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

项目摘要/摘要： 免疫刺激疗法阻断PD-1轴所取得的成功揭示了 调节肿瘤微环境中的免疫抑制信号。然而，这些疗法只对 病人的一部分。目前的主要挑战之一是确定治疗大多数人的机制。 在缺乏明显淋巴细胞浸润和PD-L1的所谓“非炎症性”肿瘤患者中 表情。肿瘤的免疫原性受新抗原产生的显著影响。 新抗原产生于体细胞突变，有可能被 免疫系统，导致肿瘤细胞在使用检查点封锁的免疫恢复时被杀死。 因此，突变负荷高的肿瘤(一种高突变表型)更有可能含有新的表位。 以及对免疫疗法的反应。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ADP核糖聚合酶(PARP)抑制剂ABT-1的I期临床试验 888(Veliparib)，结合MPDL3280A，这是一种含有修饰的Fc的人源性单抗 直接与PD-L1结合的结构域，从而阻止晚期患者与PD-1和CD80的结合 (转移性的或不可切除的)标准治愈或姑息性治疗的实体BRCA1或BRCA2突变肿瘤 措施不存在或不再有效。这项试验的科学前提是治疗 BRCA1/2缺陷肿瘤与维拉帕利布联合应用将导致突变负荷增加，从而使肿瘤有反应 为抗PD-L1。 我们提议的研究的广泛、长期目标是确定是否使用PARP抑制剂治疗 结合DNA修复图景增加癌细胞的突变负荷，并阐明 PARP抑制剂致突变的潜在机制。其他长期目标包括增加 我们对突变信号、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BRCA1/2的治疗 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 维拉帕利治疗BRCA1/2缺陷型乳腺癌患者的疗效增加 他们肿瘤内的突变负荷。我们将研究BRCA的体外细胞突变反应 突变细胞用PARP抑制剂处理，重点关注突变负荷。我们还将确定是否 作为临床试验的一部分，用维利帕利治疗肿瘤增加了突变负荷。我们的研究是 意义重大，因为它们有可能提供关于关系的重要机械性见解 PARP抑制剂治疗、DNA修复情况和突变负荷之间的关系，因为它们与结果相关。

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.