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: 9570361
• 负责人: Derek Alan Wainwright
• 金额: $ 25.56万
• 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/9570361
• 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; Imagery; 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; Mus; Myelogenous; Myeloid-derived suppressor cells; Newly Diagnosed; PD-1 blockade; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Population; Positron-Emission Tomography; Radiation; Radiation therapy; Radiolabeled; Regulatory T-Lymphocyte; Research; Research Activity; Resistance; SLEB2 gene; 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; Work; base; checkpoint inhibition; combinatorial; enzyme activity; experience; experimental study; immune checkpoint; immune checkpoint blockade; immunoregulation; indoleamine; inhibitor/antagonist; innovation; multimodality; novel; outcome forecast; patient subsets; patient variability; phase II trial; pre-clinical; pre-clinical research; preclinical study; primary endpoint; 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：概要 免疫疗法在包括恶性胶质瘤在内的几种实体瘤的治疗中具有很大的前景。 但为了在疾病过程中产生真正的影响，可能需要一种组合策略。在 特别是胶质母细胞瘤，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，放射治疗与 通过检查点抑制剂和IDO抑制剂两者的伴随免疫调节可以证明是有效的。中 通过一系列临床前实验，我们已经证明，放射治疗、检查点 抑制和IDO抑制发挥增强的抗肿瘤活性。引人注目的是，这种三联疗法导致了持久的 在患有大颅内GBM小鼠中的存活益处。我们证实，这种方法抑制了 免疫抑制性IDO 1代谢，如通过肿瘤内色氨酸的增加和 降低犬尿氨酸水平。这些临床前发现现在将在临床试验中转化， 患有新诊断的GBM的患者。本试验的创新之处在于， α-[11 C]-甲基-L-色氨酸（AMT）-PET成像，这是一种定量色氨酸摄取和/或 IDO 1酶活性和全面的免疫监测面板。因此，AMT-PET成像有助于 实时评价颅内IDO 1酶抑制，有利于肿瘤患者 其对于重复的组织取样来说不方便接近。临床试验将包括相关 分析全身和肿瘤内免疫标志物、肿瘤基因表达和致突变负荷， 定量AMT-PET数据和治疗结果（总生存期作为主要终点）。同时，我们将 用重建了人类免疫系统并接种了肿瘤的小鼠进行进一步的实验 人类起源（PDX）。这将允许测试来自临床经验的假设，以及 其他的治疗方法，可以纳入未来的临床试验，是正在测试的衍生物 在这里的病人。最终，我们的研究将影响未来的免疫策略， 神经胶质瘤患者的综合治疗。