Increasing Thiols for Improving T cell Immunotherapy

增加硫醇以改善 T 细胞免疫治疗

基本信息

批准号：
10603006
负责人：
Shikhar Mehrotra
金额：
$ 39.42万
依托单位：
LIPO-IMMUNO TECH, LLC
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：
2022-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603006
关键词：
Adoptive Cell Transfers Adoptive Transfer Antigens Antioxidants Biological Markers Cancer Patient Cell Death Cell surface Cells Chronic Data Effectiveness Ensure Epitopes Exhibits FRAP1 gene Generations Glycolysis Human Human Engineering Immunosuppression Immunotherapy Legal patent Malignant Neoplasms Measures Mediating Membrane Potentials Memory Metabolic Metabolism Methods Oxidation-Reduction Oxidative Phosphorylation Pathway interactions Patients Phase I Clinical Trials Phenotype Play Population Predisposition Property Prostate Protocols documentation Recombinants Recurrence Research Retroviral Vector Role Signaling Molecule Solid Neoplasm Standardization Stress Sulfhydryl Compounds T cell response T cell therapy T memory cell T-Lymphocyte TXN gene Transcription Factor AP-1 Transgenic Mice Translating Translations Treatment Efficacy Tumor Immunity Tumor-Derived Tumor-Infiltrating Lymphocytes Xenograft Model commercialization cost experimental study glucose uptake improved in vivo in vivo Model innovation innovative technologies mitochondrial membrane mitochondrial metabolism neoplastic cell overexpression preservation programs stem-like cell subcutaneous tumor tumor growth tumor microenvironment

项目摘要

ABSTRACT New strategies to improve adoptive cell therapy (ACT) protocols are emerging to enhance in vivo persistence of adoptively transferred tumor epitope-specific T cells and overcome tumor-induced immunosuppression. Our preliminary data suggests that there is a direct correlation between the long-lived central memory T cells (Tcm) and their anti-oxidant capacity. Overexpression of thioredoxin-1 (Trx), a critical molecule that regulates cell- surface thiols (c-SH), increased Tcm phenotype in T cells obtained from TCR transgenic mouse crossbred with Trx transgenic mouse, or engineering human T cells with a retroviral vector with TCR and Trx together. These preliminary observations led us to hypothesize that “the presence of Trx drives tumor-reactive T cells to a c-SHhi phenotype, which results in increased persistence in the oxidative tumor microenvironment and improved tumor control." We propose to further strengthen the translational aspect of this strategy by determining if strategies to increase anti-oxidant capacity in presence of recombinant thioredoxin (rTrx) can reprogram tumor-infiltrating lymphocytes and improve TIL-mediated ACT. The experiments are planned under the following specific aims: 1) To determine if human tumor-derived TILs could be ex vivo programmed with rTRx and exhibit enhanced anti- tumor phenotype, 2) To establish if rTrx TILs are superior to conventional TILs in controlling tumor growth in vivo. We believe that our studies are innovative and will uncover essential aspects that need to be considered when generating tumor-specific Tcm/Tscm cells for the ACT and enhance its wider use by decreasing the prohibitive costs.

抽象的改进过继细胞疗法 (ACT) 方案的新策略正在出现，以增强体内持久性过继转移肿瘤表位特异性 T 细胞并克服肿瘤诱导的免疫抑制。初步数据表明，长寿的中央记忆 T 细胞 (Tcm) 之间存在直接相关性及其抗氧化能力硫氧还蛋白-1 (Trx) 的过度表达，硫氧还蛋白-1 是调节细胞的关键分子。表面硫醇（c-SH），从与 TCR 转基因小鼠杂交获得的 T 细胞中 Tcm 表型增加 Trx 转基因小鼠，或使用带有 TCR 和 Trx 的逆转录病毒载体改造人类 T 细胞。初步观察使我们发现“Trx 的存在会驱动肿瘤反应性 T 细胞转化为 c-SHhi 表型，导致氧化肿瘤微环境的持久性增加并改善肿瘤控制。”我们建议通过确定策略是否能够进一步加强该策略的转化方面重组硫氧还蛋白 (rTrx) 存在时提高抗氧化能力，可以重新编程肿瘤浸润淋巴细胞并改善 TIL 介导的 ACT 实验计划的具体目标如下：1) 确定人类肿瘤衍生的 TIL 是否可以用 rTRx 进行离体编程并表现出增强的抗- 肿瘤表型，2) 确定 rTrx TIL 在控制肿瘤生长方面是否优于传统 TIL 我们相信我们的研究具有创新性，并将揭示需要考虑的重要方面。当为 ACT 生成肿瘤特异性 Tcm/Tscm 细胞时，并通过减少成本高昂。