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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要：阻断 PD-1 轴的免疫刺激疗法取得的成功揭示了然而，调节肿瘤微环境中的免疫抑制信号，这些疗法只能带来一定的益处。当前的主要挑战之一是确定治疗大多数患者的机制。患有缺乏明显淋巴细胞浸润和 PD-L1 的所谓“非炎症”肿瘤的患者肿瘤的免疫原性主要受新抗原产生的影响。新抗原源自体细胞突变，有可能被识别为“非自身” 免疫系统，通过使用检查点封锁进行免疫重振，导致肿瘤细胞被杀死。因此，具有高突变负荷（超突变表型）的肿瘤更有可能含有新表位以及对免疫疗法的反应。耶鲁大学综合癌症中心 (YCCC) 早期治疗。该项目最近获得了美国国家癌症研究所 (NCI) 癌症治疗评估的批准计划 (CTEP) 进行聚 ADP 核糖聚合酶 (PARP) 抑制剂 ABT 的 I 期临床试验 888（veliparib），与 MPDL3280A 组合，这是一种含有修饰 Fc 的人单克隆抗体直接与 PD-L1 结合的结构域，从而防止晚期患者与 PD-1 和 CD80 结合（转移性或不可切除的）实体 BRCA1 或 BRCA2 突变肿瘤，其标准治疗或姑息治疗该试验的科学前提是治疗措施不存在或不再有效。 BRCA1/2 缺陷肿瘤使用 veliparib 将导致突变负荷增加，使肿瘤能够做出反应抗 PD-L1。我们提出的研究的广泛、长期目标是确定 PARP 抑制剂治疗是否能与 DNA 修复景观相结合会增加癌细胞的突变负荷并阐明 PARP 抑制剂诱变的潜在机制还包括增加其他长期目标。我们对突变特征、DNA 修复和癌症治疗之间关系的理解本申请的具体目的是 (1) 确定 BRCA 1/2 的治疗是否有效。使用 PARP 抑制剂的缺陷细胞会导致突变负荷增加；以及 (2) 确定是否使用 veliparib 治疗 BRCA1/2 缺陷型乳腺癌患者会导致我们将描述 BRCA 的体外细胞突变反应。我们还将确定突变细胞是否接受 PARP 抑制剂治疗，重点关注突变负荷。作为临床试验的一部分，使用 veliparib 治疗肿瘤会增加突变负荷。我们的研究是重要的是因为它们有潜力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，因为它们与结果相关。