：
Frigault MJ;Lee J;Basil MC;Carpenito C;Motohashi S;Scholler J;Kawalekar OU;Guedan S;McGettigan SE;Posey AD Jr;Ang S;Cooper LJ;Platt JM;Johnson FB;Paulos CM;Zhao Y;Kalos M;Milone MC;June CH
通讯作者：
June CH