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Immune Therapy for Brain Metastasis

脑转移的免疫治疗

基本信息

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
项目类别：
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

项目摘要

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至中枢神经系统（CNS）的实体瘤。虽然主要治疗转移性黑色素瘤已取得进展，治疗黑色素瘤脑转移取得进展（MBM）落后。这是因为未经治疗的脑转移患者几乎被普遍排除在治疗之外。临床试验，只有在脑外疾病的治疗方案得到充分确立后，才会在 MBM 患者中进行研究。此外，MBM 的临床前研究因缺乏临床前模型和有限的研究而受到阻碍。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治疗。因此，我们开发了基础设施和资源，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。我们首先研究 PD-1 的活性抑制剂 pembrolizumab (pembro) 在一项 II 期试验中用于未经治疗的 MBM 患者。虽然回复率适度（26%），两年生存率为 48%，放射性坏死和/或神经系统疾病的发生率与水肿相关的症状很高。因此，我们启动了 pembro 加贝伐珠单抗治疗 MBM 的后续试验；最初队列的响应率为 55%，超出了我们的预期，值得进一步评估。该反应率与 MBM 中纳武单抗和易普利姆玛的反应率相似，但毒性特征远非如此。优越，贝伐珠单抗仅增加最小的毒性。我们建议进一步研究共同目标 MBM 中的 PD-1 和 VEGF/VEGF-R 通路，并确定这些通路的机制串扰促进大脑内肿瘤的生长。我们将在新的试验中巩固抗 VEGF 药物的成功涉及 pembro 和 VEGF-R 抑制剂（VEGFRi）lenvatinib。在我们的临床研究工作的同时，我们开发了新型的具有免疫能力的 MBM 模型，该模型对抗 PD-1 有适度的反应，并开发了体外血脑屏障模型研究这些药物对血管渗漏的影响。这些临床前模型将用于检验以下假设：在抗 PD-1 中添加 VEGF 通路阻断可增强 T 细胞迁移和功能并直接降低紧密连接泄漏。我们还假设抗 VEGF 对 VEGFRis 有不同的作用。我们将使用我们的新型免疫系统剖析发生这种情况的机制有能力的小鼠模型和单细胞转录组和原位蛋白质组策略（目标 1）并确定是否应该用 VEGF-Ris 替代 VEGF 抑制药物来治疗 MBM。我们正在扩大我们正在进行的通过招募第二组黑色素瘤患者来验证我们的初步结果，进行 pembro 和贝伐珠单抗的临床试验结果。我们已经启动了 pembro 和 lenvatinib 的新试验。我们将分析肿瘤和血液样本参与这些试验的患者试图验证小鼠实验的机制结果并确定对该方案的反应或耐药性的预测因素（目标 2）。该提案响应 PAR 21-033，其中涉及早期临床试验以及生物标志物和机制研究。这些研究可能具有重要意义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。