Targeting the DNA damage response in combination with radiation to induce innate immunity and improve immunotherapy efficacy in pancreatic cancer

靶向 DNA 损伤反应并结合放射诱导先天免疫并提高胰腺癌免疫治疗效果

• 批准号: 10352416
• 负责人: Meredith A Morgan
• 金额: $ 44.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352416
• 关键词: ATM deficient; Abbreviations; Affect; Antigen-Presenting Cells; Apical; CD8B1 gene; CHEK2 gene; Cancer Detection; Cancer Etiology; Cell Count; Cell physiology; Cells; Cessation of life; Clinical Management; Clinical Trials; DNA; DNA Damage; DNA Repair; Data; Defect; Dose; Dose Fractionation; Foundations; Future; Genetic; Genetically Engineered Mouse; Goals; IFNAR1 gene; Immune; Immune response; Immunologic Surveillance; Immunologics; Immunotherapy; Innate Immune Response; Interferon Type I; Interferons; Ionizing radiation; Link; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mission; Natural Immunity; Nature; Oncogenes; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pattern recognition receptor; Pharmacology; Phosphotransferases; Production; Proteins; Proto-Oncogene Proteins c-akt; Radiation; Radiation Dose Unit; Radiation therapy; Refractory; Regulation; Role; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; Survival Rate; T-Lymphocyte; TBK1 gene; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Tumor Immunity; Tumor-infiltrating immune cells; United States; United States National Institutes of Health; advanced pancreatic cancer; base; clinical candidate; clinical development; clinical efficacy; effector T cell; immune activation; immune checkpoint blockade; immunogenic; improved; in vivo; inhibitor; innate immune pathways; innate immune sensing; macrophage; neoplastic cell; novel; novel therapeutics; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; pharmacodynamic biomarker; preclinical study; programmed cell death ligand 1; radiation response; receptor; replication stress; response; small molecule inhibitor; synergism; tumor; tumor DNA; tumor growth; tumor microenvironment; type I interferon receptor; ATM deficient; Abbreviations; Affect; Antigen-Presenting Cells; Apical; CD8B1 gene; CHEK2 gene; Cancer Detection; Cancer Etiology; Cell Count; Cell physiology; Cells; Cessation of life; Clinical Management; Clinical Trials; DNA; DNA Damage; DNA Repair; Data; Defect; Dose; Dose Fractionation; Foundations; Future; Genetic; Genetically Engineered Mouse; Goals; IFNAR1 gene; Immune; Immune response; Immunologic Surveillance; Immunologics; Immunotherapy; Innate Immune Response; Interferon Type I; Interferons; Ionizing radiation; Link; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mission; Natural Immunity; Nature; Oncogenes; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pattern recognition receptor; Pharmacology; Phosphotransferases; Production; Proteins; Proto-Oncogene Proteins c-akt; Radiation; Radiation Dose Unit; Radiation therapy; Refractory; Regulation; Role; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; Survival Rate; T-Lymphocyte; TBK1 gene; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Tumor Immunity; Tumor-infiltrating immune cells; United States; United States National Institutes of Health; advanced pancreatic cancer; base; clinical candidate; clinical development; clinical efficacy; effector T cell; immune activation; immune checkpoint blockade; immunogenic; improved; in vivo; inhibitor; innate immune pathways; innate immune sensing; macrophage; neoplastic cell; novel; novel therapeutics; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; pharmacodynamic biomarker; preclinical study; programmed cell death ligand 1; radiation response; receptor; replication stress; response; small molecule inhibitor; synergism; tumor; tumor DNA; tumor growth; tumor microenvironment; type I interferon receptor

ABSTRACT Therapeutic strategies are needed to improve the efficacy of immune checkpoint blockade (ICB) therapy in pancreatic ductal adenocarcinomas (PDAC). PDACs have an increased reliance on the DNA damage response (DDR) for mitigating oncogene-induced replication stress and, the DDR regulates innate immunity via regulation of cGAS/STING/TBK1-mediated detection of cancer DNA. ATM is the apical kinase in the DDR and the target of small molecule inhibitors in clinical development. Furthermore, ionizing radiation stimulates the cGAS/STING/TBK1 innate immune pathway to modulate immune responses in a type 1 interferon (T1IFN)- dependent fashion that are required for the synergy of radiation with ICB. Therefore, the central hypothesis of this proposal is that a novel direct link between ATM and innate immune sensing pathways can be leveraged therapeutically in combination with radiation to enhance the tumoral T1IFN pathway and improve ICB efficacy in otherwise poorly immunogenic PDACs. This hypothesis will be tested in three specific aims: Aim 1 will define the immunologic consequences of ATM inhibition in combination with radiation and the mechanisms by which ATM affects innate immunity in PDAC. In this aim we will assess the contributions of cytoplasmic DNA (1A), ATM substrates (1B), and pattern recognition receptor pathway signaling (1C) to immune endpoints such as T1IFN-mediated signaling, PD-L1 expression, and T cell-mediated killing (1D). Aim 2 will investigate the immune contribution to the sensitivity of ATM depleted PDAC tumors to the combination of radiation and PD-L1 therapy. Our preliminary data suggest that ATM has both tumor and host immune-dependent mechanisms (i.e. T1IFN secretion) that influence the sensitivity of tumors to combined anti-PD-L1 and radiation. We will determine the contribution of tumoral and host T1IFN signaling to the sensitivity of ATM-deficient tumors to combined anti-PD-L1 and radiation therapy (2A) as well as the immune consequences (2B). We hypothesize that the therapeutic advantages of ATM deficiency will be diminished in T1IFNR deficient tumor cells and hosts since tumoral T1IFN production likely increases tumor immunosurveillance through both tumor and host-dependent mechanisms. In Aim 3 we will develop a therapeutic strategy combining ATM inhibitors and radiation with anti-PD-L1 in PDAC. Our preliminary data show that pharmacologic ATM inhibition activates the immune pathway. We will determine the efficacy of the clinical candidate ATM inhibitor AZD0156 in combination with anti-PD-L1 and the optimal radiation dose/fractionation schema in syngeneic PDAC tumors and autochthonous PDAC tumors in genetically engineered mouse models (3A). We will also develop pharmacodynamic biomarkers that will be predictive of the therapeutic efficacy of ATM inhibition and radiation in combination with anti-PD-L1 (3B). Completion of these aims will define a new connection between ATM, radiation and innate immunity that will be leveraged therapeutically to extend the efficacy of ICB to PDAC which is highly relevant to the mission of the NIH.

抽象的 需要进行治疗策略来提高免疫检查点封锁（ICB）治疗的功效 胰腺导管腺癌（PDAC）。 PDAC对DNA损伤响应的依赖增加了 （DDR）用于缓解癌基因诱导的复制应力，DDR通过调节调节先天免疫力 CGA/Sting/TBK1介导的癌症DNA的检测。 ATM是DDR和目标中的顶端激酶 临床发育中的小分子抑制剂。此外，电离辐射刺激 CGA/Sting/TBK1先天免疫途径可调节1型干扰素（T1IFN） - 辐射与ICB协同作用所需的依赖方式。因此，中心假设 该建议的是，ATM与先天免疫传感途径之间的新型直接联系可以是 与辐射结合使用治疗，以增强肿瘤T1IFN途径和 提高ICB的免疫原性PDAC的功效。该假设将在三个 具体目的：AIM 1将定义ATM抑制的免疫学后果 辐射和ATM影响PDAC先天免疫的机制。在此目标中，我们将评估 细胞质DNA（1A），ATM底物（1B）和模式识别受体途径的贡献 信号（1C）对免疫端点，例如T1IFN介导的信号传导，PD-L1表达和T细胞介导的 杀人（1d）。 AIM 2将研究ATM耗尽PDAC的敏感性的免疫贡献 肿瘤与辐射和PD-L1治疗的结合。我们的初步数据表明ATM都具有 肿瘤和宿主免疫依赖性机制（即T1IFN分泌），影响肿瘤的敏感性 抗PD-L1和辐射组合。我们将确定肿瘤和宿主T1IFN信号对 ATM缺乏肿瘤对抗PD-L1和放射治疗（2A）的敏感性以及免疫 后果（2b）。我们假设ATM缺乏症的治疗优势将在 T1IFNR缺乏肿瘤细胞和宿主，因为肿瘤T1IFN的产生可能会增加肿瘤 通过肿瘤和宿主依赖机制的免疫监护。在AIM 3中，我们将开发一个 PDAC中的ATM抑制剂和辐射与抗PD-L1相结合的治疗策略。我们的初步 数据表明，药理学ATM抑制会激活免疫途径。我们将确定 临床候选ATM抑制剂AZD0156结合使用抗PD-L1和最佳辐射 遗传学上的合成PDAC肿瘤和自闭症PDAC肿瘤中的剂量/分级模式 工程鼠标模型（3A）。我们还将开发药效生物标志物，以预测 ATM抑制和辐射与抗PD-L1（3B）的治疗功效。这些完成 目标将定义ATM，辐射和先天免疫之间的新联系 在治疗上，将ICB的功效扩展到PDAC，这与NIH的任务高度相关。