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.

项目总结