Oncolytic virus therapeutic responses occur from changes in the glioblastoma immune microenvironment

摘要 胶质母细胞瘤(GBM)是一种致命的脑癌，经过标准治疗后，几乎100%的时间会复发。那里 免疫疗法引起了人们的极大兴趣，因为它最近在治疗多种癌症方面取得了成功， 但最近在GBM中使用免疫检查点抑制剂、多肽疫苗或树突状细胞进行的随机临床试验 细胞疗法并不成功。免疫治疗不成功的一个主要原因可能是 这种高度免疫抑制的微环境导致这种肿瘤在免疫上处于“冷”状态。 我们正在利用一种溶瘤的HSV1(OHSV)，因为它具有直接的GBM复制细胞毒性和 在复发性GBM的1期临床试验中有效的原位免疫刺激作用。当我们开始分析数据时， 在这项试验中，出现了与OHSV剂量和常用的伴随治疗有关的问题，如 类固醇或贝伐单抗。对这些问题的回答将有助于设计下一步的临床试验 OHSV。为了回答这些问题，我们在GBM的小鼠模型上开发了试点数据，以显示如何变化 在免疫细胞中，当使用OHSV治疗时，TME会影响GBM的进展或消退。具体来说，我们的研究 似乎表明来自OHSV治疗的抗GBM反应的特征是激活的 TIL针对一种模型肿瘤抗原，而GBM进展的特点是缺乏这种扩张。 因此，我们假设观察到的OHSV介导的抗GBM反应依赖于TIL的扩张 抗肿瘤抗原和因素，如OHSV剂量和其他伴随治疗，如 类固醇和贝伐单抗对此有调节作用。我们计划通过评估动力学来检验这些假说。 扩大针对模型GBM抗原的TIL(目标1)并确定护理标准 治疗，如地塞米松和/或贝伐单抗，改变到对模型GBM的扩张 抗原(目标2)。如果成功，这些目标的总体影响将使我们能够理解为什么有些目标 GBM患者似乎对OHSV治疗有反应，并改善了我们增加 响应者。

Abstract Glioblastoma (GBM) is a fatal brain cancer that recurs after standard of care almost 100 % of the time. There has been great interest in immunotherapy because it has shown recent success against many types of cancers, but recent randomized clinical trials in GBM using immune checkpoint inhibitors, peptide vaccines, or dendritic cell therapies have not been successful. A major reason for the lack of immunotherapy success is likely due to the highly immunosuppressive microenvironment of GBMs which leads this tumor to be immunologically “cold”. We are utilizing an oncolytic HSV1 (oHSV) for its dual properties of direct GBM replicative cytotoxicity and of potent in situ immunostimulation in a phase 1 clinical trial in recurrent GBM. As we begin to analyze data from this trial, questions arise related to the dose of oHSV and to commonly used concomitant treatments, such as steroids or bevacizumab. Answers to these questions will help in design of the next steps in clinical trials of this oHSV. To answer these questions, we have developed pilot data in mouse models of GBM to show how changes in the immune cell TME affect GBM progression or regression when treated with oHSV. Specifically, our studies appear to show that anti-GBM responses from oHSV therapy are characterized by an expansion of activated TILs against a model tumor antigen, whereas GBM progression is characterized by a lack of this expansion. We thus hypothesize that observed oHSV-mediated anti-GBM responses depend on TIL expansion against tumor antigen and that factors such as oHSV dose and other concomitant treatments such as steroids and bevacizumab modulate this. We plan to test these hypotheses by evaluating the kinetics of expansion of TILs against a model GBM antigen (aim 1) and by determining if standard of care treatments, such as dexamethasone and/or bevacizumab change TIL expansion against a model GBM antigen (aim 2). The overall impact of these aims if successful would thus allow us to understand why some GBM patients appear to respond to oHSV therapy and improve our ability to increase the percentage of responders.