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

随着免疫的发展，肿瘤免疫疗法用于实体瘤已大大扩展检查点抑制剂，尤其是在许多癌症中批准的PD-1/PD-L1抗体。但是，甚至在黑色素瘤中，单药PD1抑制的响应率最高（40-45％），大多数患者不会反应，最终会屈服于疾病。识别内在和在肿瘤免疫学和也许是医学肿瘤学。在PD-1的情况下，肿瘤如何抵抗免疫系统的阐明抑制作用以及针对这些抵抗机制的战略的发展是改变癌症患者的治疗方式。我们最近发现，约有30％的黑色素瘤患者具有特异性的特异性 β-2-微球蛋白（B2M）基因中的突变，这对于向T细胞呈现抗原至关重要直接肿瘤识别和杀戮。在两个独立队列中，有105例和38例黑色素瘤患者分别使用抗CTLA4和抗PD1，我们发现B2M的缺失富集在非反应器中（30％）与响应者（10％），并且与较低的总生存率显着相关 - 与仅在非反应者中发现的B2M的纯合损失。这些结果暗示B2M损失是基本的对检查点抑制剂的内在和获得性的机制。令人惊讶的结果是单个B2M缺失的某些肿瘤几乎没有或根本没有表达肿瘤细胞中的B2M蛋白由IHC。此外，我们假设并发现NK细胞在控制B2M缺陷的生长中起作用黑色素瘤小鼠模型中的肿瘤缺乏B2M。在此提案中，我们将分析进化黑色素瘤和NSCLC患者接受抗PD1治疗的B2M突变的对检查点阻滞疗法的电阻的实时跟踪。此外，我们将测试 B2M的表观遗传沉默，以解释其在缺少一个基因副本的肿瘤中的表达丧失，并且将尝试通过调节表观遗传调节剂来恢复B2M表达。因为中心目标是克服抗性，我们将激活自然杀手（NK）细胞，以试图杀死小鼠缺乏B2M的细胞黑色素瘤模型。在所有研究中，我们都将使用包括CTEP的代理的组合。经过我们的研究将有助于提供解决这种基本阻力的基本形式对检查点封锁的途径