Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
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DOI：
10.1038/s41467-019-13088-3
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发表时间：
2019-11-13
影响因子：
16.6
通讯作者：
Valton, Julien
中科院分区：
文献类型：
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作者：
Sachdeva, Mohit;Busser, Brian W.;Valton, Julien
赋予嵌合抗原受体（CAR）T细胞额外的有效功能具有改善其抗肿瘤活性的强大潜力。然而，由于效力可能是有害的，没有控制，这些额外的功能需要严格监管。免疫途径提供了一系列严格调控的基因，这些基因可以被重新利用，以高度受控的方式表达有效的功能。在这里，我们通过重新利用T细胞活化途径的三个主要参与者TCR，CD 25和PD 1来探索这一概念。我们将CAR插入到TCRa基因（TRACCAR）中，并将IL-12 P70插入到IL 2 Ra或PDCD 1基因中。该过程导致瞬时的抗原浓度依赖性IL-12 P70分泌，增加TRACCAR T细胞的细胞毒性并延长荷瘤小鼠的存活期。这种基因网络再利用策略可以扩展到其他细胞途径，从而为生成能够整合生物输入并以高度调控的方式将其转化为治疗输出的智能CAR T细胞铺平道路。
Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRa gene (TRACCAR), and IL-12P70 into either IL2Ra or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRACCAR T cell cytotoxicity and extends survival of tumor-bearing mice. This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner.