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

• 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
• 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

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.

项目总结/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，在本发明中， 应该开发不同的治疗方法。一种有希望的替代疗法是使用溶瘤病毒， Delta-24-RGD，这导致高达15%的GB患者完全缓解。Delta-24-RGD原因 通过癌细胞裂解和免疫原性细胞死亡而死亡。我们的初步数据显示，患有GB的小鼠可以 用名为Delta-24-RGDOX的武装溶瘤腺病毒治疗治愈， 激动剂，OX 40 L。OX 40信号通路可以增强效应T细胞对癌细胞的应答。 相反，GB的肿瘤微环境可以采用免疫抑制和无能机制， 停止针对肿瘤的免疫反应。例如，吲哚胺-2，3-双加氧酶的活化 (IDO)已报道其在GB中上调，可激活免疫抑制调节性T细胞。 因此，我们假设Delta-24-RGDOX和IDO抑制剂的联合治疗将导致 免疫调节肿瘤微环境，使其细胞毒性更强，免疫抑制性更低 性质和有效的治疗GB。为了验证这一假设，我们的目标是1）比较治疗 在鼠GB中使用Delta-24-RGDOX与和不与IDO抑制剂的功效，和2）分析功效 在GB的小鼠模型中，将Delta-24-RGDOX与IDO抑制剂组合以克服T细胞无反应性。 完成这项研究将提供一个更好的理解免疫肿瘤逃避机制的发生 在用Delta-24-RGDOX和/或IDO抑制剂治疗后，导致更好的GB治疗靶点。