Targeting Lag-3 and PD -1 in Myeloid Cells of GBM

靶向 GBM 骨髓细胞中的 Lag-3 和 PD -1

基本信息

批准号：
10367804
负责人：
Michael Lim
金额：
$ 40.28万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367804
关键词：
Ablation Adoptive Transfer Adult Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Antitumor Response Binding Biological Assay Blood Blood specimen Bone Marrow Brain Neoplasms CTLA4 gene Cells Cellular Assay Clinical Clone Cells Coculture Techniques Congenic Mice Correlative Study Data Flow Cytometry Funding Future Glioblastoma Glioma Histology Human Immune Immune checkpoint inhibitor Immune response Immune system Immunosuppression Immunotherapy Infiltration Investigation Ions Knockout Mice Knowledge Laboratories Long-Term Survivors Magnetic Resonance Imaging Malignant neoplasm of brain Malignant neoplasm of lung Measures Mediating Metabolic Mus Mutation Myelogenous Myeloid Cells Myeloid Progenitor Cells Myeloid-derived suppressor cells PD-1 blockade PTPRC gene Patients Peripheral Phase I Clinical Trials Phenotype Prognosis Progression-Free Survivals Recurrence Renal Cell Carcinoma Resistance Role Sampling Site Solid Neoplasm Surface T cell clonality T cell response T-Cell Activation T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Time Translating Tumor Antigens Tumor Expansion Wild Type Mouse anti-CTLA4 anti-PD-1 anti-PD1 antibodies anti-PD1 therapy anti-cancer anti-tumor immune response cancer type combinatorial cytotoxicity design draining lymph node effector T cell exhaustion extracellular functional improvement immune checkpoint blockade improved in vivo inflammatory milieu insight macrophage melanoma monocyte mouse model neoantigens neoplastic cell novel peripheral blood phase I trial pre-clinical prevent programmed cell death protein 1 radiological imaging recruit response single cell sequencing standard of care success tumor tumor progression tumor-immune system interactions

项目摘要

Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumor in adults. GBM has a bleak prognosis of approximately 12-15 months, despite continuing advances to the standard of care. Immunotherapy has demonstrated the significant potential to boost immune responses against many cancer types; inhibitors of checkpoint molecules, such as CTLA-4 and PD-1, have been used to treat many solid tumors with varying success. While it has demonstrated efficacy in treating some tumors with an inflammatory milieu and high degree of infiltration by anti-tumor T cells, it has shown little to no response in treating tumors such as GBM. This tumor type is characterized by a particularly immunosuppressive microenvironment with a notable paucity of T cells. Targeted approaches designed to reduce immunosuppression in the tumor and increase anti-tumor T cell activity are crucial to successfully treat GBM. Recent preclinical data from our laboratory and preliminary findings from a Phase I clinical trial have shown promising signs of efficacy with co-blockade of PD-1 and the alternative checkpoint LAG-3. We have observed long-term survivors and radiographic responses in trial patients. We have noted improved T cell responses against the tumor and a reduction in myeloid-derived suppressor cells (MDSCs), following dual therapy of patients. We propose to study the mechanism by which the immune system is enhanced against GBM via PD-1/LAG-3 blockade. We hypothesize that dual therapy recruits cells of the myeloid compartment in order to boost anti-cancer T cell activity, and reduces the presence of immunosuppressive myeloid cells in the tumor itself. To test our hypothesis, we will investigate the: i) priming of T cells by antigen presenting myeloid cells in response to dual therapy in murine models of GBM, ii) role of soluble product generated from cleavage of surface LAG-3 molecule in inducing myeloid-mediated immunosuppression in the tumor (using both murine models and patient samples), and iii) expansion of anti-tumor T cells and reduction in MDSCs levels in patients following dual therapy. We will correlate our findings with overall survival and progression free survival of the trial patients. We expect that the data generated from these studies will provide novel insights into a previously unexplored mechanism by which dual immune checkpoint blockade therapy can modulate the myeloid response against tumors. The knowledge obtained from this study will contribute to improving the design of future therapeutic strategies to treat GBM patients.

胶质母细胞瘤（GBM）是原发性恶性脑肿瘤中最具侵袭性的类型成年人。 GBM 的预后很暗淡，大约 12-15 个月，尽管进步到护理标准。免疫疗法已显示出显着的增强针对多种癌症类型的免疫反应的潜力；检查点抑制剂 CTLA-4和PD-1等分子已被用于治疗许多实体瘤不同的成功。虽然它已被证明可以有效治疗某些肿瘤炎症环境和抗肿瘤 T 细胞的高度浸润，但几乎没有表现出对治疗 GBM 等肿瘤没有反应。这种肿瘤类型的特点是特别是 T 细胞显着缺乏的免疫抑制微环境。旨在减少肿瘤免疫抑制并增加免疫抑制的靶向方法抗肿瘤 T 细胞活性对于成功治疗 GBM 至关重要。最近的临床前数据来自我们的实验室和一期临床试验的初步结果显示出良好的前景联合阻断 PD-1 和替代检查点 LAG-3 的疗效迹象。我们有观察试验患者的长期幸存者和放射学反应。我们注意到改善 T 细胞对肿瘤的反应并减少骨髓源性患者双重治疗后的抑制细胞（MDSC）。我们建议研究通过 PD-1/LAG-3 增强免疫系统对抗 GBM 的机制封锁。我们假设双重疗法会招募髓样室的细胞为了增强抗癌 T 细胞活性，并减少免疫抑制的存在肿瘤本身的骨髓细胞。为了检验我们的假设，我们将研究： i) 启动小鼠模型中抗原呈递骨髓细胞响应双重治疗的 T 细胞 GBM 的作用，ii) 表面 LAG-3 分子裂解产生的可溶性产物在在肿瘤中诱导骨髓介导的免疫抑制（使用两种小鼠模型和患者样本），以及 iii）抗肿瘤 T 细胞的扩增和 MDSC 的减少双重治疗后患者的水平。我们将把我们的发现与总体生存率联系起来和试验患者的无进展生存期。我们期望生成的数据这些研究将为以前未探索过的机制提供新的见解双重免疫检查点阻断疗法可以调节骨髓反应肿瘤。从这项研究中获得的知识将有助于改进设计治疗 GBM 患者的未来治疗策略。