Targeting Neoantigens in Glioblastoma

靶向胶质母细胞瘤中的新抗原

基本信息

  • 批准号:
    10015359
  • 负责人:
  • 金额:
    $ 47.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-15 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY This proposal focuses on targeting neoantigens in malignant brain tumors in well defined orthotopic, syngeneic preclinical models, understanding how type 1 conventional dendritic cells (cDC1) prime neoantigens, and how immune responses to neoantigens develop in newly diagnosed glioblastoma (GBM) patients enrolled in a novel clinical trial combining personalized vaccination with checkpoint blockade. GBM remains a lethal cancer and carries a median survival of 15 months with standard-of-care treatments, highlighting a clear need for more effective treatments. The application of genomics to immunotherapeutic approaches is an exciting area of investigation in many cancer types, and this proposal employs this methodology. This nexus, termed “cancer immunogenomics”, is used to identify tumor-specific somatic mutations that may be processed and presented on major histocompatibility molecules. These “neoantigens” can be recognized by the immune system and form the basis for anti-tumor immune responses. We have applied the cancer immunogenomics approach to the study of GBM both in preclinical models as well as in a novel personalized immuno-oncology cancer vaccine program for GBM patients. However, in order to fully exploit the potential of targeting neoantigens in GBM, further work is needed to understand whether targeting multiple neoantigen targets using polyvalent vaccines can improve tumor control and how neoantigens are presented to the immune system in brain cancers. How antigen is presented in the central nervous system remains unclear, and understanding the immunobiology of this process is inextricably linked to effective neoantigen targeting. In parallel, it is critical to determine how anti-tumor immunity is amplified in patients treated with personalized cancer vaccines in combination with immunopotentiating checkpoint blockade therapies. To this end, we are applying cancer immunogenomics preclinically and translationally to address these key questions. In Aim 1, we will determine the effectiveness of polyvlalent neoantigen vaccination targeting MHC class and and/or MHC class II neoantigens on survival and the immunologic effects of these vaccines on the brain tumor microenvironment. In Aim 2, we will test the hypothesis that cDC1 present neoantigen in vivo and can augment the efficacy of neoantigen-targeting vaccines. We will also further characterize the anatomic location of this critical cell population during the anti-tumor immune response. In Aim 3, we will perform correlative analysis of a novel clinical trial we are conducting to determine whether checkpoint blockade agents augment the immune responses generated with personalized vaccines and whether the genomes of recurrent tumors that progress on this trial are remodeled and/or show evidence of neoantigen specific cancer immunoediting. Together, these Aims will provide new insights into an immunogenomics-centered approach to treating GBM as well as the immunobiology of neoantigen presenation and T cell specific immune priming that has clear and imperative clinical implications.
项目总结 这项建议主要针对定义明确的原位、同基因的恶性脑肿瘤中的新抗原。 临床前模型,了解1型常规树突状细胞(CDc1)如何启动新抗原,以及如何 新诊断的胶质母细胞瘤(GBM)患者对新抗原的免疫应答 个性化疫苗接种与关卡封锁相结合的新型临床试验。基底细胞瘤仍是一种致命的癌症 标准护理治疗的中位生存期为15个月,突显出明显需要 更有效的治疗方法。基因组学在免疫治疗方法中的应用是一个令人兴奋的领域 许多癌症类型的研究,而这项提案采用了这一方法。这种纽带被称为“癌症” 免疫基因组学“是用来鉴定可能被处理和呈现的肿瘤特异性体细胞突变 主要的组织相容性分子。这些“新抗原”可以被免疫系统识别, 形成抗肿瘤免疫反应的基础。我们已经将癌症免疫基因组学方法应用于 GBM在临床前模型和一种新的个体化免疫肿瘤学肿瘤中的研究 针对GBM患者的疫苗计划。然而,为了充分发挥靶向新抗原的潜力, GBM,还需要进一步的工作来了解是否使用多价靶向多个新抗原 疫苗可以改善肿瘤的控制,以及新抗原如何呈现给大脑中的免疫系统 癌症。目前尚不清楚抗原是如何在中枢神经系统中提呈的,而对 这个过程的免疫生物学与有效的新抗原靶向有着千丝万缕的联系。同时,至关重要的是 确定使用个性化癌症疫苗治疗的患者的抗肿瘤免疫是如何增强的 结合免疫增强型检查点阻断疗法。为此,我们正在应用癌症 临床前和翻译免疫基因组学来解决这些关键问题。在目标1中,我们将确定 针对MHC类和/或MHC II类的多价新抗原疫苗的效果 新抗原对生存的影响以及这些疫苗对脑瘤微环境的免疫学影响。 在目标2中,我们将检验假设,即cDc1在体内呈递新抗原,并可以增强 新抗原靶向疫苗。我们还将进一步确定这个关键细胞的解剖位置。 人群在抗肿瘤期间的免疫反应。在目标3中,我们将对一部小说进行关联分析 我们正在进行临床试验,以确定检查点阻滞剂是否增强了免疫力 个性化疫苗产生的反应以及复发肿瘤的基因组是否进展 在这项试验中进行了改造和/或显示了新抗原特异性癌症免疫编辑的证据。一起, 这些目标将为以免疫基因组学为中心的治疗GBM以及 新抗原的免疫生物学和T细胞特异性免疫启动具有明确和迫切的意义 临床意义。

项目成果

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Gavin Peter Dunn其他文献

Gavin Peter Dunn的其他文献

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{{ truncateString('Gavin Peter Dunn', 18)}}的其他基金

Targeting Neoantigens in Glioblastoma
靶向胶质母细胞瘤中的新抗原
  • 批准号:
    10240743
  • 财政年份:
    2019
  • 资助金额:
    $ 47.2万
  • 项目类别:
Targeting Neoantigens in Glioblastoma
靶向胶质母细胞瘤中的新抗原
  • 批准号:
    10584342
  • 财政年份:
    2019
  • 资助金额:
    $ 47.2万
  • 项目类别:
IMMUNOBIOLOGY OF MALIGNANT GLIOMA
恶性胶质瘤的免疫生物学
  • 批准号:
    9563324
  • 财政年份:
    2015
  • 资助金额:
    $ 47.2万
  • 项目类别:
IMMUNOBIOLOGY OF MALIGNANT GLIOMA
恶性胶质瘤的免疫生物学
  • 批准号:
    8949252
  • 财政年份:
    2015
  • 资助金额:
    $ 47.2万
  • 项目类别:
IMMUNOBIOLOGY OF MALIGNANT GLIOMA
恶性胶质瘤的免疫生物学
  • 批准号:
    9063099
  • 财政年份:
    2015
  • 资助金额:
    $ 47.2万
  • 项目类别:

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