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，在标准治疗后几乎100%复发。那里 对免疫疗法产生了极大的兴趣，因为它最近在对抗许多类型的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，肽疫苗或树突状细胞的随机临床试验， 细胞疗法尚未成功。免疫治疗缺乏成功的一个主要原因可能是由于 GBM的高度免疫抑制微环境导致该肿瘤在免疫学上是“冷的”。 我们正在利用溶瘤HSV 1（oHSV）的双重性质，即直接GBM复制细胞毒性和 在复发性GBM的1期临床试验中，当我们开始分析来自 在这项试验中，出现了与oHSV剂量和常用伴随治疗相关的问题，例如 类固醇或贝伐单抗。这些问题的答案将有助于设计临床试验的下一步。 oHSV。为了回答这些问题，我们已经开发了GBM小鼠模型的试验数据，以显示GBM的变化 在免疫细胞中，当用oHSV治疗时，TME影响GBM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应答的特征在于活化的GBM的扩增。 TIL针对模型肿瘤抗原，而GBM进展的特征在于缺乏这种扩增。 因此，我们假设观察到的oHSV介导的抗GBM应答依赖于TIL扩增， 以及诸如oHSV剂量和其它伴随治疗（例如 类固醇和贝伐单抗调节这种情况。我们计划通过评估这些假设的动力学， 扩增针对模型GBM抗原的TIL（目的1），并通过确定标准治疗是否 例如地塞米松和/或贝伐单抗的治疗改变了针对模型GBM的TIL扩增 抗原（目的2）。如果这些目标取得成功，其总体影响将使我们能够理解为什么有些人会这样做。 GBM患者似乎对oHSV治疗有反应，并提高了我们增加GBM患者百分比的能力。 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.