Synthetic metabolism to armor and enhance a new class of cell therapies

项目摘要/摘要 肿瘤通过许多途径抑制免疫反应，预防 多种免疫抑制机制是充分释放新生抗肿瘤反应所必需的。更改后的 代谢功能是癌症的标志，而促进癌细胞增殖的代谢变化 也可以通过饥饿、关闭或杀死T细胞来抑制免疫系统。癌症用了两把钥匙 肿瘤代谢改变抑制T细胞功能的机制：(1)营养耗竭和(2) 免疫抑制代谢副产物的积累。这些代谢变化被认为是 实体瘤限制自体T细胞疗法疗效的重要机制 检查点抑制抗体，目前还没有治疗方法可以让免疫系统对此进行反击 免疫抑制的代谢环境。因此，这项提议寻求开发创新的解决方案，以 抵制和积极补救免疫抑制的代谢机制，通过有史以来第一次努力增强 T细胞的功能与合成代谢有关。 本项目将应用代谢工程和合成生物学的概念来增强T 细胞与肿瘤细胞竞争有限的营养，允许T细胞直接降解免疫抑制 代谢副产物，并使实体瘤直接激活合成T细胞遗传程序 环境。这些努力将是利用基因工程技术控制肿瘤代谢的首次尝试。 免疫细胞，以及这种重新编程人类细胞代谢能力的创新方法很容易 适用于以代谢失调为特征的其他疾病状态。 这里提出的这项研究意义重大，因为代谢功能的改变和由此产生的 肿瘤的免疫抑制环境是癌症的特征，但缺乏足够的治疗方法。 因此，开发适当的方法来允许T细胞抵抗或以其他方式修复这种改变的新陈代谢是 最重要的是。这里描述的技术也将产生广泛的影响，帮助打击关键 抗体检查点疗法的耐药机制及其合成结构和新的研究进展 这里开发的方法将可用于人体研究，以提高CAR-T和其他药物的疗效 针对实体瘤的自体T细胞疗法。

Project Summary/Abstract Tumors inhibit immune responses through many routes, and it has become widely accepted that preventing multiple immunosuppressive mechanisms is necessary to fully unleash the nascent anti-tumor response. Altered metabolic function is a hallmark of cancer, and the metabolic alterations that enhance cancer cell proliferation also suppress the immune system by starving, shutting down, or killing T cells. Cancers employ two key mechanisms to suppress T cell function via metabolic alterations in tumors: (1) nutrient depletion and (2) accumulation of immunosuppressive metabolic byproducts. These metabolic alterations are recognized as important mechanisms employed by solid tumors to limit the efficacy of autologous T cells therapies and checkpoint inhibitor antibodies, and no therapies exist to allow the immune system to fight back against this immunosuppressive metabolic environment. Therefore, this proposal seeks to develop innovative solutions to resist and actively remediate metabolic mechanisms of immunosuppression, via the first-ever efforts to enhance T cell function with synthetic metabolism. This project will apply the concepts of metabolic engineering and synthetic biology to enhance the ability of T cells to compete with tumoral cells for limited nutrients, to allow T cells to directly degrade immunosuppressive metabolic byproducts, and to enable the direct activation of synthetic T cell genetic programs by the solid tumor environment. These efforts will represent the first attempt to control tumoral metabolism with engineered immune cells, and such innovative approaches to reprogram the metabolic capacity of human cells could easily be applied to other disease states characterized by dysregulated metabolism. The research proposed here is significant because altered metabolic function and the resulting immunosuppressive environment of tumors are hallmarks of cancer, for which adequate therapies are lacking. Therefore, developing suitable approaches to allow T cells to resist or to otherwise fix this altered metabolism is of the utmost importance. The techniques described here will also have broad impact by helping combat key mechanisms of resistance to antibody checkpoint therapeutics, and the synthetic constructs and new approaches developed here will be translatable to human studies to improve the efficacy of CAR-T and other autologous T cell therapies against solid tumors.