Enhancing mitochondrial metabolism to improve anti-tumor CD8 immune response

增强线粒体代谢，提高抗肿瘤CD8免疫反应

基本信息

批准号：
10578743
负责人：
Mercedes Rincon
金额：
$ 37.04万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578743
关键词：
ATP Synthesis Pathway Acute Lymphocytic Leukemia Affect B-Cell Leukemia CAR T cell therapy CD19 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cell Survival Cell physiology Cells Cellular Metabolic Process Cellular biology Chronic Clinical Trials Complex Cytoplasmic Granules Cytosol Cytotoxic Chemotherapy Data Engineering Environment Exocytosis FDA approved Failure Generations Glucose Glycolysis Goals Human Immune Immune response Immunology Immunotherapy In Vitro In complete remission Inner mitochondrial membrane Integral Membrane Protein Interleukin-2 Knockout Mice Maintenance Malignant Neoplasms Membrane Potentials Memory Metabolic Metabolic Pathway Metabolism Methylation Mitochondria Multiple Myeloma Mus NADH dehydrogenase (ubiquinone)Non-Hodgkin&apos s Lymphoma Nonesterified Fatty Acids Nucleotide Biosynthesis Outcome Oxidative Phosphorylation Pathway interactions Patients Production Protein Deficiency Proteins Refractory Regimen Relapse Respiration Role Source T-Cell Proliferation T-Lymphocyte Testing Therapeutic Treatment Failure Xenograft Model cancer cell cancer immunotherapy chimeric antigen receptor T cells clinical translation clinically relevant conventional therapy cytokine cytotoxic cytotoxicity effector T cell efficacy evaluation fatty acid oxidation healthy volunteer immune function improved in vivo influenzavirus interest leukemia/lymphoma melanoma mitochondrial membrane mitochondrial metabolism mouse model neoplastic cell optimal treatments protein expression relapse prevention success tumor

项目摘要

SUMMARY CAR-T immunotherapy has great promise as a salvage regimen for patients who will no longer respond to conventional therapies. Five CAR-T cell therapies (four targeting CD19 on cancer cells) have been approved by FDA for treatment of relapsed and/or refractory (r/r) B-lineage malignancies, including ALL, Non-Hodgkin Lymphoma, CLL and multiple myeloma. However, about 50% of B cell leukemia and lymphoma patients treated with CD19 CAR-T therapy relapse within a year after CAR-T therapy. The success of CAR-T therapy has been associated with several factors, including: 1) the initial expansion of CAR-T cells after transfer into the patients in an IL-2-deprived environment, 2) maintenance of the CAR-T cell effector function 3) long-term survival of CAR-T cells. These T cell biology aspects are highly influence by their metabolic stage, and CAR-T cell outcome is known to be influenced by their metabolism. Metabolism is now considered as a major regulatory factor of the function of immune cells and influences the course of an immune response. We have identified MCJ (Methylation-Controlled J protein) as a protein localized in the inner membrane of mitochondria that acts as an endogenous negative regulator of Complex I and mitochondrial respiration (mitochondrial ATP production). We have shown that loss of MCJ in CD8 cells enhances cytokine secretion as well as cytotoxic activity. Memory MCJ KO CD8 cells have superior protective activity against influenza virus. MCJ deficient CD8 cells are also more efficient in killing tumor cells. Thus, we hypothesize that eliminating MCJ as a metabolic brake in CD8 cells will result in enhanced cytokine production, tumor killing activity and survival of CAR-T cells and that MCJ could be an attractive target to improve the success of CAR-T immunotherapy. To test this hypothesis and show its clinical relevance, we propose: 1) to evaluate the role of MCJ as a regulator of mitochondrial metabolism and effector function in human CD8 cells; 2) to evaluate the in vitro and vivo potency and efficacy of mouse MCJ-deficient CAR T cells, 3) to develop an MCJ-deficient human CD8 CAR-T with improved survival, expansion and cytotoxic activity.

概括 CAR-T 免疫疗法作为对不再有反应的患者的挽救方案具有广阔的前景常规疗法。五种 CAR-T 细胞疗法（四种靶向癌细胞上的 CD19）已获得批准 FDA 批准用于治疗复发和/或难治性 (r/r) B 系恶性肿瘤，包括 ALL、非霍奇金淋巴瘤淋巴瘤、CLL 和多发性骨髓瘤。然而，约50%的B细胞白血病和淋巴瘤患者接受CD19 CAR-T疗法治疗后一年内复发。 CAR-T疗法的成功与多种因素相关，包括：1）CAR-T 细胞转移至细胞后的初始扩增处于 IL-2 剥夺环境中的患者，2) 维持 CAR-T 细胞效应功能 3) 长期 CAR-T 细胞的存活。这些 T 细胞生物学方面受其代谢阶段的影响很大，而 CAR-T 已知细胞结果受其新陈代谢的影响。新陈代谢现在被认为是一个主要的免疫细胞功能的调节因素并影响免疫反应的过程。我们有鉴定出 MCJ（甲基化控制 J 蛋白）是一种定位于线粒体内膜的蛋白质作为复合物 I 和线粒体呼吸（线粒体 ATP）的内源性负调节因子生产）。我们已经证明 CD8 细胞中 MCJ 的缺失会增强细胞因子的分泌以及细胞毒性活动。记忆MCJ KO CD8细胞对流感病毒具有优异的保护活性。 MCJ 缺陷 CD8细胞也能更有效地杀死肿瘤细胞。因此，我们假设消除 MCJ 作为 CD8 细胞的代谢制动将导致细胞因子产生增强、肿瘤杀伤活性和细胞存活率增强。 CAR-T 细胞和 MCJ 可能成为提高 CAR-T 免疫疗法成功率的有吸引力的靶点。到为了检验这一假设并展示其临床相关性，我们建议：1）评估 MCJ 作为调节器的作用人类 CD8 细胞线粒体代谢和效应器功能的研究； 2) 体外和体内评价小鼠 MCJ 缺陷型 CAR T 细胞的效力和功效，3) 开发 MCJ 缺陷型人 CD8 CAR-T 具有改善的存活、扩增和细胞毒活性。