Processed Antigen Characterization by Mass Spectrometry

通过质谱分析处理抗原表征

• 批准号: 7917390
• 负责人: DONALD F HUNT
• 金额: $ 57.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917390
• 关键词: Ablation; Acute Myelocytic Leukemia; Adenocarcinoma; Affinity; Binding; CD8B1 gene; Cell Therapy; Cell surface; Cells; Characteristics; Chronic Lymphocytic Leukemia; Colorectal; Combination Drug Therapy; Cytotoxic T-Lymphocytes; Genes; Health Status; Histocompatibility Antigens Class I; Human; Human body; Immune system; MHC Class I Genes; Malignant Neoplasms; Mass Spectrum Analysis; Metastatic Melanoma; Methods; Mutate; Normal Cell; Pancreas; Parasitic infection; Patients; Peptide/MHC Complex; Peptides; Phosphopeptides; Proteins; Renal carcinoma; Research; Sampling; Signal Transduction Pathway; Staging; T-Lymphocyte; Technology; Thymus Gland; Tissue Transplantation; Tumor-Infiltrating Lymphocytes; Viral; Whole-Body Irradiation; antigen processing; cancer cell; cohort; effective therapy; improved; instrumentation; killings; lymph nodes; melanoma; metaplastic cell transformation; receptor; tumor

DESCRIPTION (provided by applicant): Cells in the human body communicate their health status to the immune system by degrading cellular proteins and presenting fragments of each on the cell surface in association class I MHC proteins. Appropriately educated, cytotoxic T-lymphocytes (CTL) (CD8+ T-cells) bind to the class I MHC molecules on the cell surface, sample the peptides being presented and kill those cells that express new peptides as a result of viral, bacterial and parasitic infection, tissue transplantation and cellular transformation (cancer). Presently, the most effective treatment for late stage metastatic melanoma involves adoptive cell therapy (ACT) with CD8+ T-cells. In this approach, tumor-infiltrating lymphocytes (TIL) are isolated from surgically removed tumor, expanded ex vivo and then re-introduced to the patient after ablation of his or her immune system by a combination of chemotherapy and total body irradiation. Efforts to improve this technology are in progress and involve transfecting patient CD8+ T-cells (prior to expansion) with high affinity receptors for specific tumor associated class I MHC peptides. With this additional step, it should be possible to use ACT to treat any human tumor. What is lacking are MHC class I peptides that are; (a) differentially displayed on cancer vs normal cells, (b) shared by large cohorts of patients with the same cancer (c) shared by multiple tumor types, (d) derived from proteins whose genes cannot be mutated or deleted without compromising tumor survival, and (e) not available for display on MHC molecules in the thymus or lymph nodes to trigger deletion of reactive CD8+ T-cells. Proposed here is research to develop new mass spectrometry instrumentation and methods for the identification of class I MHC phosphopeptides that are derived from dysregulated signal transduction pathways associated with cellular transformation characteristic of cancer cells and thus satisfy the above criteria. This research should make it possible to extend adoptive T-cell therapy to a number of other cancers including acute myeloid leukemia, chronic lymphocytic leukemia, pancreatic-,colorectal- and heptocellullar- adenocarcinoma and renal cancer. PUBLIC HEALTHE RELEVANCE: Proposed here is research to develop new mass spectrometry instrumentation and methods for the identification of class I MHC phosphopeptides that are derived from dysregulated signal transduction pathways associated with cellular transformation. This research should make it possible to extend adoptive Tcell therapy beyond melanoma to other cancers including acute myeloid leukemia, chronic lymphocytic leukemia, pancreatic-, colorectal-, and heptocellullar adenocarcinoma and renal cancer

描述（由申请人提供）：人体中的细胞通过降解细胞蛋白并呈现在I类MHC蛋白的细胞表面上的细胞蛋白和呈现片段，从而将其健康状况传达给免疫系统。经过适当教育的细胞毒性T淋巴细胞（CTL）（CD8+ T细胞）与细胞表面上的I类MHC分子结合，对呈现的肽进行采样，并杀死那些因病毒，细菌和寄生虫感染，组织和组织性传播和细胞移植和细胞转换和癌症而表达新肽的细胞。目前，对晚期转移性黑色素瘤的最有效治疗涉及用CD8+ T细胞的过养细胞疗法（ACT）。在这种方法中，从手术切除的肿瘤中分离出肿瘤浸润淋巴细胞（TIL），后体内膨胀，然后通过化学疗法和全身辐射的结合消融其免疫系统后将其重新引入患者。改进该技术的努力正在进行中，并涉及将患者CD8+ T细胞（在扩展之前）具有高亲和力受体对特定肿瘤相关的I类MHC肽的高亲和力。通过这一额外的步骤，应该有可能使用ACT治疗任何人类肿瘤。缺少的是MHC I类肽； （a）在癌症与正常细胞上的差异显示，（b）由大量患有相同癌症的患者共享多种肿瘤类型的患者（c），（c）源自蛋白质的蛋白质，其基因无法突变或删除肿瘤存活而不损害thymus或lymphers deetions thymus或lymphers deetions deetions deetions deletions deetions trection+ conty+ trestion。此处提出的研究是为了开发新的质谱仪器和用于鉴定I类MHC磷酸肽的方法，这些方法来自与癌细胞的细胞转化特征相关的失调信号转导途径，从而满足上述标准。这项研究应使得将过继的T细胞疗法扩展到许多其他癌症，包括急性髓样白血病，慢性淋巴细胞性白血病，胰腺癌，结直肠癌和七甲状腺癌 - 腺癌和肾癌。公共卫生相关性：这里提出的研究是为了开发新的质谱仪器和用于鉴定I类MHC磷酸肽的方法，这些方法是从与细胞转化相关的失调信号转导途径中得出的。这项研究应使得将收养TCELL疗法延伸到黑色素瘤之外