The Study of Immune Effects in Gliomas Treated with Oncolytic Viruses in Combination with IDO Inhibitors

溶瘤病毒联合 IDO 抑制剂治疗胶质瘤的免疫效应研究

基本信息

批准号：
10053720
负责人：
Teresa T Nguyen
金额：
$ 2.21万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2021-07-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053720
关键词：
Address Adenovirus Infections Adult Aftercare Agonist Alternative Therapies Antigen Presentation Antiviral Agents Apoptosis Autophagocytosis Biology CD8-Positive T-Lymphocytes CTLA4 gene Catabolism Cause of Death Cell Cycle Arrest Cell Death Cells Chromosome Pairing Clinic Clinical Clinical Trials Combined Modality Therapy Complex Cytolysis Cytotoxic T-Lymphocytes Data Diagnosis Dioxygenases Effectiveness Feedback Future Glioblastoma Glioma Immune Immune response Immune system Immunocompetent Immunomodulators Immunosuppression In complete remission Infection Infiltration Kynurenine Life Expectancy Lymphocyte Activation MHC antigen Malignant - descriptor Mediating Molecular Mus Names Nature OX40 Signaling Pathway Oncolytic Immunotherapy Oncolytic viruses Operative Surgical Procedures Patients Pattern Phase I Clinical Trials Phase II Clinical Trials Primary Brain Neoplasms Production Prognosis Public Health Publishing Radiation therapy Recurrence Regulatory T-Lymphocyte Reporting Research Resistance Role Signal Transduction Survival Rate T cell anergy T cell response T-Cell Receptor T-Lymphocyte TNF gene TNFSF4 gene Testing Translating Translations Treatment Efficacy Tryptophan Tumor Escape Virotherapy Virus Diseases anergy anti-tumor immune response antitumor effect base biological adaptation to stress cancer cell chemotherapy conventional therapy cytotoxic effector T cell immune cell checkpoints immune resistance immunogenic cell death indoleamine inhibitor/antagonist member mouse model neoplastic cell novel oncolytic adenovirus oncolytic virotherapy pathogen phase 1 study preclinical study programmed cell death protein 1 stem therapeutic target tumor tumor immunology tumor microenvironment

项目摘要

Project Summary/Abstract With current treatment options, the five year survival rate of patients with glioblastoma (GB) is only 5%. Thus, different therapies should be developed. One promising alternative therapy is the use of the oncolytic virus, Delta-24-RGD, which has resulted in complete responses in up to 15% of GB patients. Delta-24-RGD causes death by cancer cell lysis and immunogenic cell death. Our preliminary data show that mice with GB can be cured with treatment of the armed oncolytic adenoviruses, named Delta-24-RGDOX, which expresses immune agonist, OX40L. The OX40 signaling pathway can enhance effector T-cell responses against cancer cells. Conversely, the tumor microenvironment of GB can employ immunosuppressive and anergic mechanisms to halt immune responses directed against the tumor. For example, the activation of indoleamine-2,3-dioxygenase (IDO), which has been reported to be upregulated in GB, can activate immunosuppressive regulatory T-cells. Thus, we hypothesize that the combination treatment of Delta-24-RGDOX and IDO inhibitors will immunomodulate the tumor microenvironment towards a more cytotoxic and less immunosuppressive nature and be effective in the treatment of GB. To test this hypothesis, we aim to 1) Compare the therapeutic efficacy of using Delta-24-RGDOX with and without IDO inhibitors in murine GB and 2) Analyze the effectiveness of Delta-24-RGDOX in combination with IDO inhibitors to overcome T-cell anergy in mouse models of GB. Completing this study will provide a greater understanding of the immune tumor evasion mechanisms that occur after treatment with Delta-24-RGDOX and/or IDO inhibitors leading to better therapeutic targets for GB.

项目概要/摘要根据目前的治疗方案，胶质母细胞瘤 (GB) 患者的五年生存率仅为 5%。因此，应开发不同的疗法。一种有前途的替代疗法是使用溶瘤病毒， Delta-24-RGD，使高达 15% 的 GB 患者完全缓解。 Delta-24-RGD 原因癌细胞裂解和免疫原性细胞死亡导致的死亡。我们的初步数据表明，患有 GB 的小鼠可以通过武装溶瘤腺病毒（名为 Delta-24-RGDOX）的治疗治愈，该病毒表达免疫激动剂，OX40L。 OX40 信号通路可以增强效应 T 细胞针对癌细胞的反应。相反，GB 的肿瘤微环境可以利用免疫抑制和无反应机制来停止针对肿瘤的免疫反应。例如，吲哚胺-2,3-双加氧酶的激活据报道，IDO（IDO）在 GB 中表达上调，可以激活免疫抑制性调节 T 细胞。因此，我们假设 Delta-24-RGDOX 和 IDO 抑制剂的联合治疗将免疫调节肿瘤微环境，使其具有更强的细胞毒性和更少的免疫抑制性质并能有效治疗 GB。为了检验这一假设，我们的目标是 1) 比较治疗方法使用带有或不带有 IDO 抑制剂的 Delta-24-RGDOX 在小鼠 GB 中的功效和 2) 分析有效性 Delta-24-RGDOX 与 IDO 抑制剂组合，克服 GB 小鼠模型中的 T 细胞无反应性。完成这项研究将有助于更好地了解发生的免疫肿瘤逃避机制使用 Delta-24-RGDOX 和/或 IDO 抑制剂治疗后，可实现更好的 GB 治疗目标。