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：
10598471
负责人：
Michael Lim
金额：
$ 40.03万
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/10598471
关键词：
Ablation Adoptive Transfer Adult Antibodies Antigen Presentation Antigen-Presenting Cells Antitumor Response Binding Biological Assay Blood Blood specimen Bone Marrow Brain Neoplasms CTLA4 gene Cells 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 Macrophage 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 Proliferating Recurrence Renal Cell Carcinoma Resistance Role Sampling Site Solid Neoplasm Sorting 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 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 synergism 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）是最激进的原发性恶性脑肿瘤类型成年人。尽管继续晋升到护理标准。免疫疗法已经证明了重要的潜在提高针对许多癌症类型的免疫反应；检查点的抑制剂分子（例如CTLA-4和PD-1）已被用于治疗许多实体瘤不同的成功。虽然它已经证明了用抗肿瘤T细胞的炎症环境和高度浸润，几乎没有显示在治疗诸如GBM之类的肿瘤时无反应。这种肿瘤类型的特征是特别是免疫抑制微环境，T细胞显着稀少。旨在减少肿瘤中免疫抑制并增加的目标方法抗肿瘤T细胞活性对于成功治疗GBM至关重要。最近的临床前数据我们从I期临床试验中的实验室和初步发现显示了有希望的与PD-1的共阻形和替代检查点LAG-3有效性的迹象。我们有在试验患者中观察到的长期幸存者和射线照相反应。我们指出改善了针对肿瘤的T细胞反应，并减少了髓样衍生的双重治疗患者后，抑制细胞（MDSC）。我们建议研究通过PD-1/LAG-3增强免疫系统的机制封锁。我们假设双重疗法在为了增强抗癌T细胞活性，并减少免疫抑制的存在肿瘤本身中的髓样细胞。为了检验我们的假设，我们将研究：i）启动抗原呈现髓样细胞的抗原响应鼠模型中的双重治疗 GBM的ii）可溶性产物的作用是从表面lag-3分子裂解产生的作用在肿瘤中诱导髓样介导的免疫抑制（使用两种鼠模型和患者样品），iii）抗肿瘤T细胞的扩展和MDSC的减少双重治疗后患者的水平。我们将将我们的发现与整体生存相关联和试验患者的无进展生存。我们希望从这些研究将为以前未开发的机制提供新的见解双免疫检查点阻滞疗法可以调节髓样反应肿瘤。从这项研究中获得的知识将有助于改善未来治疗GBM患者的治疗策略。