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

• 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
• 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' 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

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.

总结 CAR-T免疫疗法作为一种挽救方案，对于那些不再对化疗有反应的患者具有很大的前景。 传统疗法。五种CAR-T细胞疗法（四种靶向癌细胞上的CD 19）已获得批准 FDA批准用于治疗复发性和/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CD 19 CAR-T治疗的患者在CAR-T治疗后一年内复发。CAR-T疗法的成功 已经与几个因素相关，包括：1）CAR-T细胞在转移到 患者处于IL-2剥夺环境中，2）CAR-T细胞效应子功能的维持，3）长期 CAR-T细胞的存活。这些T细胞生物学方面受到其代谢阶段的高度影响，并且CAR-T 已知细胞结果受到其新陈代谢的影响。代谢现在被认为是一个主要的 免疫调节因子是免疫细胞功能的调节因子，并影响免疫应答的过程。我们有 发现MCJ（甲基化控制的J蛋白）是一种定位于线粒体内膜的蛋白质 其作为复合物I和线粒体呼吸（线粒体ATP）的内源性负调节剂 生产）。我们已经表明，CD 8细胞中MCJ的缺失增强了细胞因子分泌以及细胞毒性。 活动记忆MCJ KO CD 8细胞对流感病毒具有上级保护活性。MCJ缺陷 CD 8细胞在杀死肿瘤细胞方面也更有效。因此，我们假设，消除MCJ作为一个 CD 8细胞中的代谢制动将导致增强的细胞因子产生、肿瘤杀伤活性和肿瘤细胞的存活。 CAR-T细胞和MCJ可能是一个有吸引力的目标，以提高CAR-T免疫治疗的成功。到 为了验证这一假设并显示其临床意义，我们建议：1）评估MCJ作为调节剂的作用 人CD 8细胞中线粒体代谢和效应子功能的研究; 2）评估体外和体内 小鼠MCJ缺陷型CAR T细胞的效力和功效，3）开发MCJ缺陷型人CD 8 CAR-T 具有改善的存活、扩增和细胞毒活性。