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.

黑色素瘤是最频繁地转移到中枢神经系统（CNS）的实体瘤。虽然主要 在治疗转移性黑色素瘤，治疗黑色素瘤脑转移方面的进步已经取得了进步 （MBM）滞后。这是由于几乎全额外排除未处理脑转移的患者 在MBM患者中研究了临床试验，并且只有在脑外疾病中建立了良好的疗法。 此外，MBM的临床前研究受到了临床前模型的匮乏和有限的限制。 访问中枢神经系统标本进行分析，因为这些患者通常接受辐射而不是手术治疗。 因此，我们开发了我们建议采用的基础设施和资源，以更好地理解 脑转移的分子，血管和细胞基础。我们首先研究PD-1的活动 II期试验中未经治疗的MBM患者的抑制剂Pembrolizumab（Pembro）。虽然回应率 谦虚（26％），两年生存率为48％，辐射坏死的发生率和/或神经系统 与水肿有关的症状很高。因此，我们在MBM中启动了Pembro Plus Bevacizumab的续集试验。 最初队列的回应率为55％，超过了我们的预期并保证进一步评估。 该缓解率类似于Nivolumab和MBM中ipilimumab的回应率，但毒性特征很远 优质仅来自贝伐单抗的最小添加毒性。我们建议进一步研究 MBM中的PD-1和VEGF/VEGF-R途径，并确定这些途径的机制 串扰以促进大脑内肿瘤的生长。我们将在一项新试验中以反VEGF的成功为基础 涉及pembro和VEGF-R抑制剂（VEGFRI），lenvatinib。与我们的临床研究努力平行 开发了新型的MBM免疫能力模型，这些模型对抗PD-1有适度的反应，并开发了 血脑屏障的体外模型研究这些药物对血管泄漏的作用。这些临床前 模型将用于检验以下假设：在抗PD-1中添加VEGF途径阻断增强了T 细胞迁移和功能，并直接降低紧密的连接泄漏。我们还假设反VEGF 对Vegfris有不同的影响。我们将使用我们的新型免疫来剖析这种机制发生的机制 有能力的鼠模型和单细胞转录组和原位蛋白质组学策略（AIM 1）并确定 VEGF抑制药物是否应替换为VEGF-RIS来治疗MBM。我们正在扩大我们正在进行的 通过招募第二群黑色素瘤患者来验证我们的初步 结果。我们已经开始了Pembro和Lenvatinib的新试验。我们将分析来自 这些试验的患者试图验证鼠实验的机理结果并确定 预测对该方案的反应或抵抗力（AIM 2）。该提议对2月21日的par响应，这是 涉及早期临床试验以及生物标志物和机械研究。这些研究可能很重要 对其他疾病的影响，例如肺癌，这种疾病经常转移到中枢神经系统中。