Simultaneous Radiotherapy with PD-1 and IDO1 Blockade for Overcoming Immune Suppression in Glioblastoma

PD-1 和 IDO1 阻断同时放疗克服胶质母细胞瘤的免疫抑制

• 批准号: 10224125
• 负责人: Derek Alan Wainwright
• 金额: $ 23.79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224125
• 关键词: Address; Blood Vessels; Brain; Cells; Clinical; Clinical Research; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Complement; Data; Diagnostic; Diagnostic radiologic examination; Dioxygenases; Disease; Dose; Environment; Enzyme Inhibition; Enzymes; Essential Amino Acids; Evaluation; Failure; Future; Gene Expression; Glioblastoma; Glioma; Human; Image; Imaging Techniques; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunohistochemistry; Immunologic Markers; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Investigation; Kynurenine; MGMT gene; Magnetic Resonance Imaging; Malignant Glioma; Malignant neoplasm of brain; Maximum Tolerated Dose; Metabolism; Methods; Molecular; Monitor; Monoclonal Antibodies; Mus; Myelogenous; Myeloid-derived suppressor cells; Newly Diagnosed; Nivolumab; PD-1 blockade; Pathway interactions; Patients; Phase; Phase I/II Clinical Trial; Population; Positron-Emission Tomography; Prognosis; Radiation; Radiation therapy; Radiolabeled; Regulatory T-Lymphocyte; Research; Research Activity; Resistance; Series; Solid; Solid Neoplasm; Specimen; Subgroup; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Sample; Tracer; Translating; Treatment outcome; Tryptophan; Tryptophan Metabolism Pathway; Visualization; Work; base; checkpoint inhibition; combinatorial; enzyme activity; experience; experimental study; immune checkpoint; immune checkpoint blockade; immunoregulation; indoleamine; inhibitor/antagonist; innovation; multimodality; novel; patient subsets; patient variability; phase I trial; phase II trial; pre-clinical; pre-clinical research; preclinical study; primary endpoint; programmed cell death protein 1; promoter; reconstitution; responders and non-responders; response; safety and feasibility; secondary endpoint; standard care; synergism; temozolomide; tool; translational approach; treatment response; tryptophan analog; tumor; uptake

PROJECT 2: SUMMARY Immunotherapy carries great promise for the treatment of several solid tumors, including malignant glioma. But in order to have a true impact in the disease course, a combinatorial strategy is likely required. In particular in glioblastoma, a heterogeneous disease characterized by local immunosuppression and an immune-privileged environment as well as increased vascularity, a combination of radiotherapy with concomitant immunomodulation by both a checkpoint inhibitor and IDO inhibitor could prove effective. In a series of preclinical experiments, we have shown that the triple combination of radiotherapy, checkpoint inhibition and IDO inhibition exert enhanced antitumor activity. Strikingly, this triple therapy led to a durable survival benefit in mice with large, intracranial GBM. We confirmed that this approach inhibited immunosuppressive IDO1 metabolism, as determined by an increase of intratumoral tryptophan and a decrease of kynurenine levels. These preclinical findings are now to be translated within a clinical trial to patients suffering from newly diagnosed GBM. The innovation of this trial is enhanced by the incorporation of α-[11C]-methyl-L-Trp (AMT)-PET imaging, which is a noninvasive method to quantify tryptophan uptake and/or IDO1 enzyme activity, and a comprehensive immunmonitoring panel. AMT-PET imaging therefore facilitates the real-time evaluation of intracranial IDO1 enzyme inhibition, which is advantageous to patients with tumors that are not conveniently accessible for repeat tissue sampling. The clinical trial will include correlative analysis of systemic and intratumoral immunological markers, tumor gene expression and mutagenic burden, quantitative AMT-PET data, and treatment outcome (overall survival as primary endpoint). In parallel, we will conduct further experiments with mice reconstituted with human immune systems and inoculated with tumors of human origin (PDX). This will allow for testing hypotheses arising from the clinical experience, as well as additional therapeutics that could be incorporated in future clinical trials that are derivative of that being tested in patients here. Ultimately, our research will influence future immunotherapeutic strategies in the multimodality management of patients with glioma.

项目 2：总结 免疫疗法对于治疗包括恶性神经胶质瘤在内的多种实体瘤具有广阔的前景。 但为了对疾病进程产生真正的影响，可能需要采取组合策略。在 特别是胶质母细胞瘤，这是一种以局部免疫抑制为特征的异质性疾病， 免疫豁免环境以及增加的血管分布，放疗与 检查点抑制剂和 IDO 抑制剂的伴随免疫调节可能被证明是有效的。在一个 通过一系列的临床前实验，我们已经证明放疗、检查点的三重组合 抑制和IDO抑制发挥增强的抗肿瘤活性。引人注目的是，这种三联疗法带来了持久的效果 具有较大颅内 GBM 的小鼠的生存获益。我们证实这种方法抑制了 免疫抑制 IDO1 代谢，通过瘤内色氨酸的增加和 犬尿氨酸水平降低。这些临床前研究结果现在将在临床试验中转化为 患有新诊断的 GBM 的患者。本次试验的创新之处在于加入了 α-[11C]-甲基-L-Trp (AMT)-PET 成像，这是一种量化色氨酸摄取和/或 IDO1 酶活性和综合免疫监测组。因此，AMT-PET 成像有利于 实时评估颅内IDO1酶抑制情况，有利于肿瘤患者 不便于重复组织取样。临床试验将包括相关 分析全身和瘤内免疫标志物、肿瘤基因表达和诱变负荷， 定量 AMT-PET 数据和治疗结果（总生存期作为主要终点）。与此同时，我们将 用重组人类免疫系统并接种肿瘤的小鼠进行进一步的实验 人类起源（PDX）。这将允许测试根据临床经验以及 可以纳入未来临床试验的其他疗法，这些疗法是正在测试的衍生疗法 在这里的病人身上。最终，我们的研究将影响未来的免疫治疗策略 胶质瘤患者的多学科治疗。