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

胶质母细胞瘤（GBM）是脑内最具侵袭性的原发性恶性脑肿瘤。 成年人了GBM有大约12-15个月的暗淡预后，尽管持续 提高护理标准。免疫疗法已经证明了 增强对许多癌症类型的免疫反应的潜力;检查点抑制剂 分子，如CTLA-4和PD-1，已经用于治疗许多实体瘤， 不同的成功。虽然它已经证明了在治疗一些肿瘤中的有效性， 炎症环境和抗肿瘤T细胞的高度浸润， 对治疗肿瘤如GBM没有反应。这种肿瘤类型的特征是 特别是具有显著缺乏T细胞的免疫抑制微环境。 靶向方法旨在减少肿瘤中的免疫抑制， 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I期临床试验的初步结果显示， PD-1和替代检查点LAG-3的共阻断的有效性迹象。我们有 观察试验患者的长期存活率和放射学反应。我们注意到 改善T细胞对肿瘤的反应，减少骨髓来源的 抑制细胞（MDSC），在患者的双重疗法之后。我们建议研究 免疫系统通过PD-1/LAG-3增强抗GBM的机制 封锁我们假设双重疗法募集骨髓间室的细胞， 以增强抗癌T细胞活性，并减少免疫抑制因子的存在。 肿瘤中的骨髓细胞为了验证我们的假设，我们将研究：i）启动 在小鼠模型中，抗原呈递髓样细胞对双重治疗的应答 ii）由表面LAG-3分子裂解产生的可溶性产物在GBM中的作用， 在肿瘤中诱导骨髓介导的免疫抑制（使用两种鼠模型 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生存率联系起来 以及试验患者的无进展生存期。我们预计， 这些研究将为以前未探索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， 肿瘤的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。

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.