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DEVELOPMENT OF GENOMICS BASED PERSONALIZED CANCER IMMUNOTHERAPY

基于基因组学的个性化癌症免疫治疗的发展

基本信息

批准号：
8887618
负责人：
ROBERT DAVID SCHREIBER
金额：
$ 46.91万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887618
关键词：
3-Methylcholanthrene Adverse effects Algorithms Antigens Bioinformatics CD8B1 gene Cancer Patient Cancer Vaccines Cells Characteristics Complex Data Development Effectiveness Equilibrium Favorable Clinical Outcome Foundations Frequencies Genomic approach Genomics Goals Growth Human Immune Immune system Immunity Immunocompetent Immunodeficient Mouse Immunosuppressive Agents Immunotherapy Individual Journals Knowledge Laboratories Learning Malignant Neoplasms Mediating Methods Methylcholanthrene Mus Mutate Mutation Natural Immunity Phase Process Proteins Publishing Science Specific qualifier value Specificity System T cell response T-Lymphocyte Testing Therapeutic Translating Translations Transplantation Tumor Antigens Tumor Suppressor Proteins Tumor-Derived Vaccines Wild Type Mouse Work adaptive immunity base cancer cell cancer immunotherapy chemical carcinogen early onset immunogenic immunogenicity improved insight interest melanoma mouse model mutant neoplastic cell next generation sequencing pre-clinical prevent protein function public health relevance research study response sarcoma success therapeutic effectiveness transcriptome sequencing tumor tumor growth tumor microenvironment tumorigenic

项目摘要

DESCRIPTION (provided by applicant): In 2012, we described one of the first uses of next-generation sequencing and bioinformatics approaches to rapidly and accurately identify a tumor-specific mutant protein that functioned as a major rejection antigen in a highly immunogenic (unedited), chemically induced mouse tumor line that was rejected when transplanted into naïve syngeneic wild type mice. Since publishing this work, we have generated compelling preliminary data leading us to form the hypothesis that the antigens in clinically apparent (edited) tumor cells that are recognized by CD8+ T cells stimulated during successful checkpoint blockade cancer immunotherapy may also be tumor-specific mutant proteins and that they too can be rapidly identified using our genomics approach. In this proposal, we wish to formally test this hypothesis to provide a foundation for the eventual translation of our method to human cancer patients so as to facilitate personalization of cancer immunotherapies. To achieve this goal we will pursue three specific aims. Specific Aim I: Identify Tumor-specific Mutational Antigens Eliciting CD8+ T Cell Responses to MCA Sarcomas and B16-F10 Melanoma With Differential Sensitivities to Checkpoint Blockade Therapy. Here we will focus our efforts on further validating and perhaps even improving our capacity to identify those antigens derived from tumor-specific mutant proteins that have potential therapeutic utility in cancer. We will ask whether tumor-specific mutant proteins are the favored targets of checkpoint blockade therapy and whether checkpoint blockade selects only the most antigenic of these mutations. Specific Aim II. Determine Whether Vaccines Targeting Tumor-Specific Mutational Antigens, Either Alone or in Combination with Checkpoint Blockade, Can Therapeutically Control Growth of MCA Sarcomas or B16-F10 Melanoma. Here we will explore whether the tumor-specific mutant antigens we identify in Aim I can be used as a basis for therapeutic tumor-specific cancer vaccines. We will investigate the following three questions: Can personalized vaccines: (a) be used instead of checkpoint blockade? (b) improve checkpoint blockade in sensitive tumors? (c) evoke checkpoint blockade effectiveness in insensitive tumors? Specific Aim III. Define the Characteristics of Tumor-specific CD8+ T Cells that Specify Their Therapeutic Effectiveness. These experiments will seek to define the characteristics of activated tumor antigen-specific CD8+ T cells that result in successful cancer immunotherapy. We want to test the hypothesis that CyTOF and RNA-Seq analyses will facilitate identification of tumor-specific CD8+ T cells expressing specific phenotypic markers that can predict a favorable clinical outcome.