(PQ11) Targeting STING in the context of chemoradiation therapy to overcome poor preexisting immunity in mouse models of pancreatic cancer.

(PQ11) 在放化疗背景下靶向 STING,以克服胰腺癌小鼠模型中先前存在的较差免疫力。

基本信息

  • 批准号:
    9766083
  • 负责人:
  • 金额:
    $ 36.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-02 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Nearly two-thirds of all cancer patients will receive radiation therapy (RT) during treatment, but radiation's curative potential is limited to local-regional disease in either the definitive or adjuvant setting. Locally advanced, unresectable disease represents 30-40% of pancreatic cancer patients at diagnosis and carries a 5- year survival rate of less than 1%. While RT is frequently used and highly effective in metastatic cancer for palliation of symptomatic disease, it has little impact on unirradiated distant sites and thus no impact on survival in the metastatic setting. Likewise in the setting of locally advanced regional disease, such as in pancreatic cancer, radiation is frequently studied in the neoadjuvant setting but with little apparent improvement in overall survival. We have found that radiation therapy activates a myeloid response in the tumor that suppresses adaptive immunity. By targeting the STING (STimulator of INterferon Genes) sensor with cyclic dinucleotides (CDN), we have found that we can prevent suppressive myeloid responses, and when CDN are combined with radiation therapy we can control aggressive murine tumors. We hypothesize that provision of STING ligands in combination with chemoradiation therapy removes the biomarkers of poor response to immunotherapy. We propose that ligation of STING in systemic monocytes that are recruited to tumors following radiation and/or chemotherapy prevents transition to a tumor-promoting environment and enhances tumor associated T cell responses. The specific aims of this study are to 1: Test the hypothesis that the multicomponent chemoradiation therapy for pancreatic cancer contains core components critical to generate adaptive tumor-specific immune response when combined with systemic STING ligand treatment; 2: Test the hypothesis that the enhanced tumor control provided by systemic STING ligand in combination with radiation therapy and/or chemotherapy results from recruitment of repolarized monocytes to the tumor that in turn promote adaptive immunity in the post-treatment tumor environment; 3: Test the hypothesis that immunotherapies targeting the myeloid compartment via STING ligands will be required for tumors with the biomarkers of poor preexisting immunity and high myeloid involvement. Our study design incorporates preclinical chemoradiation therapy of transplantable and spontaneous models of pancreatic cancer in immune competent mice using an advanced imaging and treatment platform. This proposal particularly focuses on control of both local-regional and distant disease to extend the curative potential of immunotherapy for cancer patients.
项目概要 近三分之二的癌症患者在治疗期间会接受放射治疗 (RT),但放射治疗 治疗潜力仅限于确定性或辅助性治疗中的局部区域疾病。本地 晚期、不可切除的疾病占诊断时胰腺癌患者的 30-40%,并且携带 5- 年生存率不足1%。虽然放疗经常用于治疗转移性癌症并且非常有效 缓解症状性疾病,对未受照射的远处部位影响很小,因此对 转移环境中的存活率。同样,在局部晚期区域疾病的情况下,例如 胰腺癌,放射治疗经常在新辅助治疗中进行研究,但很少有明显的研究 总体生存率的改善。我们发现放射治疗可以激活骨髓细胞的反应 抑制适应性免疫的肿瘤。通过靶向 STING(干扰素基因 STimulator)传感器 使用环状二核苷酸(CDN),我们发现我们可以预防抑制性骨髓反应,并且当 CDN 与放射治疗相结合,我们可以控制侵袭性小鼠肿瘤。我们假设 提供 STING 配体与放化疗结合可消除不良的生物标志物 对免疫治疗的反应。我们建议在系统单核细胞中连接 STING,这些单核细胞被募集到 放疗和/或化疗后的肿瘤可阻止向促肿瘤环境的转变,并且 增强肿瘤相关 T 细胞反应。本研究的具体目的是 1:检验假设 胰腺癌的多成分放化疗包含对治疗至关重要的核心成分 与全身性 STING 配体治疗相结合,产生适应性肿瘤特异性免疫反应; 2: 检验以下假设:全身性 STING 配体与 放射治疗和/或化学治疗是由于将复极化的单核细胞募集到肿瘤中而引起的 进而促进治疗后肿瘤环境中的适应性免疫; 3:检验假设 对于具有以下特征的肿瘤,需要通过 STING 配体靶向骨髓区室的免疫疗法 先前存在的免疫力差和骨髓受累程度高的生物标志物。我们的研究设计包含 可移植和自发性胰腺癌免疫模型的临床前放化疗 使用先进的成像和治疗平台的有能力的小鼠。该提案特别关注 控制局部区域和远处疾病,以扩大免疫疗法治疗癌症的潜力 患者。

项目成果

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Marka Crittenden其他文献

Marka Crittenden的其他文献

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{{ truncateString('Marka Crittenden', 18)}}的其他基金

Increasing the potency of Listeria monocytogenes-based vaccines by eliminating vaccine-related gamma delta T cell responses.
通过消除疫苗相关的 γ δ T 细胞反应来提高基于单核细胞增生李斯特氏菌的疫苗的效力。
  • 批准号:
    9167982
  • 财政年份:
    2016
  • 资助金额:
    $ 36.61万
  • 项目类别:
Increasing the potency of Listeria monocytogenes-based vaccines by eliminating vaccine-related gamma delta T cell responses.
通过消除疫苗相关的 γ δ T 细胞反应来提高基于单核细胞增生李斯特氏菌的疫苗的效力。
  • 批准号:
    9296084
  • 财政年份:
    2016
  • 资助金额:
    $ 36.61万
  • 项目类别:
(PQ11) Targeting STING in the context of chemoradiation therapy to overcome poor preexisting immunity in mouse models of pancreatic cancer.
(PQ11) 在放化疗背景下靶向 STING,以克服胰腺癌小鼠模型中先前存在的较差免疫力。
  • 批准号:
    9172633
  • 财政年份:
    2016
  • 资助金额:
    $ 36.61万
  • 项目类别:
Generation of a novel fusion protein to redirect macrophage differentiation following radiation therapy.
生成一种新型融合蛋白,以在放射治疗后重定向巨噬细胞分化。
  • 批准号:
    8957541
  • 财政年份:
    2015
  • 资助金额:
    $ 36.61万
  • 项目类别:
Generation of a novel fusion protein to redirect macrophage differentiation following radiation therapy.
生成一种新型融合蛋白,以在放射治疗后重定向巨噬细胞分化。
  • 批准号:
    9105775
  • 财政年份:
    2015
  • 资助金额:
    $ 36.61万
  • 项目类别:

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