Processed Antigen Characterization by Mass Spectrometry

通过质谱分析处理抗原表征

• 批准号: 8304313
• 负责人: DONALD F HUNT
• 金额: $ 53.27万
• 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/8304313
• 关键词: Ablation; Acute Myelocytic Leukemia; Adenocarcinoma; Adult; Affinity; Antigens; Bacterial Infections; Binding; CD8B1 gene; Carcinoma; Cell Therapy; Cell surface; Cells; Characteristics; Chronic Lymphocytic Leukemia; Clinical Trials; Colorectal; Combination Drug Therapy; Cyclin D1; Cytotoxic T-Lymphocytes; Development; Dissociation; Electron Transport; Elements; Embryo; Gene Deletion; Gene Mutation; Genes; Goals; Haplotypes; Health Status; Histocompatibility Antigens Class I; Human; Human body; Immune Tolerance; Immune system; In complete remission; Interleukin-2; Laboratories; Large Intestine Carcinoma; MHC Class I Genes; MHC Class II Genes; Malignant Neoplasms; Mass Spectrum Analysis; Melanoma Cell; Metastatic Melanoma; Methods; Molecular; Mutate; Mutation; Neoplasm Metastasis; Normal Cell; PTEN gene; Pancreas; Pancreatic Adenocarcinoma; Parasitic infection; Patients; Peptides; Phosphopeptides; Proteins; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Renal carcinoma; Research; Resected; Sampling; Side; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; T cell therapy; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Thymus Gland; Tissue Transplantation; Tissues; Tumor-Infiltrating Lymphocytes; Virus Diseases; Whole-Body Irradiation; angiogenesis; antigen processing; cancer cell; cohort; cytokine; effective therapy; improved; instrumentation; kidney cell; killings; lymph nodes; mass spectrometer; melanocyte; melanoma; metaplastic cell transformation; neoplastic cell; receptor; response; 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.

描述（由申请人提供）：人体细胞通过降解细胞蛋白并在细胞表面以 I 类 MHC 蛋白的形式呈递每种蛋白的片段，将其健康状态传达给免疫系统。经过适当训练的细胞毒性 T 淋巴细胞 (CTL)（CD8+ T 细胞）与细胞表面的 I 类 MHC 分子结合，对呈递的肽进行采样，并杀死因病毒、细菌和寄生虫感染、组织移植和细胞转化（癌症）而表达新肽的细胞。目前，晚期转移性黑色素瘤最有效的治疗方法是使用 CD8+ T 细胞进行过继细胞疗法 (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），离体扩增，然后通过化疗和全身放疗的组合消融患者的免疫系统后重新引入患者体内。改进这项技术的努力正在进行中，包括用特定肿瘤相关 I 类 MHC 肽的高亲和力受体转染患者 CD8+ T 细胞（扩增前）。通过这一额外步骤，应该可以使用 ACT 治疗任何人类肿瘤。所缺乏的是 MHC I 类肽： (a) 在癌症细胞和正常细胞上有差异地显示，(b) 患有相同癌症的大群患者共有，(c) 多种肿瘤类型共有，(d) 衍生自其基因不能在不影响肿瘤存活的情况下突变或删除的蛋白质，以及 (e) 不能显示在胸腺或淋巴结中的 MHC 分子上以触发反应性 CD8+ T 细胞的删除。这里提出的研究是开发新的质谱仪器和方法，用于鉴定 I 类 MHC 磷酸肽，这些磷酸肽源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。这项研究应该能够将过继性 T 细胞疗法扩展到许多其他癌症，包括急性髓性白血病、慢性淋巴细胞白血病、胰腺癌、结直肠癌和肝细胞腺癌以及肾癌。