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)：人体内的细胞通过降解细胞蛋白，并在细胞表面呈I型MHC相关蛋白的片段，向免疫系统传达其健康状况。受过适当教育的细胞毒性T淋巴细胞(CTL)(CD8+T细胞)与细胞表面的I类MHC分子结合，对呈现的多肽进行采样，并杀死那些由于病毒、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，对晚期转移性黑色素瘤最有效的治疗方法是采用CD8+T细胞的过继细胞疗法(ACT)。在这种方法中，肿瘤浸润性淋巴细胞(TIL)从手术切除的肿瘤中分离出来，体外扩增，然后在患者的免疫系统被化疗和全身照射相结合后重新引入患者体内。改进这项技术的努力正在进行中，包括将特定的肿瘤相关I类MHC多肽的高亲和力受体导入患者CD8+T细胞(扩增前)。有了这一额外的步骤，应该可以使用ACT来治疗任何人类肿瘤。缺少的是：(A)在癌症和正常细胞上差异显示的MHC-I类肽，(B)在同一癌症的大量患者中共享的MHC-I类多肽，(C)多种肿瘤类型所共有的，(D)源自其基因不能突变或删除而不会危及肿瘤生存的蛋白质，以及(E)不能在胸腺或淋巴中的MHC分子上展示以触发反应性CD8+T细胞缺失的MHC分子。本研究旨在开发新的质谱学仪器和方法来鉴定I类MHC磷酸肽，这些磷酸肽来源于与癌细胞的细胞转化特性相关的失调信号转导途径，从而满足上述标准。这项研究应该可以将过继T细胞疗法扩展到其他一些癌症，包括急性髓系白血病、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。公共卫生相关性：这里提出了一项研究，旨在开发新的质谱仪和方法来鉴定I类MHC磷酸肽，这些肽来自与细胞转化相关的失调信号转导通路。这项研究应该可以将过继T细胞疗法从黑色素瘤扩展到其他癌症，包括急性髓系白血病、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。