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

• 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
• 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

 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.

 DESCRIPTION (provided by application): 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.自发表这项工作以来，我们已经产生了引人注目的初步数据，这使我们形成了这样一个假设，即在成功的检查点阻断癌症免疫疗法期间刺激的临床明显（编辑）肿瘤细胞中的抗原也可能是肿瘤特异性突变蛋白，也可以使用我们的基因组方法来快速识别。在此提案中，我们希望正式检验该假设，为我们的方法转化为人类癌症患者的事件翻译为促进癌症免疫疗法的个性化提供基础。为了实现这一目标，我们将追求三个具体目标。特定目的I：鉴定肿瘤特异性突变抗原，引起对MCA肉瘤的CD8+ T细胞反应，而B16-F10黑色素瘤具有差异敏感性，可检查点阻断疗法。在这里，我们将重点放在进一步验证的能力上，并可能提高我们的能力，以鉴定那些从肿瘤特异性突变蛋白中得出的抗原，这些突变蛋白具有潜在的癌症治疗效用。我们将询问肿瘤特异性突变蛋白是否是检查点阻滞治疗的首选靶标，以及检查点阻滞是否仅选择这些突变中最抗原的靶标。具体目标II。确定靶向肿瘤特异性突变抗原的疫苗，无论是单独还是与检查点阻滞结合使用，都可以控制MCA肉瘤或B16-F10黑色素瘤的治疗性控制生长。在这里，我们将探讨我们在目标中识别的肿瘤特异性突变抗原是否可以用作治疗性肿瘤特异性癌症疫苗的基础。我们将调查以下三个问题：个性化疫苗可以：（a）用于使用检查点封锁？ （b）改善敏感肿瘤中的检查点阻滞？ （c）唤起敏感肿瘤中的检查点阻滞效果？特定目标III。定义指定其治疗有效性的肿瘤特异性CD8+ T细胞的特征。这些实验将寻求定义活化的肿瘤抗原特异性CD8+ T细胞的特征，从而成功进行癌症免疫疗法。我们想检验以下假设：Cytof和RNA-Seq分析将有助于鉴定出表达特定表型标记的肿瘤特异性CD8+ T细胞，这些标志物可以预测有利的临床结果。