Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants

溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤

• 批准号: 10557162
• 负责人: Juan Fueyo
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557162
• 关键词: Adenoviruses; Adjuvant; Agonist; Antineoplastic Agents; Aryl Hydrocarbon Receptor; Attenuated; Biological; Biological Products; Brain Neoplasms; CD8-Positive T-Lymphocytes; Catabolism; Categories; Cell Cycle; Cells; Characteristics; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; DNA biosynthesis; Data; Development; Disease; Dose; Drug Industry; Environment; Essential Amino Acids; Functional disorder; Future; Glioblastoma; Glioma; Goals; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunocompetent; Immunosuppression; Immunotherapy; In Situ; Infection; Injections; Interleukin-2; Kynurenine; Laboratories; Lymphocyte; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Mediating; Mesocricetus auratus; Metabolic; Modeling; Modification; Mus; Names; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Population; Positioning Attribute; Production; Publishing; Recurrence; Regulatory T-Lymphocyte; Safety; Shapes; Site; Solid Neoplasm; Specimen; Survival Rate; T cell anergy; T cell infiltration; T-Cell Activation; T-Lymphocyte; T-cell receptor repertoire; TNFSF4 gene; Testing; Therapeutic; Time; Translating; Tryptophan; Vaccination; Viral; Virotherapy; Virus; Virus Diseases; Virus Replication; adenoviral mediated; anti-cancer; anti-tumor immune response; cancer immunotherapy; cancer therapy; cytotoxic; deprivation; effective therapy; first-in-human; immune activation; immunogenic cell death; immunotherapeutic virotherapy; improved; indoleamine; inhibitor; interest; mouse model; neoplastic cell; novel; oncolysis; oncolytic adenovirus; oncolytic virotherapy; patient subsets; permissiveness; pre-clinical; prevent; recruit; response; standard care; tumor; tumor microenvironment

SUMMARY / ABSTRACT With current treatment options, the five-year survival rate of patients with glioblastoma (GBM) is only 5%. Oncolytic viruses are promising treatments against solid tumors, including malignant gliomas. In a phase I clinical trial evaluating Delta-24-RGD, an oncolytic adenovirus characterized in our laboratory, 20% of recurrent GBM patients receiving the virus achieved a durable response, surviving more than 3 years from the time of treatment, suggesting the existence of a subgroup of patients who would respond to adenoviral treatments. The clinical trial also showed that the efficacy of Delta-24-RGD was due to not only direct tumor cell oncolysis, but also indirect activation of anti-tumor immune responses, a paradigm-shifting finding that radically repositions virotherapy as a type of immunotherapy. Therefore, understanding the interplay between the oncolytic effects of adenoviruses and the viral-mediated anti-glioma immune activation is critical in determining how to increase the efficacy of these promising agents. Our group generated and preclinically characterized an immune agonist-armed version of Delta-24-RGD, named Delta-24-RGDOX, which expresses the T-cell activator OX40L, which will be soon translated to the clinical setting. In this project, we aim to amplify the effect of Delta-24-RGDOX with the administration of inhibitors of the factors that maintain the immunosuppression characteristic of gliomas. Because indoleamine-2,3-dioxgenase (IDO) expression increases significantly after virus infection, we are particularly interested in developing strategies to downmodulate IDO during virotherapy. The catabolism of tryptophan by IDO has important metabolic effects in glioma cells. In addition, the metabolites of tryptophan, including kynurenine (Kyn), activate the aryl hydrocarbon receptor (AhR) that induces Treg differentiation and CD8+ T-cell dysfunction. The central hypothesis of this study is that therapy consisting of Delta-24-RGDOX in combination with IDO and AhR inhibitors will stimulate a cytotoxic immune effect and inhibit the suppressive immune response against the tumor cells, thereby providing a potential effective novel treatment for malignant gliomas. To test this hypothesis, we propose three aims: Specific Aim 1: Examine the activation of the IDO-Kyn-AhR pathway during the infection of gliomas with Delta-24-RGDOX oncolytic adenovirus; Specific Aim 2: Identify the metabolic and immune modifications in the tumor microenvironment produced by the inhibition of the IDO-Kyn-AhR pathway in gliomas treated with Delta-24- RGDOX; and Specific Aim 3: Test the combination of Delta-24-RGDOX and IDO/AhR inhibitors in pre- clinically relevant models of gliomas. This project is the next step in achieving our long-term goal of legitimizing viro-immunotherapy as standard treatment for malignant gliomas.

摘要 /摘要 有了当前的治疗选择，胶质母细胞瘤（GBM）患者的五年存活率仅为5％。 溶瘤病毒是针对包括恶性神经胶质瘤在内的实体瘤的有希望的治疗方法。在第一阶段 评估Delta-24-RGD的临床试验，这是一种在我们的实验室中特征的溶瘤腺病毒，20％的经常性 接受该病毒的GBM患者达到了持久的反应，自结束时生存了3年以上 治疗，表明存在对腺病毒治疗反应的患者亚组。 临床试验还表明，Delta-24-RGD的疗效不仅是由于直接肿瘤细胞闭塞所致 但也间接激活抗肿瘤免疫反应，这是一种范式转移发现，从根本上讲 重新定位病毒疗法作为一种免疫疗法。因此，了解 腺病毒的溶瘤作用和病毒介导的抗神经瘤免疫激活对于确定至关重要 如何提高这些有前途的药物的功效。我们的小组生成并彻底表征了 Delta-24-RGD的免疫激动剂臂版本，名为Delta-24-rgdox，表达T细胞 激活剂OX40L，将很快转化为临床环境。在这个项目中，我们旨在扩大效果 Delta-24-rgdox和维持免疫抑制因素的抑制剂的施用 神经胶质瘤的特征。因为吲哚胺-2,3-二氧酶（IDO）表达在 病毒感染，我们特别有兴趣制定病毒疗法期间下调IDO的策略。 色氨酸对伊多（Ido）的分解代谢对神经胶质瘤细胞具有重要的代谢作用。另外， 色氨酸的代谢产物，包括kynurenine（Kyn），激活芳基碳氢化合物受体（AHR） 诱导Treg分化和CD8+ T细胞功能障碍。这项研究的中心假设是治疗 由Delta-24-rgdox与IDO和AHR抑制剂组成，将刺激细胞毒性免疫 作用并抑制针对肿瘤细胞的抑制性免疫反应，从而提供潜力 有效的恶性神经胶质瘤治疗。为了检验这一假设，我们提出了三个目标：特定目标 1：检查胶质瘤感染Delta-24-rgdox期间IDO-KYN-AHR途径的激活 溶瘤腺病毒；特定目标2：确定肿瘤中的代谢和免疫修饰 通过抑制Delta-24-处理的胶质瘤中IDO-KYN-AHR途径产生的微环境 rgdox;和特定目标3：测试三角洲-24-rgdox和IDO/AHR抑制剂的组合 神经胶质瘤的临床相关模型。该项目是实现合法化的长期目标的下一步 Viro免疫疗法作为恶性神经胶质瘤的标准治疗方法。