MICA: Multiplexed genome editing for stealth and persistence of hypoimmunogenic 'universal' CAR T cells

MICA：多重基因组编辑可实现低免疫原性“通用”CAR T 细胞的隐形和持久性

• 批准号: MR/X004619/1
• 负责人: Christos Georgiadis
• 金额: $ 51.79万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX004619%2F1
• 关键词: MICA; Multiplexed; genome; editing; stealth

Immunotherapy has greatly improved outcomes in patients who have relapsed with refractory leukaemias. This has relied mostly on manipulating patient's own immune cells, known as T cells, and arming them with a chimeric antigen receptor (CAR) to recognise and kill tumour. However, obtaining enough cells from patients or of sufficient quality, especially in from children, remains a key obstacle driving the search for alternative cell sources from healthy donors. One major issue is the need to match donors/recipients to prevent immune rejection. Recent developments in genome editing have allowed for 'universal' CAR T cells from healthy volunteers to be made by removing flags from the surface of T cells that would otherwise be recognised as foreign. A single 'universal' CAR T cell product has the potential to treat >20 patients. thereby eliminating variability of bespoke manufacture, reducing costs to the healthcare system and importantly increasing timely accessibility to multiple patients who have otherwise failed all other treatments. Early phase clinical trials at UCL GOSH have demonstrated their potential to eliminate B cell leukaemia in several patients. Initial versions used TALEN genome editing tools to create targeted breaks in the DNA for the removal of the T cell receptor, a key driver of rejection, and of a surface marker recognised by a therapeutic antibody used for pre-conditioning. The first modification acts to make the cells 'invisible' whereas the second protects the CAR T cells from being destroyed by the antibody. We have generated newer versions using CRISPR/Cas9 technology that are currently being tested in clinic. While mostly successful, in some cases the 'universal' CAR T cells were cleared by the patient before they could eliminate the leukaemia. Increasing stealth by removing additional foreign flags from their surface could help tackle these hurdles and allow CAR T cells to persist long enough to clear disease. We now have cutting-edge genome editing tools, known as base editors, that offer a safer way of making multiple modifications to the DNA without compromising on safety. This project will test this strategy and compare different routes to efficiently and safely manufacture stealthy 'universal' CAR T cells for application in leukaemias and solid tumours.

免疫疗法大大改善了复发性难治性白血病患者的预后。这主要依赖于操纵患者自身的免疫细胞，称为T细胞，并用嵌合抗原受体（CAR）武装它们来识别和杀死肿瘤。然而，从患者身上获得足够的细胞或足够质量的细胞，特别是从儿童身上获得细胞，仍然是推动从健康供体中寻找替代细胞来源的关键障碍。一个主要问题是需要匹配供体/受体以防止免疫排斥。基因组编辑的最新发展允许通过去除T细胞表面的标记来制备来自健康志愿者的“通用”CAR T细胞，否则这些标记将被识别为外来细胞。单一的“通用”CAR T细胞产品具有治疗>20名患者的潜力。从而消除了定制制造的可变性、降低了医疗保健系统的成本，并且重要的是增加了对多个患者的及时可及性，否则这些患者在所有其他治疗中都失败了。在UCL GOSH的早期临床试验已经证明了它们在几个患者中消除B细胞白血病的潜力。最初的版本使用TALEN基因组编辑工具在DNA中创建靶向断裂，以去除T细胞受体，这是排斥反应的关键驱动因素，以及用于预处理的治疗性抗体识别的表面标记。第一种修饰作用是使细胞“不可见”，而第二种修饰则保护CAR T细胞不被抗体破坏。我们已经使用CRISPR/Cas9技术生成了更新的版本，目前正在临床上进行测试。虽然大多数情况下是成功的，但在某些情况下，“通用”CAR T细胞在消除白血病之前被患者清除。通过从其表面去除额外的外来标志来增加隐形性可以帮助解决这些障碍，并允许CAR T细胞持续足够长的时间来清除疾病。我们现在拥有尖端的基因组编辑工具，称为碱基编辑器，它提供了一种更安全的方式来对DNA进行多次修改，而不会影响安全性。该项目将测试这一策略，并比较不同的路线，以有效和安全地制造隐形的“通用”CAR T细胞，用于白血病和实体瘤。