Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants

总结/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%。 溶瘤病毒是针对实体瘤（包括恶性神经胶质瘤）的有希望的治疗。在i期 一项临床试验评估Delta-24-RGD，一种在我们实验室表征的溶瘤腺病毒，20%的复发性 接受该病毒的GBM患者获得了持久的反应，从接种时起存活超过3年。 治疗，表明存在一个亚组的患者谁会响应腺病毒治疗。 临床试验还表明，Delta-24-RGD的功效不仅是由于直接的肿瘤细胞溶瘤作用， 而且还间接激活了抗肿瘤免疫反应，这是一个范式转变的发现， 将病毒疗法重新定位为一种免疫疗法。因此，了解 腺病毒的溶瘤作用和病毒介导的抗胶质瘤免疫激活是决定 如何提高这些有前途的药物的功效。我们的小组产生并临床前表征了 Delta-24-RGD的免疫激动剂武装版本，称为Delta-24-RGDOX，其表达T细胞 激活剂OX 40 L，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与维持免疫抑制的因子的抑制剂的给药 神经胶质瘤的特征。由于吲哚胺-2，3-二氧合酶（IDO）表达在 因此，我们特别感兴趣的是开发在病毒治疗期间下调IDO的策略。 IDO对色氨酸的催化作用在胶质瘤细胞中具有重要的代谢作用。此外该 色氨酸的代谢物，包括犬尿氨酸（Kyn），激活芳基烃受体（AhR）， 诱导Treg分化和CD 8 + T细胞功能障碍。这项研究的中心假设是， 由Delta-24-RGDOX与IDO和AhR抑制剂组合组成的组合物将刺激细胞毒性免疫 影响和抑制针对肿瘤细胞的抑制性免疫应答，从而提供潜在的 恶性胶质瘤有效新疗法。为了验证这一假设，我们提出了三个目标： 1：检查在用Delta-24-RGDOX感染神经胶质瘤期间IDO-Kyn-AhR途径的激活 溶瘤腺病毒;特定目标2：鉴定肿瘤中的代谢和免疫修饰 在用Delta-24-Kyn-AhR处理的胶质瘤中抑制IDO-Kyn-AhR通路产生的微环境。 具体目标3：在预处理中测试Δ-24-RGDOX和IDO/AhR抑制剂的组合。 神经胶质瘤的临床相关模型。这个项目是实现我们长期目标的下一步， 病毒免疫疗法作为恶性胶质瘤的标准治疗。

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.