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

项目总结-RP 2 胰腺导管腺癌（PDAC）的特点是肿瘤突变负荷低，抗原- - 低水平的浸润性细胞毒性CD 8 + T细胞和非免疫原性肿瘤微环境- 导致免疫疗法抗性的集体特征。需要识别敏感患者 亚组和有效的PDAC免疫治疗组合。最近的研究表明，聚ADP核糖 聚合酶抑制剂（PARPi）可以增强免疫检查点阻断的功效， 死亡蛋白1（PD-1）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批准的铂类药物的维持治疗， 敏感生殖系BRCA突变（gBRCA-m）转移性PDAC。我们的小组也报告了非常高的反应 gBRCA-m和gPALB 2-m PDAC患者的发生率仅占接受铂类治疗的PDAC患者的5-7% 进行第二阶段试验通过最近的回顾性分析（Park等人，CCR 2020），我们确定PDAC与 核心同源重组（HR）基因（BRCA和PALB 2）或非核心HR基因中的突变具有 更大的基因组不稳定性并且对DNA损伤反应（DDR）靶向剂（例如，铂或 PARPi），具有存活益处，特别是当HR基因具有双等位基因丢失时。令人惊讶的是，某些患者 没有已知的HR基因突变的患者对DDR靶向药物的反应异常，表明可能存在 除了典型的HR基因突变之外，还有其他未识别的生物学指标，可能与肿瘤相关 肿瘤微环境的遗传学和/或免疫特征。我们假设PARPi可以使PDAC 同源重组患者亚组中的免疫原性和对PD-1阻断敏感性 GBRCA-M缺乏症（HRD）。为了验证这一假设，我们设计了一项2期试验， 评价派姆单抗和奥拉帕尼（POLAR）在转移性PDAC伴HRD患者中的抗肿瘤活性 （典型BRCA或其他HR基因）和具有异常铂类缓解但无HR基因的患者 突变在本SPORE研究项目中，我们将使用从POLAR试验患者中获得的系列生物标本 了解肿瘤遗传学和与肿瘤相关的宿主和肿瘤免疫生态系统的特征， 放射学极反应和电阻。我们将使用复杂的基因组，单细胞 转录组学和计算方法，以：（1）确定区分POLAR的突变特征 反应和功能后果，（2）表征细胞生物标志物，包括肿瘤亚群， 免疫浸润和与POLAR反应相关的肿瘤微环境特征，以及（3）研究 如果POLAR增强肿瘤新抗原性。我们希望找出区分反应者的潜在因素 和无应答者，并提供对PARPi的应答和抗性的生物学机制的见解- 免疫治疗组合，可以指导未来的精确免疫基因组学策略，以治疗晚期 PDAC并为HR基因突变患者以外的患者选择相关治疗提供机会。

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.