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: 10333516
• 负责人: Eileen Mary O'Reilly
• 金额: $ 55.52万
• 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/10333516
• 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; 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; Ligands; 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) Polymerases; Pre-Clinical Model; Production; Proteins; Reporting; Research Project Grants; Resistance; Resolution; Role; Sampling; Stimulator of Interferon Genes; Stress; Subgroup; T-Lymphocyte; Testing; Therapeutic; Tissue imaging; Tumor-infiltrating immune cells; base; cancer cell; cohort; cytokine; cytotoxic CD8 T cells; cytotoxicity; design; gemcitabine; genome sequencing; genomic signature; genotoxicity; homologous recombination; immune checkpoint blockade; immunogenic; immunogenicity; improved; improved outcome; inclusion criteria; inhibitor; insight; morphogens; neoantigens; neoplastic cell; novel; novel strategies; pancreatic cancer patients; patient subsets; pembrolizumab; peripheral blood; phase II trial; 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）的特征是低肿瘤突变伯嫩，抗原受损 表现，低水平的细胞毒性CD8+ T细胞和非免疫原性肿瘤微环境 - 有助于免疫疗法的集体特征。有必要识别敏感的患者 PDAC的亚组和有效的免疫疗法组合。最近的研究表明，聚ADP结合 聚合酶抑制剂（PARPI）可以通过编程细胞提高免疫切解点的效率 死亡蛋白1（PD-1）阻滞，可能通过增强肿瘤抗原性和/或调节肿瘤 免疫微环境。 parpi olaparib被FDA批准为铂 - 敏感的种系BRCA-氧化（GBRCA-M）转移性PDAC。我们的小组也报告了很高的反应 用铂对GBRCA-M和GPALB2-M PDAC患者（仅占PDAC的5-7％）的速率 在第二阶段试验中。通过最近的回顾性分析（Park等，CCR 2020），我们确定了PDAC与 核心同源重组（HR）基因（BRCA和PALB2）或非核HR基因的突变具有 更大的基因组不稳定性，对DNA损伤反应（DDR）靶向剂的反应良好（例如铂或 Parpi），具有生存益处，尤其是当HR基因造成双重损失时。令人惊讶的是，某些患者 没有已知的HR基因突变对DDR靶向剂的反应异常，表明可能存在 除规范HR基因突变以外的其他未识别的生物学指标，也许与肿瘤有关 肿瘤微环境的遗传学和/或免疫特征。我们假设PARPI可以渲染PDAC 在同源重组的患者亚组中，免疫原性和对PD-1封锁敏感 传统上定义的GBRCA-M以外的缺陷（HRD）。为了检验这一假设，我们设计了一个2期试验 评估pembrolizumab和Olaparib（Polar）在HRD转移性PDAC患者中的抗肿瘤活性 （Canonical BRCA或其他HR基因）以及具有特殊铂反应但没有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中获得的串行生物测量 了解宿主和肿瘤免疫生态系统的肿瘤遗传学和特征 影像学极性响应和电阻。我们将结合复杂的基因组单细胞 转录组和计算方法：（1）确定区分极地的突变特征 反应和功能后果，（2）表征了细胞生物标志物，包括肿瘤亚群， 免疫浸润和与极性反应相关的肿瘤微环境特征，（3）研究 如果极性增强肿瘤新抗原性。我们希望确定与响应者区分的潜在因素 和无反应者，并提供对反应和抗性的生物学机制的见解 免疫疗法组合可以指导未来的精度免疫基因组策略来治疗先进的 PDAC和为患者选择的机会，超出患者的HR基因突变以进行相关疗法。