Metabolically improving the generation, function, and persistence of therapeutic T cells for the treatment of cancer

通过代谢改善治疗性 T 细胞的生成、功能和持久性，以治疗癌症

• 批准号: 10348167
• 负责人: Andrew Frisch
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348167
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Affect; Antitumor Response; Biological; Biological Assay; Cell Count; Cell Respiration; Cell Survival; Cell Therapy; Cell physiology; Cells; Cellular Metabolic Process; Confocal Microscopy; Cyclic GMP; DNA; DNA Damage; Data; Dichloroacetate; Disease; Down-Regulation; Engraftment; Excision; FDA approved; Functional disorder; Gene Expression; Generations; Genes; Glucose; Glycolysis; Hematologic Neoplasms; Hyperglycemia; Immune; Immune response; Immunotherapy; In Vitro; In complete remission; Infusion procedures; Interferons; Knockout Mice; Long-Term Effects; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Mus; Nutrient; PDH kinase; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phenotype; Probability; Production; Secondary to; Shunt Device; Solid; Stimulator of Interferon Genes; Stress; System; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Treatment Efficacy; Tumor-infiltrating immune cells; anti-cancer; antigen-specific T cells; arm; cancer therapy; clinical application; clinical development; combinatorial; cost effective; effector T cell; immune checkpoint; implantation; improved; in vivo; inhibitor; metabolic abnormality assessment; metabolic phenotype; metabolic profile; novel; prevent; programs; response; sensor; transcriptomics; treatment strategy; tumor; tumor microenvironment

Project Summary Immunotherapy has shifted the paradigm in the understanding and treatment of cancer. Within this arsenal of new treatment strategies, adoptive cell therapy (ACT) has shown great promise; however, several barriers to efficacy remain. One major hurdle is the high metabolic requirements of T cell anti-tumor cytoxicity within the nutrient-poor tumor microenvironment (TME). Current culturing strategies used to generate high numbers of T cells in vitro exacerbate this problem by using hyperglycemic and hyperoxic culture conditions. This strategy favors the metabolic needs of T cells during expansion but ignores their metabolic requirements for persistence within the TME. Our preliminary data indicate that treatment with the pyruvate dehydrogenase kinase 1 (PDHK1) inhibitor dichloroacetate (DCA) during in vitro expansion of therapeutic T cells maintains therapeutic T cell proliferation while improving anti-tumor clearance in vivo. Intriguingly, transcriptomic analysis of DCA-treated T cells reveals a downregulation of interferon-stimulated genes (ISGs) seen in response to mitochondrial DNA (mtDNA) damage. We hypothesize that DCA shunts glycolysis in a manner that re-directs metabolism to a more oxidative state and thus prevents T cell mitochondrial stress and mtDNA releases during initial expansion allowing for more fit T cells pre-infusion. Within this study, we aim to determine how DCA’s metabolic effects and abrogation of ISGs contribute to improved anti-tumor efficacy. Determining the mechanism of action of DCA on therapeutic T cells will not only inform the field of the benefits of using DCA as an in vitro culture supplement for the generation of more efficacious therapeutic T cells, but will also allow for a better understanding of the biological requirements for T cell function overall.

项目概要 免疫疗法改变了癌症的理解和治疗范式。 新的治疗策略，过继细胞疗法（ACT）已显示出巨大的前景，但仍存在一些障碍； 疗效仍然存在的一个主要障碍是 T 细胞抗肿瘤细胞毒性的高代谢要求。 当前用于产生大量 T 的培养策略。 细胞在体外使用高血糖和高氧培养条件加剧了这个问题。 有利于 T 细胞在扩增过程中的代谢需求，但忽略了其持久性的代谢需求 我们的初步数据表明，用丙酮酸脱氢酶激酶 1 (PDHK1) 进行治疗。 抑制剂二氯乙酸 (DCA) 在治疗性 T 细胞体外扩增过程中维持治疗性 T 细胞 有趣的是，DCA 处理的 T 的转录组分析。 细胞揭示了线粒体 DNA 反应中干扰素刺激基因 (ISG) 的下调 (mtDNA) 损伤，DCA 会以一种将代谢重新定向的方式分流糖酵解。 更氧化的状态，从而防止 T 细胞线粒体应激和 mtDNA 在初始阶段的释放 在这项研究中，我们的目标是确定 DCA 是如何进行扩增的。 代谢作用和 ISG 的废除有助于确定其机制。 DCA 对治疗性 T 细胞的作用不仅会让该领域了解使用 DCA 作为体外 培养补充剂可产生更有效的治疗性 T 细胞，但也将允许更好的 了解 T 细胞功能的总体生物学要求。