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.

项目总结- rp2