【Cell、Nature三篇论文聚焦】“双抗原”CAR-T系统,精准识别肿瘤!
2016/02/23
提高治疗用T细胞ON-target活性的一种有效方法是改造它们使其需要识别组合抗原。2月11日,发表在《细胞》杂志上的一项研究中,科学家们工程改造了一种需要组合激活的T细胞回路(circuit)。


借助嵌合抗原受体(CARs)或T细胞受体(TCRs),T细胞能够定向杀死癌细胞。然而,因肿瘤特异性单一抗原较为罕见,这一疗法的发展受到了一定的制约。此外,目标抗原在其它组织中也存在时还会引发危及生命的不良反应。

提高治疗用T细胞ON-target活性的一种有效方法是改造它们使其需要识别组合抗原。2月11日,发表在《细胞》杂志上的一项研究中,科学家们工程改造了一种需要组合激活的T细胞回路(circuit)。

在这一回路中,对应其中一个抗原的一种合成Notch受体能够诱导对应第二个抗原的CAR表达。这种双受体AND-gate T细胞(dual-receptor AND-gate T cells)只有在肿瘤细胞同时表达两种抗原的情况下才会被激活。体内实验中,这些T细胞展现出了精准的识别与治疗,能够区分出只拥有单个抗原的非目标肿瘤,且有效清除携带组合抗原的肿瘤。

2月19日,基于《细胞》上的这项研究成果,Nature Reviews Cancer杂志发布的一篇题为“Two antigens are better than one”的文章指出,提高工程T细胞特异性的一个解决途径是设计一种独立于CAR 和TCR通路之外的新受体。

2月11日,发布在《细胞》杂志上的一项研究中,Leonardo Morsut和Kole T. Roybal等人首次设计了一种基于Notch的组装式受体(即SynNotch受体)。随后Roybal等人利用这一平台设计了一个特别的系统。在这一系统中,肿瘤上的一个抗原能够激活T细胞中的SynNotch,从而激活识别肿瘤上第二种抗原的CAR的转录,最终激活T细胞。


研究人员利用Jurkat T细胞设计了一个概念验证试验,经改造的T细胞具有可识别CD19抗原且包含四环素- 反式激活因子(tTa)域的SynNotch受体。tTa域会激活四环素效应元件驱动的CAR(对应抗原为mesothelin)的转录。体外培养中,这些Jurkat细胞只会被同时表达了CD19和mesothelin的肿瘤细胞激活。

随后,研究人员在primary human CD4+ or CD8+ T细胞中设计了相似的系统。在这些细胞中,他们发现包括Gal4 VP64转录激活域的SynNotch受体具有较低的基本转录活性,这一特性在第一抗原不存在时可帮助防止CAR的表达。

这些表达SynNotch–Gal4 VP64的T细胞在癌细胞上对应的“约束条件”是绿色荧光蛋白(GFP)和CD19。体外试验中,只有同时表达GFP 和CD19的K562白血病细胞可激活这些primary T细胞。这两个不同的SynNotch–CAR系统展示出了相似的实验结果。

最终,经工程改造后拥有GFP SynNotch和CD19 CAR的primary 人类T细胞在体内试验中也获得了喜人的结果。免疫功能不全的小鼠被注射了CD19+ Daudi B cell lymphoblastoid细胞,这些细胞均为GFP+。肿瘤形成后,向小鼠注入工程T细胞。结果显示,只有在GFP+肿瘤中,T细胞才表达CD19 CAR。

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits

    T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual-receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo—sparing single antigen “bystander” tumors while efficiently clearing combinatorial antigen “disease” tumors. This type of precision dual-receptor circuit opens the door to immune recognition of a wider range of tumors.

    展开 收起
  • Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors

    The Notch protein is one of the most mechanistically direct transmembrane receptors—the intracellular domain contains a transcriptional regulator that is released from the membrane when engagement of the cognate extracellular ligand induces intramembrane proteolysis. We find that chimeric forms of Notch, in which both the extracellular sensor module and the intracellular transcriptional module are replaced with heterologous protein domains, can serve as a general platform for generating novel cell-cell contact signaling pathways. Synthetic Notch (synNotch) pathways can drive user-defined functional responses in diverse mammalian cell types. Because individual synNotch pathways do not share common signaling intermediates, the pathways are functionally orthogonal. Thus, multiple synNotch receptors can be used in the same cell to achieve combinatorial integration of environmental cues, including Boolean response programs, multi-cellular signaling cascades, and self-organized cellular patterns. SynNotch receptors provide extraordinary flexibility in engineering cells with customized sensing/response behaviors to user-specified extracellular cues.

    展开 收起
  • Two antigens are better than one

    T cells carrying chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have shown remarkable efficacy against some tumour types, primarily B cell malignancies. However, the use of these engineered T cells is limited to tumours that express highly specific antigens; in most cases tumour antigens are also expressed…

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test