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

• 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
• 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

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)是世界上最具侵袭性的原发恶性脑肿瘤 成年人。GBM的预后大约为12-15个月，尽管仍在继续 向护理标准迈进。免疫疗法已经证明了 有可能提高对多种癌症的免疫反应；检查点的抑制剂 CTLA-4和PD-1等分子已被用于治疗许多实体肿瘤 成就参差不齐。虽然它在治疗一些肿瘤方面显示出了有效性，但 炎性环境和高度的抗肿瘤T细胞的侵袭，它几乎没有表现出来 在治疗基底膜等肿瘤时无反应。这种肿瘤的特征是 尤其是免疫抑制的微环境，T细胞明显稀少。 旨在减少肿瘤中的免疫抑制并增加 抗肿瘤T细胞活性是成功治疗GBM的关键。最近的临床前数据来自 我们的实验室和I期临床试验的初步结果显示前景看好。 共同封锁PD-1和替代检查站LAG-3的有效迹象。我们有 观察长期存活者和试验患者的放射学反应。我们已经注意到 改善T细胞对肿瘤的反应并减少髓系来源的 抑制细胞(MDSCs)，患者双重治疗后。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。我们假设双重治疗招募了髓系间室的细胞 以增强抗癌T细胞活性，减少免疫抑制的存在 肿瘤本身的髓样细胞。为了检验我们的假设，我们将研究：i)启动 双重治疗对小鼠髓系细胞抗原提呈对T细胞的影响 GbM，II)表面LAG-3分子裂解产生的可溶性产物在 在肿瘤中诱导髓系免疫抑制(使用两种小鼠模型 和患者样本)，以及iii)扩增抗肿瘤T细胞和减少MDSCs 双重治疗后患者的血药浓度。我们将把我们的发现与总体存活率联系起来。 以及试验患者的无进展存活率。我们预计，从 这些研究将为一种以前未探索的机制提供新的见解 双免疫检查点阻断治疗可调节髓系反应 肿瘤。从这项研究中获得的知识将有助于改进设计 未来治疗GBM患者的治疗策略。