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。而主要 在治疗转移性黑色素瘤方面取得了进展，在治疗黑色素瘤脑转移方面取得了进展， (MBM)落后。这是由于几乎普遍排除了未经治疗的脑转移患者， 临床试验，并且只有在脑外疾病中建立了良好的方案后，才在MBM患者中进行研究。 此外，MBM的临床前研究受到临床前模型缺乏和有限的限制。 获取CNS样本进行分析，因为这些患者通常接受放射治疗而不是手术治疗。 因此，我们发展了基础设施和资源，我们建议利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（pembro）治疗未经治疗的MBM患者的II期试验。虽然回复率 中度（26%），2年生存率为48%，放射性坏死和/或神经系统损伤的发生率为10%。 与水肿相关的症状是高的。因此，我们在MBM中启动了pembro加贝伐单抗的后续试验; 第一批的回应率为55%，超出我们的预期，因此需要进一步评估。 该反应率与纳武单抗和伊匹单抗在MBM中观察到的反应率相似，但毒性特征远低于纳武单抗和伊匹单抗。 上级，仅具有来自贝伐单抗的最小附加毒性。我们建议进一步研究联合靶向 PD-1和VEGF/VEGF-R通路在MBM中的作用，并确定这些通路 串话来促进脑内肿瘤的生长。我们将在抗VEGF成功的基础上进行新的试验 包括pembro和VEGF-R抑制剂（VEGFRi）乐伐替尼。在临床研究的同时，我们 开发了对抗PD-1有适度应答的新型免疫活性MBM模型，并开发了 血脑屏障的体外模型，以研究这些药物对血管渗漏的影响。这些临床前 模型将被用来检验这一假设，即在抗PD-1抗体中加入VEGF通路阻断剂可以增强T细胞增殖。 细胞迁移和功能，并直接降低紧密连接渗漏。我们还假设抗VEGF 对VEGF有不同的影响。我们将使用我们的新型免疫系统来剖析这种情况发生的机制。 能力的小鼠模型和单细胞转录组学和原位蛋白质组学策略（目的1），并确定 是否应该用VEGF-Ris替代VEGF抑制剂治疗MBM。我们正在扩大我们正在进行的 pembro和贝伐单抗的临床试验，通过招募第二组黑色素瘤患者来验证我们最初的 结果.我们已经启动了一项新的pembro和lenvatinib试验。我们将分析肿瘤和血液样本， 在这些试验中，试图验证来自小鼠实验的机制结果，并确定 对该方案的反应或抗性的预测因子（目的2）。本提案是对PAR 21-033的响应， 涉及早期临床试验和生物标志物及机制研究。这些研究可能具有重要的 对其他疾病也有影响，如肺癌，它同样经常转移到中枢神经系统。