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

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 需要采取治疗策略来提高免疫检查点阻断（ICB）疗法的疗效 胰腺导管腺癌（PDAC）。 PDAC 对 DNA 损伤反应的依赖性增加 (DDR) 用于减轻癌基因诱导的复制应激，并且 DDR 通过调节来调节先天免疫 cGAS/STING/TBK1 介导的癌症 DNA 检测。 ATM 是 DDR 中的顶端激酶，其靶点 小分子抑制剂的临床开发。此外，电离辐射会刺激 cGAS/STING/TBK1 先天免疫通路调节 1 型干扰素 (T1IFN) 的免疫反应 - 辐射与 ICB 协同作用所需的依赖性时尚。因此，中心假设 该提案的主要内容是，ATM 和先天免疫传感途径之间存在一种新颖的直接联系 与放射治疗相结合，增强肿瘤 T1IFN 通路， 提高免疫原性较差的 PDAC 中 ICB 的功效。这个假设将在三个方面进行检验 具体目标：目标 1 将定义 ATM 抑制与 辐射以及 ATM 影响 PDAC 先天免疫的机制。为了这个目标，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 至免疫终点的信号传导 (1C)，例如 T1IFN 介导的信号传导、PD-L1 表达和 T 细胞介导的信号传导 杀戮（1D）。目标 2 将研究免疫对 ATM 耗尽的 PDAC 敏感性的贡献 肿瘤放疗和 PD-L1 联合治疗。我们的初步数据表明，ATM 具有以下特点： 肿瘤和宿主免疫依赖性机制（即 T1IFN 分泌）影响肿瘤的敏感性 联合抗 PD-L1 和放射治疗。我们将确定肿瘤和宿主 T1IFN 信号转导对 ATM 缺陷肿瘤对抗 PD-L1 联合放射治疗 (2A) 以及免疫治疗的敏感性 后果（2B）。我们假设 ATM 缺陷的治疗优势将会减弱 T1IFNR 缺陷的肿瘤细胞和宿主，因为肿瘤 T1IFN 的产生可能会增加肿瘤的发生 通过肿瘤和宿主依赖性机制进行免疫监视。在目标 3 中，我们将开发一个 PDAC 中 ATM 抑制剂和放射治疗与抗 PD-L1 相结合的治疗策略。我们的初步 数据显示，药理 ATM 抑制可激活免疫途径。我们将确定其功效 临床候选ATM抑制剂AZD0156联合抗PD-L1和最佳放射治疗 同基因 PDAC 肿瘤和本地 PDAC 肿瘤在遗传上的剂量/分次方案 工程小鼠模型（3A）。我们还将开发可预测的药效生物标志物 ATM 抑制和放射与抗 PD-L1 联合治疗的疗效 (3B)。完成这些 目标将定义 ATM、辐射和先天免疫之间的新联系，并将加以利用 治疗上将 ICB 的功效扩展到 PDAC，这与 NIH 的使命高度相关。