Project-003

项目-003

基本信息

批准号：
10005207
负责人：
Ryan Bruce Corcoran
金额：
$ 55.96万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2017-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005207
关键词：
Address Aftercare Alleles Antibodies Antigens Bladder Urothelium Blood specimen CRISPR/Cas technology Cancer Patient Cancer Therapy Evaluation Program Cell Therapy Chromatin DNA Development Disease Drug resistance Engineering Epigenetic Process Evolution FDA approved Foundations Genes Genetic Goals Growth Head and Neck Squamous Cell Carcinoma Hodgkin Disease Homozygote Hypermethylation Immune checkpoint inhibitor Immune system Immunotherapy Ligands Link Loss of Heterozygosity Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Medical Oncology Methods Modification Monitor Monoclonal Antibodies Mutation Natural Killer Cells Nivolumab Non-Small-Cell Lung Carcinoma PD-1 inhibitors PD-1/PD-L1 PDL1 inhibitors Patients Play Pre-Clinical Model Proteins Recording of previous events Refractory Renal Cell Carcinoma Research Resistance Role Sampling Site Solid Neoplasm Stress T-Lymphocyte Testing Time anti-CTLA4 anti-PD-1 anti-PD-1/PD-L1 anti-PD1 antibodies anti-PD1 therapy beta-2 Microglobulin cell killing checkpoint therapy cohort immune checkpoint blockade melanoma mouse model neoplasm immunotherapy neoplastic cell programmed cell death protein 1 receptor resistance mechanism response restoration success targeted treatment translational approach tumor tumor immunology

项目摘要

The use of tumor immunotherapy for solid tumors has expanded dramatically with the development of immune checkpoint inhibitors, especially antibodies to PD-1/PD-L1 that are approved across many cancers. Yet, even in melanoma, where single-agent PD1 inhibition has the greatest response rates (40-45%), the majority of patients will not respond and ultimately succumb to disease. Identification of mechanisms of intrinsic and acquired resistance to anti-PD1 therapy remains the greatest unmet need in the field of tumor immunology and perhaps medical oncology. The elucidation of how tumors resist the immune system in the setting of PD-1 inhibition, and the development of strategies to target these mechanisms of resistance stands to change the way cancer patients are treated. We have recently discovered that ~30% of melanoma patients harbor tumorspecific mutations in the beta-2-microglobulin (B2M) gene, which is essential for presenting antigens to T cells for direct tumor recognition and killing. In two independent cohorts of 105 and 38 melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we found deletions of B2M to be 3-fold enriched in nonresponders (30%) vs. responders (10%) and significantly associated with lower overall survival -- with homozygote loss of B2M found only in non-responders. These results imply that B2M loss is a fundamental mechanism of intrinsic and acquired resistance to checkpoint inhibitors. A surprising result was that even in some of the tumors with single B2M deletions there was little or no expression of the B2M protein in tumor cells by IHC. In addition, we hypothesized and found that NK cells play a role in controlling growth of B2M-deficient tumors in a mouse model of melanoma that is deficient in B2M. In this proposal, we will analyze the evolution of B2M mutations in melanoma and NSCLC patients receiving anti-PD1 therapy and thus create a method for real time tracking of resistance to checkpoint blockade therapies. Furthermore, we will test the role of epigenetic silencing of B2M to explain the loss of its expression in tumors missing one copy of the gene, and will attempt to restore B2M expression by modulating epigenetic regulators. Since a central goal is to overcome resistance, we will activate natural killer (NK) cells in an attempt to kill cells lacking B2M in mouse models of melanoma. In all the studies, we will use a combination of agents that include ones from CTEP. By monitoring, explaining and hopefully overcoming resistance to checkpoint therapy by B2M loss, our research will help provide a path to address this fundamental form of resistance to checkpoint blockade

随着免疫学的发展，肿瘤免疫疗法在实体瘤中的应用急剧扩大检查点抑制剂，尤其是已批准用于多种癌症的 PD-1/PD-L1 抗体。然而，即使在黑色素瘤中，单药 PD1 抑制的缓解率最高 (40-45%)，大多数患者不会做出反应并最终死于疾病。识别内在机制和对抗 PD1 治疗的获得性耐药仍然是肿瘤免疫学领域最大的未满足需求也许是肿瘤内科。阐明肿瘤在 PD-1 背景下如何抵抗免疫系统抑制，以及针对这些耐药机制制定策略将改变治疗癌症患者的方式。我们最近发现约 30% 的黑色素瘤患者具有肿瘤特异性 β-2-微球蛋白 (B2M) 基因突变，该基因对于向 T 细胞呈递抗原至关重要用于直接识别和杀死肿瘤。在两个独立队列中，分别有 105 名和 38 名接受治疗的黑色素瘤患者分别使用抗 CTLA4 和抗 PD1，我们发现无应答者中 B2M 的缺失丰富了 3 倍 (30%) 与应答者 (10%) 相比，并且与较低的总体生存率显着相关—— 仅在无反应者中发现 B2M 纯合子缺失。这些结果表明 B2M 损失是一个根本性的损失检查点抑制剂的内在和获得性耐药机制。令人惊讶的结果是，即使在一些具有单个 B2M 缺失的肿瘤，肿瘤细胞中很少或没有 B2M 蛋白表达通过免疫组化。此外，我们假设并发现 NK 细胞在控制 B2M 缺陷的细胞生长中发挥作用。缺乏 B2M 的黑色素瘤小鼠模型中的肿瘤。在这个提案中，我们将分析演变接受抗 PD1 治疗的黑色素瘤和 NSCLC 患者中的 B2M 突变，从而创建了一种方法实时跟踪检查点封锁疗法的耐药性。此外，我们将测试以下角色： B2M 的表观遗传沉默可解释其在缺少该基因副本的肿瘤中表达的丧失，以及将尝试通过调节表观遗传调节因子来恢复 B2M 表达。由于中心目标是克服抵抗力，我们将激活自然杀伤（NK）细胞，试图杀死小鼠体内缺乏 B2M 的细胞黑色素瘤模型。在所有研究中，我们将使用包括 CTEP 药物在内的药物组合。经过我们的研究监测、解释并希望克服 B2M 损失对检查点治疗的抵抗将有助于提供解决这种抵抗检查站封锁的基本形式的途径