Immune Therapy for Brain Metastasis

脑转移的免疫治疗

• 批准号: 10586310
• 负责人: Lucia Beatrice Jilaveanu
• 金额: $ 58.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-18 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586310
• 关键词: Address; Adhesions; Animal Model; Antibodies; Back; Blood - brain barrier anatomy; Blood Vessels; Blood specimen; Brain; CTLA4 gene; Cell physiology; Cells; Central Nervous System; Cephalic; Cerebrum; Characteristics; Clinic; Clinical Research; Clinical Trials; Coupled; Disease; Drug Combinations; Drug Targeting; Edema; Endothelial Cells; Endothelium; Enrollment; Evaluation; Exclusion; Future; Gene Expression; Human; Immune; Immunity; Immunocompetent; Immunophenotyping; Immunotherapy; In Situ; Incidence; Infrastructure; Institution; KDR gene; Lymphocyte; Macrophage; Maintenance; Malignant neoplasm of lung; Metastatic Melanoma; Metastatic malignant neoplasm to brain; Methods; Microglia; Modeling; Molecular; Molecular Analysis; Mus; Neoplasm Metastasis; Neurologic Symptoms; Nivolumab; Operative Surgical Procedures; PD-1 blockade; PD-1 inhibitors; PD-1 pathway; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Positioning Attribute; Pre-Clinical Model; Property; Proteomics; Radiation; Radiation necrosis; Regimen; Research Personnel; Resistance; Resources; Sampling; Series; Signal Transduction; Solid Neoplasm; Specific qualifier value; Specimen; System; Systemic Therapy; T-Lymphocyte; Testing; Therapeutic Effect; Tight Junctions; Toxic effect; Tumor Angiogenesis; Tumor Promotion; Validation; Vascular Endothelial Growth Factors; Vegf inhibition; anti-PD-1; bench to bedside; bevacizumab; blood-brain barrier function; cell motility; clinical biomarkers; clinically relevant; clinically significant; cohort; design; early phase clinical trial; expectation; experimental study; improved; improved outcome; in vitro Model; inhibitor; ipilimumab; melanoma; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; participant enrollment; pembrolizumab; pharmacologic; phase II trial; pre-clinical; preclinical study; predicting response; programmed cell death protein 1; protein expression; responders and non-responders; response; success; targeted treatment; trafficking; transcriptomics; treatment response; tumor; tumor growth; tumor microenvironment

Melanoma is the solid tumor that metastasizes most frequently to the central nervous system (CNS). While major progress has been made in treating metastatic melanoma, advances in treating melanoma brain metastases (MBM) lag behind. This is due to near-universal exclusion of patients with untreated brain metastases from clinical trials, and only once a regimen is well established in extra-cerebral disease, is it studied in MBM patients. Moreover, pre-clinical studies of MBM have been hampered by a paucity of pre-clinical models and limited access to CNS specimens for analysis, as these patients are typically treated with radiation rather than surgery. We therefore developed infrastructure and resources which we propose to employ to better understand molecular, vascular and cellular underpinnings of brain metastasis. We started by studying activity of the PD-1 inhibitor pembrolizumab (pembro) in patients with untreated MBM on a phase II trial. Although the response rate was modest (26%), the two-year survival was 48%, and the incidence of radiation necrosis and/or neurologic symptoms related to edema was high. We therefore initiated a sequel trial of pembro plus bevacizumab in MBM; the response rate in the initial cohort was 55%, exceeding our expectations and warranting further evaluation. This response rate is similar to that seen with nivolumab and ipilimumab in MBM, but the toxicity profile is far superior with only minimal added toxicity from the bevacizumab. We propose to further study co-targeting the PD-1 and VEGF/VEGF-R pathways in MBM, and to determine the mechanism by which these pathways crosstalk to promote tumor growth within the brain. We will build on our success with anti-VEGF in a new trial involving pembro and a VEGF-R inhibitor (VEGFRi), lenvatinib. In parallel to our clinical research endeavors we developed novel immune-competent models of MBM that are modestly responsive to anti-PD-1, and developed in vitro models of the blood-brain-barrier to study effects of these drugs on vascular leak. These pre-clinical models will be used to test the hypothesis that the addition of VEGF pathway blockade to anti-PD-1 enhances T cell migration and function and directly decreases tight junction leakiness. We also hypothesize that anti-VEGF has different effects to VEGFRis. We will dissect the mechanism by which this occurs using our novel immune competent murine models and single cell transcriptomic and in situ proteomic strategies (Aim 1) and determine whether VEGF inhibiting drugs should be replaced with VEGF-Ris to treat MBM. We are expanding our ongoing clinical trial of pembro and bevacizumab by enrolling a second cohort of melanoma patients to verify our initial result. We have initiated a new trial of pembro and lenvatinib. We will analyze tumors and blood samples from patients on these trials in an attempt to validate mechanistic results from the murine experiments and identify predictors of response or resistance to this regimen (Aim 2). This proposal is responsive to PAR 21-033, which involves early phase clinical trials and biomarker and mechanistic studies. These studies can have important implications for other disease as well, such as lung cancer, which similarly metastasizes frequently to the CNS.

黑色素瘤是最常转移到中枢神经系统(CNS)的实体瘤。虽然是主要的 转移性黑色素瘤的治疗进展，黑色素瘤脑转移的治疗进展 (MBM)落后。这是由于几乎普遍排除了未经治疗的脑转移瘤患者。 临床试验，只有当一种疗法在脑外疾病中得到很好的确立后，才会在MBM患者中进行研究。 此外，MBM的临床前研究一直受到临床前模型的缺乏和有限的阻碍。 获取中枢神经系统标本进行分析，因为这些患者通常接受放射治疗，而不是手术。 因此，我们开发了基础设施和资源，我们建议使用这些基础设施和资源来更好地了解 脑转移的分子、血管和细胞基础。我们从研究PD-1的活性开始 抑制剂pembrolizumab(Pbro)在II期试验中用于未经治疗的MBM患者。尽管响应率 不严重(26%)，两年存活率为48%，放射性坏死和/或神经病变的发生率 与浮肿相关的症状较多。因此，我们在MBM中启动了Pbro加贝伐单抗的续期试验； 最初队列中的应答率为55%，超出了我们的预期，需要进一步评估。 在MBM中，这种有效率与nivolumab和ipilimumab相似，但毒性分布相去甚远。 贝伐单抗的附加毒性很小，效果更好。我们建议进一步研究联合目标 PD-1和血管内皮细胞生长因子/血管内皮细胞生长因子受体信号转导通路在MBM中的表达 相声可以促进脑部肿瘤的生长。我们将在抗血管内皮生长因子的新试验中取得成功的基础上再接再厉 涉及Pbro和血管内皮生长因子受体抑制剂(VEGFRi)lenvatinib。在我们的临床研究工作的同时，我们 开发了对抗PD-1有适度反应的新型免疫活性MBM模型，并开发了 建立血脑屏障的体外模型，研究这些药物对血管渗漏的影响。这些临床前研究 模型将被用来检验这样的假设，即在抗PD-1的基础上加入血管内皮生长因子途径阻断会增强T细胞 细胞迁移和功能，并直接减少紧密连接泄漏。我们还假设抗血管内皮生长因子 对血管内皮生长因子有不同的影响。我们将使用我们的新型免疫系统剖析这种情况发生的机制。 有能力的小鼠模型以及单细胞转录和原位蛋白质组策略(目标1)并确定 是否应用血管内皮生长因子抑制药替代血管内皮生长因子抑制药治疗MBM。我们正在扩大我们正在进行的 通过招募第二个黑色素瘤患者队列来验证我们最初的研究结果，Pbro和贝伐单抗的临床试验 结果。我们已经启动了Pbro和Lenvatinib的新试验。我们将分析肿瘤和血液样本 患者参与这些试验，试图验证小鼠实验的机械结果，并确定 对该方案的反应或抵抗的预测因素(目标2)。本提案是对PAR 21-033的响应，其中 包括早期临床试验、生物标记物和机制研究。这些研究可能具有重要的 对其他疾病也有影响，例如肺癌，它同样经常转移到中枢神经系统。