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.

项目摘要 免疫疗法改变了人们对癌症的理解和治疗模式。在这个武器库里 新的治疗策略，采用细胞疗法(ACT)已经显示出巨大的前景；然而，几个障碍 药效依然存在。其中一个主要障碍是T细胞抗肿瘤细胞毒性的高代谢要求 缺乏营养的肿瘤微环境(TME)。目前用于产生大量T细胞的培养策略 体外培养的细胞通过使用高血糖和高氧培养条件来加剧这个问题。这一战略 有利于T细胞在扩增过程中的新陈代谢需求，但忽略了其持久性新陈代谢需求 在TME内。我们的初步数据表明，丙酮酸脱氢酶激酶1(PDHK1)的治疗 治疗性T细胞体外扩增过程中的抑制剂二氯乙酸酯维持治疗性T细胞 在提高体内抗肿瘤清除能力的同时促进细胞增殖。有趣的是，DCA处理的T细胞的转录分析 细胞对线粒体DNA的反应显示干扰素刺激基因(ISGs)的下调 (MtDNA)损伤。我们假设DCA以一种将新陈代谢重定向到 一种更氧化的状态，从而防止T细胞线粒体应激和线粒体DNA的释放 扩增允许更多合适的T细胞预先输注。在这项研究中，我们的目标是确定DCA如何 代谢效应和废除异构体有助于提高抗肿瘤疗效。确定机制 DCA对治疗性T细胞作用的研究不仅将向该领域通报使用DCA作为体外实验的好处 培养补充剂用于产生更有效的治疗性T细胞，但也将允许更好的 全面了解T细胞功能的生物学要求。