Project-003

项目-003

• 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
• 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

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

随着免疫治疗技术的发展，肿瘤免疫治疗在实体瘤中的应用已经急剧扩大。 检查点抑制剂，特别是针对PD-1/PD-L1的抗体，这些抗体已被批准用于许多癌症。但即使 在黑色素瘤中，单药PD 1抑制具有最大的缓解率（40-45%），大多数 患者将不会有反应并最终死于疾病。确定内在和 对抗PD 1治疗的获得性抗性仍然是肿瘤免疫学领域中最大的未满足的需求， 也许是肿瘤内科阐明肿瘤如何在PD-1背景下抵抗免疫系统 抑制，以及针对这些耐药机制的策略的发展，将改变 癌症患者的治疗方式。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（B2 M）基因突变，该基因是将抗原呈递给T细胞所必需的 直接识别和杀死肿瘤。在两个独立的队列中，105例和38例黑色素瘤患者接受治疗， 分别使用抗CTLA 4和抗PD 1，我们发现B2 M缺失在无应答者中富集3倍。 (30%）与应答者（10%）相比，与较低的总生存率显著相关- B2 M纯合子缺失仅见于无应答者。这些结果表明，B2 M损失是一个基本的 对检查点抑制剂的内在和获得性抗性的机制。一个令人惊讶的结果是，即使在 在一些具有单一B2 M缺失的肿瘤中，肿瘤细胞中很少或没有B2 M蛋白表达 通过IHC。此外，我们假设并发现NK细胞在控制B2 M缺陷的生长中起作用。 在缺乏B2 M的黑色素瘤小鼠模型中的肿瘤。在本提案中，我们将分析 在接受抗PD 1治疗的黑色素瘤和NSCLC患者中的B2 M突变，从而创建了一种方法， 真实的时间追踪对检查点阻断疗法的抗性。此外，我们还将测试 B2 M的表观遗传沉默，以解释其在缺失一个基因拷贝的肿瘤中表达的丧失，以及 将试图通过调节表观遗传调节因子来恢复B2 M的表达。因为中心目标是 为了克服耐药性，我们将激活自然杀伤（NK）细胞，试图杀死小鼠中缺乏B2 M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。通过 监测，解释并希望克服B2 M损失对检查点治疗的抵抗，我们的研究 将有助于提供一条解决这种抵制检查站封锁的基本形式的途径