Engineering synthetic adhesion receptors to enhance the sensitivity of therapeutic chimeric antigen receptors

工程合成粘附受体以增强治疗性嵌合抗原受体的敏感性

• 批准号: MR/W031353/1
• 负责人: Omer Dushek
• 金额: $ 61.5万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW031353%2F1
• 关键词: Engineering; synthetic; adhesion; receptors; enhance

T cells are a type of white blood cell that continuously patrol the body in search of abnormal cells. They detect molecules called 'antigens' on these abnormal infected or cancerous cells using their T cell antigen receptors (TCRs). T cells are remarkably sensitive: they can become activated by the presence of a single antigen on a cell. This sensitivity is important because infectious organisms and cancer cells are very good at hiding from T cells by lowering the amount of antigen on their cell surface.An exciting new treatment for cancer is to re-programme a patient's T cells to target their cancer. This is done by using genetic engineering to express chimeric antigen receptors (CARs) on T cells. CARs have a part that binds an antigen and a part derived from the TCR that send an activating signal into the T cell. They allows a patient's T cells to recognise and kill their cancer cells. This therapy is very effective for leukemias and lymphomas expressing high levels of certain antigens. However, many patients relapse when cancer cells emerge that have lower levels of antigen on their surface. One reason that this escape is possible is that CARs are much less sensitive than TCRs and so are unable to 'see' these new cancer cells. There is an urgent need to increase the sensitivity of CARs to prevent these relapses. More sensitive CARs would also allow CAR T cells to be used in treating a wider variety of cancers.In this project we will use our understanding of why the TCR is so sensitive to improve the sensitivity of CARs. It is difficult for the relatively small TCR on the surface of T cells to 'find' what are also small target antigens on other cells. T cells use a specially-evolved adhesion receptor called CD2 that, when it binds to target cells, position the T cell and target cell membranes at precisely the right distance for the TCR to bind its target antigen. The allows the TCR to rapidly scan the other cell for antigens. We hypothesise that CD2 positions the membranes too closely for optimal scanning by CARs because they are bigger than the TCR. We will design and introduce into T cells enlarged forms of CD2 and test whether they improve the sensitivity of CARs. We will use electron microscopy to confirm that enlarging CD2 changes the distance between the T cell and the target cell membranes. This work should enable us to improve CAR T cell therapy by introducing enlarged forms of CD2 into the cells, thereby enabling them to recognise cancer cells with low levels of the antigen. In addition to improving existing CAR-T cell treatment for B cell cancers, this should allow new CAR-T cell treatments to be developed that eliminate cancers expressing low levels of target antigens.

T细胞是一种白细胞，它不断地在体内巡逻，寻找异常细胞。他们利用T细胞抗原受体（TCRs）检测这些异常感染细胞或癌细胞上的“抗原”分子。T细胞非常敏感：只要细胞上有一种抗原，它们就会被激活。这种敏感性很重要，因为感染性生物体和癌细胞非常善于通过降低细胞表面抗原的数量来躲避T细胞。一种令人兴奋的治疗癌症的新方法是对病人的T细胞进行重新编程，以靶向他们的癌症。这是通过基因工程在T细胞上表达嵌合抗原受体（CARs）来实现的。car有一部分结合抗原，另一部分来自TCR，向T细胞发送激活信号。它们可以让病人的T细胞识别并杀死他们体内的癌细胞。这种疗法对表达高水平某些抗原的白血病和淋巴瘤非常有效。然而，当表面抗原水平较低的癌细胞出现时，许多患者会复发。这种逃逸是可能的，其中一个原因是car远不如tcr敏感，因此无法“看到”这些新的癌细胞。目前迫切需要提高car的敏感性，以防止这些复发。更敏感的CAR - T细胞也将被用于治疗更多种类的癌症。在这个项目中，我们将利用我们对TCR如此敏感的原因的理解来提高car的灵敏度。T细胞表面相对较小的TCR很难“发现”其他细胞上的小靶抗原。T细胞使用一种特殊进化的粘附受体CD2，当它与靶细胞结合时，将T细胞和靶细胞膜精确地定位在合适的距离上，以便TCR与目标抗原结合。这使得TCR能够快速扫描其他细胞寻找抗原。我们假设CD2将膜放置得太近而无法通过car进行最佳扫描，因为它们比TCR大。我们将设计并将CD2的放大形式引入T细胞，并测试它们是否能提高car的敏感性。我们将使用电子显微镜来证实CD2的增大改变了T细胞和靶细胞膜之间的距离。这项工作将使我们能够通过将扩增形式的CD2引入细胞来改进CAR - T细胞疗法，从而使它们能够识别低水平抗原的癌细胞。除了改进现有的针对B细胞癌的CAR-T细胞疗法外，这应该允许开发新的CAR-T细胞疗法，以消除表达低水平目标抗原的癌症。