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的抑制剂（DNA损伤响应）增强了辐射诱导的T1IFN（I型） 干扰素）介导的先天免疫，随后是适应性免疫。我们还表明了PARP 抑制剂是在辐射诱导的DNA损伤下诱导病变时具有独特特性的辐射敏化剂 站点。在此应用中，我们研究了它们与辐射的结合，作为诱导先天免疫力的策略 并使PDAC（胰腺导管腺癌）对免疫疗法敏感。我们确认，同意 临床研究，仅辐射是一种弱免疫刺激剂。相反，辐射与 PARP抑制剂Olaparib强烈诱导T1IFN介导的PDAC中的先天免疫，从而引起敏感性 局部和全身性肿瘤进行免疫疗法。总共这些数据支持我们提出的临床 在LAPC患者（局部晚期胰腺癌）患者中，结合Olaparib，辐射和杜瓦卢马布的试验。 该提案的总体目标是临时制定将PARP抑制剂与辐射相结合的策略 通过促进肿瘤细胞DNA损伤和 免疫原性将转化为LAPC患者的临床试验。我们将在3个特定的 目标。特定的目标1将阐明先天免疫调节的新型机制及其T1IFN依赖性 PARP抑制剂在PDAC细胞中具有辐射的表型后果。我们的初步数据显示， 与仅PARP抑制剂形成鲜明对比，PARP抑制剂Olaparib与辐射协同以降低生存 并在HR（同源重组）熟练的PDAC中诱导T1IFN先天免疫反应。目标1意志 定义T1IFN产生的新机制及其随后的表型后果。我们期待 定义由Olaparib和辐射诱导的DNA引发的新型模式识别受体（PRR）途径 损害或复制应力导致肿瘤先天免疫增加。具体目标2将确定 与PARP抑制剂，辐射和ICB合并治疗的治疗益处和分子终点 PDAC。我们将定义局部和全身性抗肿瘤功效和每分剂量高剂量的毒性 辐射（即SBRT，立体定向的身体辐射或标准分数辐射）和最佳时间表 Olaparib和抗PD-L1。我们将在反射DNA损伤的肿瘤和血液中建立终点，肿瘤先天 和自适应免疫，以及更广泛的免疫特征（Cytof）。我们希望取得有利的 具有SBRT的治疗指数与肿瘤DNA损伤和T1IFN介导的先天和 自适应免疫。在特定的目标3中，我们将在Olaparib，辐射和Durvalumab中进行临床试验 LAPC患者。我们将使用事件的持续重新评估方法来升级Olaparib （Tite-Crm）与SBRT的组合（除非AIM 2另外告知）和PD-L1阻塞 LAPC患者的抗体Durvalumab。我们预计我们将实现安全有效的 Olaparib与辐射和杜瓦卢匹单抗的结合，可促进最大的免疫原性和 激励一项随机2期试验，以最终提高LAPC患者的生存率。