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

基本信息

批准号：
10478875
负责人：
Derek Alan Wainwright
金额：
$ 28.84万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10478875
关键词：
Address Blood Vessels Brain Cells Clinical Clinical Research Clinical Trials Combination immunotherapy Combined Modality Therapy Complement Data 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 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 T-Lymphocyte Testing Therapeutic Time Tissue Sample Tracer Translating Treatment outcome Tryptophan Tryptophan Metabolism Pathway Visualization Work base checkpoint inhibition combinatorial diagnostic tool enzyme activity experience experimental study immune checkpoint immune checkpoint blockade immunoregulation indoleamine inhibitor inhibitor therapy 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 radiological imaging reconstitution responders and non-responders response safety and feasibility secondary endpoint standard care synergism temozolomide translational approach treatment response tryptophan analog tumor uptake

项目摘要

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：摘要免疫疗法对包括恶性神经胶质瘤在内的几种实体瘤的治疗具有很大的希望。但是，为了对疾病病程产生真正的影响，可能需要采取组合策略。在特别是在胶质母细胞瘤中，一种以局部免疫抑制为特征的异质性疾病免疫特你的环境以及增加的血管，放疗与检查点抑制剂和IDO抑制剂伴随免疫调节可能有效。在一系列临床前实验，我们已经表明放射疗法的三重组合，检查点抑制作用和IDO抑制作用会增强抗肿瘤活性。令人惊讶的是，这种三重疗法导致了耐用的大型颅内GBM小鼠的生存益处。我们确认这种方法抑制了免疫抑制IDO1代谢，由肿瘤内色氨酸和A的增加确定雌激素水平的降低。这些临床前发现现在要在临床试验中翻译成患有新诊断的GBM的患者。该试验的创新得到了公司的增强 α-[11C] -Methyl-L-Trp（AMT）-PET成像，这是一种量化色氨酸摄取和/或的无创方法 IDO1酶活性和全面的免疫监测面板。因此，AMT-PET成像促进颅内IDO1酶抑制的实时评估，这对肿瘤患者有利对于重复组织采样，无法方便地访问。临床试验将包括相关性分析系统性和肿瘤内免疫学标记物，肿瘤基因表达和诱变伯嫩，定量AMT-PET数据和治疗结果（总生存率为主要终点）。同时，我们将用与人免疫系统重组并接种肿瘤的小鼠进行进一步的实验人类起源（PDX）。这将允许测试临床经验以及可以将未来的临床试验纳入该测试的临床试验中的其他疗法在这里的患者。最终，我们的研究将影响未来的免疫治疗策略神经胶质瘤患者的多模式管理。