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

基本信息

批准号：
10330464
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
项目类别：
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/10330464
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 Production Publishing Recurrence Regulatory T-Lymphocyte Safety Site Solid Neoplasm Specimen Survival Rate T cell anergy T-Cell Activation T-Lymphocyte T-cell receptor repertoire TNFSF4 gene Testing Therapeutic Time Translating Tryptophan Tumor-infiltrating immune cells Vaccination Viral Virotherapy Virus Virus Diseases Virus Replication adenoviral-mediated anti-cancer anti-tumor immune response base cancer immunotherapy cancer therapy clinically relevant 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 pre-clinical prevent recruit response standard care tumor tumor microenvironment

项目摘要

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/摘要根据目前的治疗方案，胶质母细胞瘤 (GBM) 患者的五年生存率仅为 5%。溶瘤病毒是治疗实体瘤（包括恶性神经胶质瘤）的有希望的方法。在第一阶段评估 Delta-24-RGD 的临床试验，这是我们实验室鉴定的一种溶瘤腺病毒，可导致 20% 的复发接受该病毒的 GBM 患者取得了持久的反应，从感染之日起存活了 3 年多治疗，表明存在对腺病毒治疗有反应的患者亚组。临床试验还表明，Delta-24-RGD的功效不仅归功于直接的肿瘤细胞溶瘤作用，而且还间接激活抗肿瘤免疫反应，这是一个范式转变的发现，从根本上将病毒疗法重新定位为免疫疗法的一种。因此，了解两者之间的相互作用腺病毒的溶瘤作用和病毒介导的抗神经胶质瘤免疫激活对于确定如何提高这些有前途的药物的功效。我们的小组生成并进行了临床前表征 Delta-24-RGD 的免疫激动剂武装版本，命名为 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，我们的目标是放大效果 Delta-24-RGDOX 与维持免疫抑制因子的抑制剂的施用胶质瘤的特征。因为吲哚胺-2,3-二加酶 (IDO) 表达在病毒感染时，我们对制定在病毒治疗期间下调 IDO 的策略特别感兴趣。 IDO 对色氨酸的分解代谢在神经胶质瘤细胞中具有重要的代谢作用。此外，色氨酸的代谢物，包括犬尿氨酸 (Kyn)，可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。本研究的中心假设是治疗由 Delta-24-RGDOX 与 IDO 和 AhR 抑制剂组合组成，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，从而提供潜在的恶性胶质瘤的有效新疗法。为了检验这个假设，我们提出了三个目标：具体目标 1：检查 Delta-24-RGDOX 感染神经胶质瘤期间 IDO-Kyn-AhR 通路的激活情况溶瘤腺病毒；具体目标 2：识别肿瘤中的代谢和免疫修饰 Delta-24-治疗的神经胶质瘤中通过抑制 IDO-Kyn-AhR 途径产生的微环境 RGOX；具体目标 3：测试 Delta-24-RGDOX 和 IDO/AhR 抑制剂的组合神经胶质瘤的临床相关模型。该项目是实现我们合法化长期目标的下一步病毒免疫疗法作为恶性胶质瘤的标准治疗。