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

项目总结/摘要 肿瘤通过许多途径抑制免疫应答，并且已经广泛接受预防 需要多种免疫抑制机制来充分释放新生的抗肿瘤应答。改变 代谢功能是癌症的一个标志，而代谢改变会增强癌细胞增殖， 还通过饥饿、关闭或杀死T细胞来抑制免疫系统。癌症使用两个关键 肿瘤中通过代谢改变抑制T细胞功能的机制：（1）营养耗尽和（2） 免疫抑制代谢副产物的积累。这些代谢改变被认为是 实体瘤限制自体T细胞治疗功效的重要机制， 检查点抑制剂抗体，并且没有治疗方法可以让免疫系统反击这种抗体。 免疫抑制代谢环境。因此，本提案寻求制定创新的解决方案， 抵抗和积极补救免疫抑制的代谢机制，通过首次努力， T细胞功能与合成代谢。 本计画将应用代谢工程与合成生物学的概念，以提升T 细胞与肿瘤细胞竞争有限的营养物质，使T细胞直接降解免疫抑制剂， 代谢副产物，并能够通过实体瘤直接激活合成T细胞遗传程序， 环境这些努力将代表第一次尝试控制肿瘤代谢与工程 免疫细胞，这种重新编程人类细胞代谢能力的创新方法可以很容易地 可以应用于以代谢失调为特征的其他疾病状态。 这里提出的研究是有意义的，因为改变代谢功能， 肿瘤的免疫抑制环境是癌症的标志，缺乏适当的治疗。 因此，开发合适的方法以允许T细胞抵抗或以其他方式修复这种改变的代谢是非常重要的。 最重要的事这里所描述的技术也将通过帮助打击关键技术而产生广泛的影响。 对抗体检查点疗法的抗性机制，以及合成构建体和新的 这里开发的方法将可转化为人类研究，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.