Directing the metabolic fate of CAR T cells

项目摘要/摘要 该项目的目标是开发具有嵌合体的下一代靶向T细胞 用于癌症和血液系统恶性肿瘤的抗原受体(CARS)。因此， 这些研究针对的是困扰美国民众的癌症流行病。小汽车 T细胞现在开始在一些试点临床试验中显示出活性，他们已经 治疗目前无法治愈的许多癌症的巨大潜力。然而，有两个 出现了阻碍该领域进一步快速进展的问题：1) 与实体癌患者不同的是，CAR T细胞的持久性有限 靶向CD19的CARS；2)T细胞变得耗尽，失去能力或在有毒的肿瘤中死亡 微环境，不像血液系统恶性肿瘤，CAR T细胞有 在有反应的患者中持续功能至少5年。我们的初步数据显示 CAR T细胞的代谢特征可以通过改变设计随意改变 汽车结构中的信令域。在这个项目中，我们将使用合成的原理 生物学和慢病毒载体技术、mRNA电穿孔技术和 规则间隔短回文重复序列(CRISPR)及其相关 蛋白9(Cas9)技术，以适应T细胞的代谢，以促进生存 恶劣的肿瘤微环境。该项目的主题是T细胞具有更强的能力和 持续的抗肿瘤作用可以被设计成抵抗代谢检查点，如缺氧， 高钾血症、酸中毒和缺糖。总而言之，这些重叠的研究将 验证合成增强的CAR T细胞将改善CAR的中心假设 将免疫疗法与目前可用的CAR T细胞疗法进行比较。在……结束时 这个项目，下一代代谢增强的CAR T细胞将可用于测试 在晚期胰腺癌患者的试点临床试验中。

Project Summary / Abstract The goal of this project is to develop the next generation of targeted T-cells with chimeric antigen receptors (CARs) for use in carcinomas and hematologic malignancies. Therefore, these studies address the cancer epidemic that afflicts the population in the United States. CAR T cells are now beginning to show activity in a number of pilot clinical trials and they have significant potential for therapy of many cancers that are currently incurable. However two issues have emerged that provide a barrier to further rapid progress in the field: 1) the persistence of CAR T cells in patients with solid cancer has been limited, unlike the case with CARs that target CD19; 2) T cells become exhausted, become anergic or die in the toxic tumor microenvironment, unlike the case of hematologic malignancies, where CAR T cells have continued to function for at least 5 years in responding patients. Our preliminary data indicates that the metabolic profiles of CAR T cells can be altered at will by changing the design of the signaling domain in the CAR construct. In this project, we will use the principles of synthetic biology and the tools of lentiviral vector technology, mRNA electroporation technology, and clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR associated protein 9 (Cas9) technology to adapt the metabolism of T cells in order to promote survival in harsh tumor microenvironments. The theme of the project is that T cells with more potent and sustained antitumor effects can be designed to resist metabolic checkpoints such as hypoxia, hyperkalemia, acidosis, and glucose deprivation. In summary, these overlapping studies will test the central hypothesis that synthetically enhanced CAR T cells will improve CAR immunotherapy compared to therapy with currently available CAR T cells. At the conclusion of this project, a next generation of metabolically enhanced CAR T cells will be available for testing in pilot clinical trials in patients with advanced pancreatic cancer.