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.

摘要 需要治疗策略来提高免疫检查点阻断（ICB）治疗在免疫缺陷综合征中的疗效。 胰腺导管腺癌（PDAC）。PDAC对DNA损伤反应的依赖性增加 (DDR)减轻癌基因诱导的复制应激，DDR通过调节 cGAS/STING/TBK 1介导的癌症DNA检测。ATM是DDR中的顶端激酶， 小分子抑制剂的临床开发。此外，电离辐射会刺激 cGAS/STING/TBK 1先天免疫途径以调节1型干扰素（T1 IFN）中的免疫应答 这是辐射与ICB协同作用所需的依赖方式。因此，中心假设 这一建议的一个新的直接联系ATM和先天免疫传感途径， 在治疗上与放射联合使用以增强肿瘤T1 IFN途径， 在其他免疫原性差的PDAC中改善ICB功效。这一假设将在三个 具体目标：目标1将定义ATM抑制与以下联合的免疫学后果： 辐射和ATM影响PDAC先天免疫的机制。为此，我们将评估 细胞质DNA（1A）、ATM底物（1B）和模式识别受体途径的作用 信号传导（1C）至免疫终点，如T1 IFN介导的信号传导、PD-L1表达和T细胞介导的免疫应答。 杀（1D）。目的2研究免疫对ATM缺失PDAC敏感性的影响 肿瘤与放射和PD-L1治疗的组合。我们的初步数据表明，ATM同时具有 肿瘤和宿主免疫依赖性机制（即T1 IFN分泌），其影响肿瘤对 抗PD-L1抗体和放射治疗我们将确定肿瘤和宿主T1 IFN信号对 ATM缺陷型肿瘤对联合抗PD-L1和放射治疗的敏感性（2A）以及免疫抑制剂的敏感性。 结果（2B）。我们假设，ATM缺陷的治疗优势将减少， T1 IFNR缺陷型肿瘤细胞和宿主，因为肿瘤T1 IFN产生可能增加肿瘤 通过肿瘤和宿主依赖性机制的免疫监视。在目标3中，我们将开发一个 在PDAC中联合ATM抑制剂和放射与抗PD-L1的治疗策略。我们的初步 数据显示，药理学ATM抑制激活免疫途径。我们将确定 临床候选ATM抑制剂AZD 0156与抗PD-L1和最佳辐射的组合 在遗传学上，同源PDAC肿瘤和自体PDAC肿瘤的剂量/分割方案 工程化小鼠模型（3A）。我们还将开发药效学生物标志物， ATM抑制和放射与抗PD-L1组合的治疗功效（3B）。完成这些 目标将定义ATM，辐射和先天免疫之间的新联系， 在治疗上将ICB的功效扩展到PDAC，这与NIH的使命高度相关。