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

胰腺癌中的同源重组缺陷及其他：从免疫和基因组角度评估派姆单抗和奥拉帕尼 (POLAR) 反应的调节因子

• 批准号: 10708749
• 负责人: Eileen Mary O'Reilly
• 金额: $ 57.5万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708749
• 关键词: Aftercare; Allelic Imbalance; Antigen Presentation; Biological; Biological Assay; Biological Markers; CCR; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Death; Cells; Cessation of life; Characteristics; Combination immunotherapy; Complex; Computing Methodologies; Cytoplasm; DNA; DNA Damage; Data; Dendritic Cells; Disease; Ecosystem; FDA approved; Future; Gene Mutation; Genes; Genetic; Genomic Instability; Genomics; Goals; Immune; Immune response; Immunogenetics; Immunogenomics; Immunologics; Immunotherapy; Impairment; Infiltration; Link; Loss of Heterozygosity; Maintenance; Maintenance Therapy; Malignant neoplasm of pancreas; Measurement; Memorial Sloan-Kettering Cancer Center; Mus; Mutate; Mutation; Organoids; PALB2 gene; Paclitaxel; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient Selection; Patients; Phenotype; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Production; Rejuvenation; Reporting; Research Project Grants; Resistance; Resolution; Role; Sampling; Stimulator of Interferon Genes; Stress; Subgroup; T-Lymphocyte; Testing; Therapeutic; Tissue imaging; cancer cell; cohort; cytokine; cytotoxic CD8 T cells; cytotoxicity; design; gemcitabine; genome sequencing; genomic signature; genotoxicity; homologous recombination; immune cell infiltrate; immune checkpoint blockade; immunogenic; immunogenicity; improved; improved outcome; inclusion criteria; insight; morphogens; neoantigens; neoplastic cell; novel; novel strategies; pancreatic cancer patients; patient subsets; pembrolizumab; peripheral blood; phase II trial; programmed cell death ligand 1; programmed cell death protein 1; prospective; radiological imaging; recruit; repaired; responders and non-responders; response; targeted agent; transcriptome; transcriptomics; treatment response; tumor; tumor microenvironment; tumor-immune system interactions; whole genome

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.

项目摘要 – RP2 胰腺导管腺癌 (PDAC) 的特点是肿瘤突变负荷低、抗原受损 表现、低水平的浸润性细胞毒性 CD8+ T 细胞和非免疫原性肿瘤微环境 – 导致免疫治疗耐药的集体特征需要识别敏感患者。 PDAC 的亚组和有效的免疫治疗组合最近的研究表明聚 ADP 核糖。 聚合酶抑制剂（PARPi）可以增强程序化细胞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/或调节肿瘤来实现 PARPi olaparib 已获得 FDA 批准作为铂类药物的维持疗法。 敏感种系 BRCA 突变 (gBRCA-m) 转移性 PDAC 的反应也非常高。 gBRCA-m 和 gPALB2-m PDAC 患者（仅占 PDAC 的 5-7%）接受铂类治疗的比例 在一项 2 期试验中（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 基因的突变 更大的基因组不稳定性并对 DNA 损伤反应 (DDR) 靶向药物（例如铂或 PARPi)，具有生存获益，特别是当 HR 基因具有双等位基因丢失时，某些患者。 没有已知 HR 基因突变的人对 DDR 靶向药物有异常反应，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指标，可能与肿瘤有关 我们发现 PARPi 可以渲染 PDAC。 同源重组患者亚组中具有免疫原性且对 PD-1 阻断敏感 缺陷（HRD）超出了传统定义的 gBRCA-m 为了检验这一假设，我们设计了一项 2 期试验来检验这一假设。 评估派姆单抗和奥拉帕尼 (POLAR) 在患有 HRD 的转移性 PDAC 患者中的抗肿瘤活性 （典型的 BRCA 或其他 HR 基因）以及对铂类反应异常但无 HR 基因的患者 在这个 SPORE 研究项目中，我们将使用从 POLAR 试验患者身上获得的系列生物样本。 了解肿瘤遗传学、宿主特征以及与之相关的肿瘤免疫生态系统 我们将使用复杂的基因组、单细胞的组合来进行放射照相 POLAR 反应和抵抗。 转录组学和计算方法：(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 能够增强肿瘤新抗原性，我们希望能够确定区分应答者的潜在因素。 和无反应者，并提供对 PARPi-反应和抵抗的生物学机制的见解 免疫治疗组合可以指导未来治疗晚期晚期的精准免疫基因组策略 PDAC 并为选择具有 HR 基因突变的患者以外的患者提供相关治疗的机会。