Project 1: Combining PARP inhibition with radiation to sensitize HR proficient pancreatic cancers to immunotherapy

项目 1：将 PARP 抑制与放射治疗相结合，使 HR 熟练的胰腺癌对免疫治疗敏感

• 批准号: 10554472
• 负责人: Meredith A Morgan
• 金额: $ 22.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554472
• 关键词: Agreement; Biopsy; Blocking Antibodies; Blood; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Survival; Cells; Cessation of life; Clinical Management; Clinical Research; Clinical Trials; Combined Modality Therapy; DNA; DNA Damage; DNA biosynthesis; Data; Dependence; Dose; Dose Limiting; Event; FDA approved; Fractionation; Generations; Goals; Immune; Immunocompetent; Immunologic Deficiency Syndromes; Immunotherapy; Innate Immune Response; Interferon Type I; Lesion; Localized Disease; Locally Advanced Malignant Neoplasm; Malignant neoplasm of pancreas; Mediating; Methods; Micrometastasis; Molecular; Molecular Target; Natural Immunity; PARP inhibition; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pattern recognition receptor; Phase; Phase I/II Trial; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; Property; Radiation; Radiation Dose Unit; Radiation Induced DNA Damage; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Randomized; Resistance; Schedule; Site; Stimulator of Interferon Genes; Survival Rate; T-Cell Depletion; Therapeutic; Therapeutic Index; Toxic effect; Translating; Treatment Efficacy; Treatment outcome; Tumor Immunity; Tumor Promotion; United States; adaptive immune response; adaptive immunity; advanced pancreatic cancer; anti-PD-L1; chemotherapy; clinical investigation; design; ds-DNA; fractionated radiation; gastrointestinal; homologous recombination; immune checkpoint blockade; immunogenicity; immunoregulation; improved; inhibitor; innate immune mechanisms; micronucleus; neoplastic cell; novel; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; phase II trial; pre-clinical; preclinical study; programmed cell death ligand 1; replication stress; response; subcutaneous; synergism; time use; tumor; tumor DNA; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT (PROJECT 1) We discovered that inhibitors of the DDR (DNA damage response) enhance radiation-induced T1IFN (Type I interferon)-mediated innate immunity and, subsequently, adaptive immunity. We have also shown that PARP inhibitors are radiation sensitizers with unique properties in inducing lesions at radiation-induced DNA damage sites. In this application, we investigate their combination with radiation as a strategy to induce innate immunity and sensitize PDAC (pancreatic ductal adenocarcinoma) to immunotherapy. We confirm, in agreement with a clinical study, that radiation alone is a weak immune stimulator. In contrast, the combination of radiation with the PARP inhibitor olaparib strongly induces T1IFN-mediated innate immunity in PDAC resulting in sensitization of both local and systemic tumors to immunotherapy. Taken together these data support our proposed clinical trial combining olaparib, radiation and durvalumab in patients with LAPC (locally advanced pancreatic cancer). The overall goal of this proposal is to preclinically develop a strategy combining PARP inhibitors with radiation for sensitizing PDAC to ICB (immune checkpoint blockade) by promoting tumor cell DNA damage and immunogenicity that will be translated to a clinical trial in LAPC patients. We will accomplish this in 3 specific aims. Specific Aim 1 will elucidate novel mechanisms of innate immune modulation and their T1IFN-dependent phenotypic consequences by PARP inhibitors with radiation in PDAC cells. Our preliminary data show, in contrast to PARP inhibitor alone, that the PARP inhibitor olaparib synergizes with radiation to reduce survival and induce a T1IFN innate immune response in HR (homologous recombination) proficient PDAC. Aim 1 will define novel mechanisms of T1IFN generation and its subsequent phenotypic consequences. We anticipate defining novel pattern recognition receptor (PRR) pathways initiated by olaparib and radiation-induced DNA damage or replication stress that result in increased tumor innate immunity. Specific Aim 2 will determine the therapeutic benefit and molecular endpoints of combined therapy with PARP inhibitor, radiation and ICB in PDAC. We will define the local and systemic anti-tumor efficacy and toxicity of high or lower dose per fraction radiation (i.e., SBRT, stereotactic body radiation or standard fractioned radiation) and the optimal schedule with olaparib and anti-PD-L1. We will establish endpoints in tumors and blood reflecting DNA damage, tumor innate and adaptive immunity, as well as the broader immune profile (CyTOF). We expect to achieve a favorable therapeutic index with SBRT that is associated with tumor DNA damage and T1IFN-mediated innate and adaptive immunity. In Specific Aim 3, we will conduct a clinical trial of olaparib, radiation, and durvalumab in patients with LAPC. We will dose escalate olaparib using the Time-to-Event Continual Reassessment Method (TiTE-CRM) with the combination of SBRT (unless otherwise informed by Aim 2) and the PD-L1 blocking antibody durvalumab in patients with LAPC. We anticipate that we will achieve a safe and efficacious combination of olaparib with radiation and durvalumab that promotes maximal immunogenicity and motivates a randomized phase 2 trial to ultimately improve survival in patients with LAPC.

项目摘要/摘要（项目 1） 我们发现 DDR（DNA 损伤反应）抑制剂可增强辐射诱导的 T1IFN（I 型 干扰素）介导的先天免疫，以及随后的适应性免疫。我们还证明了 PARP 抑制剂是辐射敏化剂，具有在辐射诱导的 DNA 损伤中诱导病变的独特特性 网站。在此应用中，我们研究了它们与辐射的结合作为诱导先天免疫的策略 并使 PDAC（胰腺导管腺癌）对免疫治疗敏感。我们确认，经同意 临床研究表明，单独的辐射是一种微弱的免疫刺激剂。相比之下，辐射与 PARP 抑制剂奥拉帕尼强烈诱导 PDAC 中 T1IFN 介导的先天免疫，导致致敏 局部和全身肿瘤的免疫治疗。综上所述，这些数据支持我们提出的临床方案 在 LAPC（局部晚期胰腺癌）患者中进行奥拉帕尼、放射治疗和 durvalumab 联合治疗的试验。 该提案的总体目标是在临床前开发一种将 PARP 抑制剂与放射治疗相结合的策略 通过促进肿瘤细胞 DNA 损伤来增强 PDAC 对 ICB（免疫检查点阻断）的敏感性， 免疫原性将转化为 LAPC 患者的临床试验。我们将通过 3 个具体任务来实现这一目标 目标。具体目标 1 将阐明先天免疫调节的新机制及其 T1IFN 依赖性 PARP 抑制剂与辐射对 PDAC 细胞的表型影响。我们的初步数据显示，在 与单独的 PARP 抑制剂相比，PARP 抑制剂奥拉帕尼与放射协同作用以降低生存率 并在 HR（同源重组）熟练的 PDAC 中诱导 T1IFN 先天免疫反应。目标1将 定义 T1IFN 产生的新机制及其随后的表型后果。我们预计 定义由奥拉帕尼和辐射诱导 DNA 启动的新型模式识别受体 (PRR) 途径 损伤或复制应激导致肿瘤先天免疫增强。具体目标 2 将确定 PARP 抑制剂、放疗和 ICB 联合治疗的治疗益处和分子终点 PDAC。我们将定义每部分高或低剂量的局部和全身抗肿瘤功效和毒性 放射治疗（即 SBRT、立体定向身体放射或标准分割放射）和最佳计划 奥拉帕尼和抗 PD-L1。我们将在肿瘤和血液中建立反映 DNA 损伤、肿瘤先天性的终点 和适应性免疫，以及更广泛的免疫特征（CyTOF）。我们期望取得有利的 SBRT 的治疗指数与肿瘤 DNA 损伤和 T1IFN 介导的先天性和 适应性免疫。在具体目标 3 中，我们将在以下国家开展奥拉帕尼、放射治疗和 durvalumab 的临床试验 LAPC 患者。我们将使用事件发生时间持续重新评估方法逐步增加奥拉帕尼的剂量 (TiTE-CRM) 结合 SBRT（除非目标 2 另有通知）和 PD-L1 阻断 LAPC 患者的抗体 durvalumab。我们预计我们将实现安全有效的 奥拉帕尼与放射和 durvalumab 的组合可促进最大免疫原性 激发了一项随机 2 期试验，以最终提高 LAPC 患者的生存率。