Homologous recombination deficiency and beyond in pancreatic cancer: evaluating the regulators of response to pembrolizumab and olaparib (POLAR) from the immune and genomic perspectives

项目摘要--RP2 胰腺导管腺癌(PDAC)的特点是肿瘤突变负荷低，抗原-DNA受损。 表现为低水平的细胞毒性CD8+T细胞，以及非免疫原性肿瘤微环境- 有助于免疫治疗的集体特征--抵抗力。有必要识别敏感患者 PDAC的亚型和有效的免疫治疗组合。最近的研究表明，多聚ADP核糖 聚合酶抑制物(PARPI)可增强程序性细胞免疫关卡阻断的效果 死亡蛋白1(PD-1)的阻断，可能通过增强肿瘤抗原性和/或调节肿瘤 免疫微环境。PARPI olaparib是FDA批准的白金维持疗法- 敏感种系BRCA突变(gBRCA-m)转移性PDAC。我们的小组也报告了非常高的反响 用铂治疗的gBRCA-m和gPALB2-m PDAC患者的比率-仅占PDAC的5%-7% 在第二阶段试验中。通过最近的回顾分析(Park等人，CCR 2020)，我们发现PDAC具有 核心同源重组(HR)基因(BRCA和PALB2)或非核心HR基因突变 更大的基因组不稳定性，对以DNA损伤反应(DDR)为靶标的药物(例如，铂或 PARPI)，具有生存益处，特别是当HR基因有双等位基因丢失时。令人惊讶的是，某些患者 在没有已知HR基因突变的情况下，对DDR靶向药物有异常反应，这表明可能存在 除了典型的HR基因突变之外，还有其他未知的生物学指标，可能与肿瘤有关 肿瘤微环境的遗传学和/或免疫特征。我们假设PARPI可以呈现PDAC 同源重组患者亚组的免疫原性和对PD-1阻断的敏感性 缺乏(HRD)超出传统定义的gBRCA-m。为了验证这一假设，我们设计了一项第二阶段试验 Pembrolizumab和olaparib(POLAR)在转移性PDAC合并HRD患者中的抗肿瘤活性 (典型的BRCA或其他HR基因)和具有特殊白金反应但没有HR基因的患者 突变。在这个孢子研究项目中，我们将使用从极地试验患者身上获得的系列生物检索剂 了解肿瘤遗传学及宿主和肿瘤免疫生态系统的特点 射线照相的极性反应和阻力。我们将结合使用复杂的基因组、单细胞 转录学和计算方法：(1)确定区分极地的突变特征 反应和功能后果，(2)表征细胞生物标记物，包括肿瘤亚群， 与极性反应相关的免疫浸润和肿瘤微环境特征，以及(3)调查 如果极地增强肿瘤的新抗原性。我们希望找出区分应答者的潜在因素 和无反应者，并提供了对PARPI反应和抵抗的生物机制的见解- 可指导未来治疗晚期癌症的精确免疫基因组学策略的免疫疗法组合 PDAC，并告知除HR基因突变患者外的患者选择相关治疗的机会。

PROJECT SUMMARY – RP2 Pancreatic ductal adenocarcinoma (PDAC) is characterized by low tumor mutational burden, impaired antigen- presentation, low levels of infiltrating cytotoxic CD8+ T cells, and a non-immunogenic tumor microenvironment – collective features which contribute to immunotherapy-resistance. There is a need to identify sensitive patient subgroups and effective immunotherapy combinations for PDAC. Recent studies suggest that poly-ADP ribose polymerase inhibitors (PARPi) can enhance the efficacy of immune checkpoint blockade with programmed cell death protein 1 (PD-1) blockade, potentially by enhancing tumor antigenicity and/or modulating the tumor immune microenvironment. The PARPi olaparib is FDA-approved as a maintenance therapy in platinum- sensitive germline BRCA-mutated (gBRCA-m) metastatic PDAC. Our group also reported a very high response rate for gBRCA-m and gPALB2-m PDAC patients—which represents only 5-7% of PDAC—treated with platinum in a phase 2 trial. Through a recent retrospective analysis (Park et al., CCR 2020), we identified that PDAC with mutations in core homologous recombination (HR) genes (BRCA and PALB2) or non-core HR genes have greater genomic instability and respond well to DNA damage response (DDR)-targeted agents (e.g., platinum or PARPi), with a survival benefit, particularly when the HR gene had biallelic loss. Surprisingly, certain patients without known HR gene mutations had exceptional responses to DDR-targeted agents, indicating there may be additional, unidentified biological indicators beyond canonical HR gene mutations, perhaps linked to tumor genetics and/or immune features of the tumor microenvironment. We hypothesize that PARPi can render PDAC immunogenic and sensitive to PD-1 blockade in a subgroup of patients with homologous recombination deficiency (HRD) beyond traditionally defined gBRCA-m. To test this hypothesis, we designed a phase 2 trial to evaluate antitumor activity of pembrolizumab and olaparib (POLAR) in metastatic PDAC patients with HRD (canonical BRCA or other HR genes) and in patients with exceptional platinum response but no HR gene mutations. In this SPORE Research Project, we will use serial biospecimens acquired from POLAR trial patients to understand the tumor genetics and features of the host and tumor immune ecosystem associated with radiographic POLAR responses and resistance. We will use a combination of sophisticated genomic, single-cell transcriptomic, and computational methods to: (1) determine mutational signatures that distinguish POLAR response and functional consequences, (2) characterize cellular biomarkers, including tumor sub-populations, immune infiltrates, and tumor microenvironment features associated with POLAR response, and (3) investigate if POLAR boosts tumor neoantigenicity. We expect to identify underlying factors that differentiate responders and non-responders and provide insights into the biologic mechanisms of response and resistance to a PARPi- immunotherapy combinations that can guide future precision immunogenomic strategies to treat advanced PDAC and inform opportunities for patient selection beyond those with HR gene mutations for relevant therapies.