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

项目摘要/摘要(项目1) 我们发现，DDR(DNA损伤反应)的抑制剂可以增强辐射诱导的T1干扰素(I型 干扰素)介导的先天免疫以及随后的获得性免疫。我们还展示了PARP 抑制剂是辐射增敏剂，在辐射诱导的DNA损伤中具有诱导损伤的独特性质 网站。在这个应用中，我们研究了它们与辐射的结合作为一种诱导天然免疫的策略。 并使PDAC(胰腺导管腺癌)对免疫治疗敏感。我们确认，在与一家 临床研究表明，单纯的辐射是一种微弱的免疫刺激剂。相比之下，辐射与辐射的结合 PARP抑制剂olaparib强烈诱导PDAC中T1干扰素介导的先天免疫致敏 局部和全身肿瘤的免疫治疗。总而言之，这些数据支持我们提出的临床 奥拉帕利、放疗和杜伐单抗联合治疗局部晚期胰腺癌患者的试验。 这项建议的总体目标是在临床前开发一种将PARP抑制剂与放射相结合的策略 通过促进肿瘤细胞DNA损伤和增强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个具体步骤来实现这一点 目标。特异性目标1将阐明先天免疫调节的新机制及其对T1干扰素的依赖 PARP抑制剂对PDAC细胞辐射的表型影响。我们的初步数据显示， 与单独使用PARP抑制剂相比，PARP抑制剂olaparib与辐射协同作用可降低存活率 并在同源重组熟练的PDAC中诱导T1干扰素的先天免疫应答。目标1将 确定T1干扰素产生的新机制及其随后的表型后果。我们期待着 确定由奥拉帕利和辐射诱导的DNA启动的新的模式识别受体(PRR)通路 损伤或复制应激，导致肿瘤天然免疫力增强。具体目标2将决定 PARP抑制剂、放射治疗和ICB联合治疗的疗效和分子终点 PDAC。我们将确定高剂量或低剂量组分的局部和全身抗肿瘤疗效和毒性。 放射治疗(即SBRT、立体定向体部照射或标准分次照射)和 奥拉帕利布和抗PD-L1。我们将在肿瘤和血液中建立反映DNA损伤的终点，肿瘤先天 和获得性免疫，以及更广泛的免疫概况(CyTOF)。我们期待着取得一个有利的结果 SBRT治疗指标与肿瘤DNA损伤及T1干扰素介导的先天和 适应性免疫。在具体目标3中，我们将进行奥拉帕利、放射和杜伐单抗的临床试验。 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利的剂量。 (Tite-CRM)，结合SBRT(除非AIM 2另行通知)和PD-L1阻断 LAPC患者血清中抗Durvalumab抗体的检测我们期待着我们将实现安全和有效的 奥拉帕利与放射和杜伐单抗的组合可促进最大的免疫原性和 推动一项随机2期试验，最终提高LAPC患者的存活率。

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.