(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
• 负责人: Marka Crittenden
• 金额: $ 37.74万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-02 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172633
• 关键词: Adjuvant; Aftercare; Anti-Bacterial Agents; Antigen Presentation; Antigens; Biological Markers; Cancer Patient; Cells; Clinical Trials Design; Clonality; Cross Presentation; Cytotoxic Chemotherapy; Data; Diagnosis; Dinucleoside Phosphates; Disease; Disseminated Malignant Neoplasm; Distant; Effectiveness; Environment; Genes; Image; Immune; Immune response; Immunity; Immunotherapy; In Situ; Interferons; Ligands; Ligation; Malignant neoplasm of pancreas; Modeling; Mus; Myelogenous; Myeloid Cells; Nature; Neoadjuvant Therapy; Pathway interactions; Radiation; Radiation therapy; Receptor Gene; Recruitment Activity; Regional Disease; Reporter; Research Design; Resectable; Residual state; Role; Signal Pathway; Site; Survival Rate; T cell response; T-Lymphocyte; Testing; Treatment Efficacy; Unresectable; Vaccines; Viral; adaptive immunity; cancer cell; checkpoint therapy; chemokine; chemoradiation; chemotherapy; cytokine; gene therapy; inhibitor/antagonist; macrophage; monocyte; mouse model; novel; palliation; palliative; pancreatic neoplasm; pre-clinical; prevent; response; sensor; standard of care; success; tumor

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.

项目摘要 近三分之二的癌症患者在治疗期间将接受放射治疗（RT），但放射治疗 在确定性或辅助性环境中，治疗潜力仅限于局部区域疾病。本地 晚期、不可切除的疾病占诊断时胰腺癌患者的30-40%，并携带5- 年生存率不到1%。虽然RT在转移性癌症中经常使用并且非常有效， 缓解有症状的疾病，它对未照射的远处部位几乎没有影响，因此对 在转移性环境中的存活率。同样，在局部晚期区域性疾病的情况下，例如在 在胰腺癌中，放射经常在新辅助治疗中进行研究，但几乎没有明显的 改善总体生存率。我们已经发现放射治疗激活了骨髓反应， 抑制适应性免疫的肿瘤。通过靶向STING（干扰素基因刺激物）传感器 使用环二核苷酸（CDN），我们发现我们可以防止抑制性骨髓反应， 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配体与放化疗联合治疗去除了不良免疫反应的生物标志物。 对免疫疗法的反应。我们提出，在系统性单核细胞中连接STING， 放疗和/或化疗后的肿瘤阻止了向肿瘤促进环境的转变， 增强肿瘤相关的T细胞反应。本研究的具体目的是：1、检验假设 胰腺癌的多组分放化疗治疗包含关键的核心成分， 当与全身性STING配体治疗组合时产生适应性肿瘤特异性免疫应答; 2： 检验由全身性STING配体与以下组合提供的增强的肿瘤控制的假设： 放射疗法和/或化学疗法是由复极化的单核细胞向肿瘤募集而引起的， 在治疗后的肿瘤环境中反过来促进适应性免疫; 3：检验假设， 通过STING配体靶向髓样区室的免疫疗法将需要用于具有以下特征的肿瘤： 生物标志物的不良预先存在的免疫和高骨髓受累。我们的研究设计包括 胰腺癌移植模型和自发模型的临床前放化疗 使用先进的成像和治疗平台，该提案特别侧重于 控制局部区域和远处疾病，以扩大癌症免疫疗法的治愈潜力 患者