Integrated Discovery Pipeline for Tumor Neoantigens

项目摘要 癌症免疫治疗现已被确定为一种主要的治疗方式。在以下方面取得重大进展 检查点抑制单抗显示转移性黑色素瘤的持久肿瘤消退， 肺癌和其他恶性肿瘤。一个明显的限制是缺乏有效的肿瘤抗原， 这阻碍了临床研究人员开发新的癌症免疫疗法。肿瘤 编码的非同义突变可能为潜在的靶抗原提供新的来源。T细胞识别 作为氨基酸取代肽的肿瘤错义突变出现在主要的 癌细胞表面的组织相容性分子，从而暗示错义突变是 患者特有的新抗原。我们最近描述了第一个使用下一代进行的人类研究 鉴定和验证肿瘤错义突变为新抗原的测序技术。我们的研究 证明接种疫苗增加了新抗原特异性T细胞的广度和多样性，从而导致 广泛的效应性CD8 T细胞，可唯一区分突变抗原和野生型多肽 确保肿瘤的特异性。这项提议旨在通过以下方式找到解决肿瘤抗原稀缺的独特方案 开发整合基因组和蛋白质组技术的新抗原发现管道。在这 Proposal，一个独特的学术和行业合作伙伴关系，由一个成熟的专家团队组成，在癌症领域 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这一具有挑战性的问题。 肿瘤新抗原的发现。长期目标是开发一条强大的管道，使用尖端技术 技术与机器学习算法相结合，为临床研究提供肿瘤新抗原。 这项提案的目标将在以下具体目标的实验中得到解决：1)确定 用下一代测序技术表达黑色素瘤体细胞突变的谱系；2) 开发一种新的蛋白质组学平台来鉴定由人类白细胞抗原I类分子呈递的黑色素瘤新抗原；3) 在疫苗接种方案中验证新抗原识别。 拟议的管道将为肿瘤抗原鉴定提供一种变革性的解决方案，应该是 可翻译为其他免疫反应性恶性肿瘤，并使精确这一新兴学科成为可能 为癌症患者提供有效和安全的免疫治疗的药物。

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.