Integrated Discovery Pipeline for Tumor Neoantigens

肿瘤新抗原的综合发现管道

• 批准号: 9349466
• 负责人: Beatriz M. Carreno
• 金额: $ 54.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-08 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349466
• 关键词: Address; Algorithms; Alleles; Amino Acid Substitution; Antigen Targeting; Antigens; Binding; Biological Assay; CD8-Positive T-Lymphocytes; Cancer Patient; Cell surface; Clinical; Clinical Investigator; Clinical Oncology; Complementary DNA; Computer Simulation; Data; Detection; Development; Discipline; Ensure; Fluorescence Polarization; Gene Expression; Genome; Genomics; Goals; HLA Antigens; Histocompatibility; Histocompatibility Antigens Class I; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunity; Immunologics; Immunologist; Immunology; Immunotherapy; Incentives; Institutes; Laboratories; Machine Learning; Malignant Neoplasms; Malignant neoplasm of lung; Metastatic Melanoma; Methods; Missense Mutation; Modality; Monoclonal Antibodies; Mutate; Mutation; Patients; Peptides; Peripheral Blood Mononuclear Cell; Privatization; Process; Proteomics; Protocols documentation; Public Health; Reporting; Series; Somatic Mutation; Source; Speed; Surface Antigens; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Tumor Antigens; Tumor-Derived; Universities; Vaccination; Vaccines; Validation; Variant; Washington; cancer cell; cancer genome; cancer genomics; cancer immunotherapy; cancer proteomics; candidate selection; clinical investigation; clinically relevant; computerized tools; exome sequencing; experimental study; human study; human subject; immunogenicity; industry partner; medical schools; melanoma; mutant; next generation; next generation sequencing; novel; novel strategies; oncology; precision medicine; response; screening; synthetic peptide; tool; tumor; tumor specificity

Project Summary Cancer immunotherapy is now established as a major therapeutic modality. Significant progress with checkpoint inhibitor monoclonal antibodies demonstrates durable tumor regression in metastatic melanoma, lung cancer and other malignancies. One conspicuous limitation is the paucity of validated tumor antigens, which impedes clinical investigators in their pursuit of developing new cancer immunotherapies. Tumor encoded non-synonymous mutations may provide a new source of potential target antigens. T cells recognize tumor missense mutations as amino acid substituted peptides presented in the context of major histocompatibility molecules on the cancer cell surface, thus implicating missense mutations as a source of patient-specific neoantigens. We recently described the first-in-human study to use next generation sequencing technologies to identify and validate tumor missense mutations as neoantigens. Our study demonstrates that vaccination increases the breadth and diversity of neoantigen-specific T cells resulting in a broad repertoire of effector CD8+ T cells that uniquely discriminates mutated antigens from wild type peptides ensuring tumor specificity. This proposal aims to find a unique solution to the scarcity of tumor antigens by developing a neoantigen discovery pipeline that integrates genomic and proteomic technologies. In this proposal, a unique academic-industry partnership comprised of an established team of experts, in cancer genomics, cancer proteomics, human immunology, and clinical oncology, aim to solve the challenging problem of tumor neoantigen discovery. The long-term goal is to develop a robust pipeline using cutting-edge technologies merged with machine learning algorithms to supply tumor neoantigens for clinical investigation. The goal of this proposal will be addressed in the experiments of the following specific aims: 1) to identify the repertoire of melanoma expressed somatic mutations by next generation sequencing technologies; 2) to develop a novel proteomics platform to identify melanoma neoantigens presented by HLA class I molecules; 3) to validate neoantigen identification in a vaccination protocol. The proposed pipeline will deliver a transformative solution for tumor antigen identification, should be translatable to other “immune responsive“ malignancies and enable the nascent discipline of precision medicine to provide effective and safe immunotherapies for cancer patients.

项目摘要 癌症免疫疗法现在被确定为一种主要的治疗方法。取得了重大进展 检查点抑制剂单克隆抗体表明转移性黑色素瘤中持久的肿瘤消退， 肺癌和其他恶性肿瘤。一个明显的限制是缺乏经过验证的肿瘤抗原， 这阻碍了临床研究人员追求发展新的癌症免疫疗法。瘤 编码的非同义突变可能会提供潜在靶抗原的新来源。 T细胞识别 肿瘤错义突变是在主要背景下呈现的氨基酸取代的辣椒 癌细胞表面上的组织相容性分子，因此隐式错义突变作为来源 患者特定的新抗原。我们最近描述了使用下一代的第一项人类研究 测序技术以识别和验证肿瘤错义突变为新抗原。我们的研究 证明疫苗会增加新抗原特异性T细胞的宽度和多样性，从而导致 效应子CD8+ T细胞的广泛曲目，这些细胞独特地区分突变的抗原与野生型肽 确保肿瘤特异性。该提案旨在通过通过 开发新抗原发现管道，该管道整合基因组和蛋白质组学技术。在这个 提案，是一个独特的学术行业伙伴关系，由癌症的既定专家团队完成 基因组学，癌症蛋白质组学，人类免疫学和临床肿瘤学旨在解决挑战问题 肿瘤新抗原的发现。长期目标是使用尖端开发强大的管道 技术与机器学习算法合并以提供肿瘤新抗原以进行临床研究。 该提案的目标将在以下特定目的的实验中解决：1）确定 黑色素瘤曲目通过下一代测序技术表达了体细胞突变。 2）到 开发一个新型的蛋白质组学平台，以鉴定HLA I类分子提出的黑色素瘤新抗原。 3） 在疫苗接种方案中验证新抗原鉴定。 所提出的管道将提供用于肿瘤抗原鉴定的变革溶液，应为 可以翻译成其他“免疫反应式”恶性肿瘤，并使精确的新生学科 为癌症患者提供有效且安全的免疫疗法的药物。