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

合成代谢来保护和增强新型细胞疗法

• 批准号: 10472794
• 负责人: John James Blazeck
• 金额: $ 135.66万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472794
• 关键词: Antibodies; Antitumor Response; Autologous; Back; CAR T cell therapy; Cell Proliferation; Cell Therapy; Cell physiology; Cells; Clinic; Disease; Environment; Genetic; Growth; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunosuppression; Malignant Neoplasms; Metabolic; Metabolism; Nutrient; Nutrient Depletion; Research; Route; Solid Neoplasm; T cell therapy; T-Lymphocyte; Techniques; Therapeutic; antibody inhibitor; cancer cell; combat; fighting; immunoengineering; improved; innovation; metabolic engineering; neoplastic cell; novel strategies; prevent; programs; resistance mechanism; synthetic biology; synthetic construct; tumor; tumor metabolism

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.

项目概要/摘要 肿瘤通过多种途径抑制免疫反应，并且人们普遍认为预防 为了充分释放新生的抗肿瘤反应，需要多种免疫抑制机制。改变 代谢功能是癌症的标志，代谢改变会增强癌细胞增殖 还可以通过饥饿、关闭或杀死 T 细胞来抑制免疫系统。癌症有两个关键 通过肿瘤代谢改变抑制 T 细胞功能的机制：(1) 营养消耗和 (2) 免疫抑制代谢副产物的积累。这些代谢改变被认为是 实体瘤用来限制自体 T 细胞疗法疗效的重要机制 检查点抑制剂抗体，并且不存在任何疗法可以让免疫系统对抗这种抗体 免疫抑制的代谢环境。因此，本提案旨在开发创新解决方案 通过首次努力增强免疫力，抵抗并积极修复免疫抑制的代谢机制 T 细胞通过合成代谢发挥作用。 该项目将应用代谢工程和合成生物学的概念来增强T细胞的能力。 细胞与肿瘤细胞竞争有限的营养，让T细胞直接降解免疫抑制 代谢副产物，并使实体瘤能够直接激活合成 T 细胞遗传程序 环境。这些努力将代表首次尝试用工程化方法控制肿瘤代谢 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。 这里提出的研究意义重大，因为代谢功能的改变以及由此产生的结果 肿瘤的免疫抑制环境是癌症的标志，目前缺乏足够的治疗方法。 因此，开发合适的方法来让 T 细胞抵抗或以其他方式修复这种改变的代谢是重要的。 至关重要。这里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。 抗体检查点疗法的耐药机制，以及合成结构和新的 这里开发的方法将可转化为人体研究，以提高 CAR-T 和其他药物的功效 针对实体瘤的自体 T 细胞疗法。