Assessing the role of the DNA repair landscape in immune checkpoint therapy

评估 DNA 修复景观在免疫检查点治疗中的作用

• 批准号: 9317114
• 负责人: Joann B. Sweasy
• 金额: $ 21.86万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317114
• 关键词: Aftercare; Applications Grants; BRCA1 gene; BRCA2 gene; Binding; Bioinformatics; Biological; Biopsy; Biopsy Specimen; Blocking Antibodies; CD80 gene; Cancer Therapy Evaluation Program; Cell Line; Cells; Clinical Trials; Comprehensive Cancer Center; DNA Damage; DNA Repair; DNA Sequence; DNA Sequence Analysis; DNA sequencing; Fc domain; Generations; Immune; Immune response; Immune system; Immunotherapy; In Vitro; Infiltration; Lead; Link; Lymphocyte; MHC Class I Genes; Measures; Methods; Mismatch Repair; Mutagenesis; Mutation; National Cancer Institute; Nonhomologous DNA End Joining; Outcome; PDCD1LG1 gene; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Play; Poly(ADP-ribose) Polymerases; Production; Proteins; RNA Sequences; Research; Role; Sampling; Signal Transduction; Solid; Somatic Mutation; T-Lymphocyte; Testing; Therapeutic; Treatment outcome; Tumor Burden; Unresectable; Work; cancer cell; cancer therapy; cell killing; checkpoint therapy; clinical material; human monoclonal antibodies; immune checkpoint; immune checkpoint blockade; immunogenicity; inhibitor/antagonist; insight; killings; malignant breast neoplasm; mutant; neoplastic cell; palliative; prevent; programs; repaired; response; success; transcriptome sequencing; tumor; tumor microenvironment

Project Summary/Abstract: The success achieved with immunostimulatory therapies blocking the PD-1 axis has uncovered the power of modulating immune inhibitory signals in the tumor microenvironment. However, these therapies benefit only a fraction of patients. One of the major current challenges is the identification of mechanisms to treat the majority of patients with the so-called "non-inflammed" tumors lacking marked lymphocyte infiltration and PD-L1 expression. The immunogenicity of tumors is prominently influenced by the production of neoantigens. Neoantigens arise from somatic mutations and have the potential to be recognized as “non-self” by the immune system, leading to tumor cell killing upon immune reinvigoration using checkpoint blockade. Therefore, tumors with high mutation burden (a hypermutator phenotype) are more likely to harbor neoepitopes and to respond to immunotherapies. The Yale Comprehensive Cancer Center (YCCC) Early Therapeutics Program has recently received approval from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) to conduct a Phase I clinical trial of the poly-ADP-ribose polymerase (PARP) inhibitor ABT- 888 (veliparib), in combination MPDL3280A, which is a human monoclonal antibody containing a modified Fc domain that binds directly to PD-L1, thereby preventing binding to PD-1 and CD80 in patients with advanced (metastatic or unresectable) solid BRCA1 or BRCA2 mutant tumors for which standard curative or palliative measures do not exist or are no longer effective. The scientific premise of this trial is that treatment of BRCA1/2 defective tumors with veliparib will result in increased mutational load, enabling the tumor to respond to anti-PD-L1. The broad, long-term objectives of our proposed research are to determine if treatment with PARP inhibitors in combination with the DNA repair landscape increases the mutational load of cancer cells and to elucidate the underlying mechanism of mutagenesis by PARP inhibitors. Additional long-term objectives include increasing our understanding of the relationship between mutational signatures, DNA repair, and cancer therapies to treatment outcomes. The specific aims of this application are (1) To determine if treatment of BRCA 1/2 defective cells with PARP inhibitors leads to increased mutational load; and (2) To determine if treatment of patients harboring BRCA1/2 deficient breast cancer with veliparib results in an increased mutational load within their tumors. We will characterize in vitro cellular mutational responses of BRCA mutant cells to treatment with PARP inhibitors, focusing on mutational load. We will also determine whether treatment of tumors with veliparib as part of the clinical trial increases mutational load.Our studies are significant because they have the potential to provide important mechanistic insights regarding the relationship between PARP inhibitor treatment, the DNA repair landscape, and mutational load as they relate to outcomes.

项目概要/摘要： 阻断PD-1轴的免疫刺激疗法所取得的成功揭示了免疫调节的力量。 调节肿瘤微环境中的免疫抑制信号。然而，这些疗法仅对 部分患者。目前的主要挑战之一是确定治疗大多数人的机制 缺乏显著淋巴细胞浸润和PD-L1的所谓“非炎症”肿瘤患者 表情肿瘤的免疫原性受新抗原产生的显著影响。 新抗原由体细胞突变产生，并且具有被免疫细胞识别为“非自身”的潜力。 免疫系统，导致在使用检查点阻断的免疫恢复活力后杀死肿瘤细胞。 因此，具有高突变负荷（超变子表型）的肿瘤更可能具有新表位 并对免疫疗法产生反应。耶鲁综合癌症中心（YCCC）早期治疗 该计划最近获得了国家癌症研究所（NCI）癌症治疗评估的批准 计划（CTEP）进行多聚ADP-核糖聚合酶（PARP）抑制剂ABT的I期临床试验- 888（维利帕尼）与MPDL 3280 A的组合，MPDL 3280 A是含有修饰的Fc 直接结合PD-L1的结构域，从而阻止晚期乳腺癌患者与PD-1和CD 80的结合。 （转移性或不可切除的）实体BRCA 1或BRCA 2突变肿瘤，其标准治愈或姑息治疗 措施不存在或不再有效。这项试验的科学前提是， 使用veliparib的BRCA 1/2缺陷型肿瘤将导致突变负荷增加，使肿瘤能够响应 抗PD-L1抗体 我们所提议的研究的广泛的长期目标是确定PARP抑制剂的治疗是否能在 结合DNA修复景观增加了癌细胞的突变负荷，并阐明了 PARP抑制剂致突变的潜在机制。其他长期目标包括： 我们对突变特征、DNA修复和癌症治疗之间关系的理解， 治疗结果。本申请的具体目的是（1）确定BRCA 1/2的治疗是否 具有PARP抑制剂的缺陷细胞导致突变负荷增加;和（2）为了确定 用维利帕尼治疗患有BRCA 1/2缺陷型乳腺癌的患者导致增加的 肿瘤内的突变负荷我们将描述BRCA的体外细胞突变反应 突变细胞与用PARP抑制剂治疗的关系，重点是突变负荷。我们还将确定 作为临床试验的一部分，用维利帕尼治疗肿瘤增加了突变负荷。 意义重大，因为它们有可能提供有关关系的重要机制见解 PARP抑制剂治疗，DNA修复景观和突变负荷之间的关系，因为它们与结果有关。