Establishment of new MRI technologies to monitor efficacy of glioma virotherapy

描述（由申请人提供）：恶性胶质瘤患者的平均预后仅为15个月，并且这些癌症没有有效的治疗方法。在治疗神经胶质瘤中遇到的主要困难是药物递送效率低。可以在肿瘤细胞中选择性复制的病毒[溶瘤病毒（OV）]代表了克服这一问题的有希望的工具，但迄今为止临床试验的结果并没有提供预期的结果。我们最近已经证明，通过肿瘤在体内扩散的OV的能力被抑制肿瘤内浸润的吞噬性小胶质细胞和外周巨噬细胞，髓过氧化物酶（MPO）的活性，并迅速清除注射的OV。我们还显示了通过使用免疫抑制药物调节肿瘤内OV扩散、吞噬细胞浸润和肿瘤大小之间存在的动态平衡来增加脑肿瘤病毒治疗功效的可能性。因此，将OV治疗与免疫抑制药物相结合似乎是提高胶质瘤治疗效果的有效方法。然而，缺乏以非侵入性方式检测肿瘤内OV扩散和吞噬细胞浸润的手段构成了在临床环境中评价这种治疗策略的结果的重要限制。我们假设，一个完整的评估胶质瘤病毒治疗联合免疫抑制药物将需要开发非侵入性的体内成像技术，监测OV扩散，吞噬细胞浸润，肿瘤大小在整个治疗。我们的目标是通过应用两种新的磁共振成像（MRI）技术来检测肿瘤内OV扩散和吞噬细胞浸润来开发这样的成像系统。我们的合作者Chen博士和Weissleder博士发明了一种技术，通过磁增强MPO活性来成像吞噬细胞的存在。由于用于该技术的磁性增强试剂是基于钆的，因此它还提供了有关肿瘤大小的信息。第二项技术涉及开发一种配备有人工报告基因的OV，该报告基因呈现频率诱导的磁对比。这种病毒将从单纯疱疹病毒（HSV）衍生的OV中工程化，该OV是在我们部门开发的，并且足够安全和有效，可用于临床试验。这两种技术可以以组合的方式用于并发想象。因此，它们将大大提高我们监测胶质瘤病毒治疗结果的能力，并为更有效的治疗策略提供新的见解。公共卫生相关性：在这个项目中，我们计划应用两种新的MRI技术来监测神经胶质瘤治疗的结果，这些病毒可以选择性地在肿瘤细胞中复制。这些技术可以成像抗病毒免疫反应的存在，确定肿瘤的大小，并量化癌症内病毒的传播。这三个因素之间的关系是至关重要的胶质瘤病毒治疗的结果和应用这些新的诊断技术在临床试验中可以帮助设计更有效的治疗方法。

DESCRIPTION (provided by applicant): The average prognosis for patients with malignant gliomas is only 15 months, and there are no effective treatments for these cancers. A major difficulty encountered in treating gliomas is inefficient drug delivery. Viruses that can selectively replicate in tumor cells [oncolytic viruses (OVs) represent a promising tool to overcome this problem, but results from clinical trials did not provide the expected results so far. We have recently demonstrated that the capacity of OVs to spread through the tumor in vivo is inhibited by intratumoral infiltration of phagocytic microglia and peripheral macrophages that present myeloperoxidase (MPO) activity and rapidly clear the injected OVs. We have also shown the possibility to increase efficacy of brain tumor virotherapy by modulating the dynamic equilibrium existing between intratumoral OV spread, infiltration of phagocytes, and tumor size through the use of an immunosuppressive drug. Thus, combining OV-therapy with immunosuppressive drugs seems to be an efficient way to increase the outcome of glioma treatment. However, the lack of means to detect intratumoral OV spread and phagocytes infiltration in a non-invasive fashion constitutes an important limitation in evaluating the results of such therapeutic strategy in the clinical setting. We hypothesize that a full assessment of glioma virotherapy performed in combination with immunosuppressive drugs will need the development of non-invasive in vivo imaging techniques that monitor OV spread, phagocytes infiltration, and tumor size throughout the treatment. Our goal is to develop such imaging systems by applying two novel magnetic resonance imaging (MRI) techniques for the detection of intratumoral OV spread and phagocytes infiltration. One technology was invented by our collaborators, Drs. Chen and Weissleder, and images presence of phagocytic cells through magnetic enhancement of MPO activity. Because the magnetic enhancing reagent used for this technology is based on gadolinium, it provides also information on tumor size. The second technology involves the development of an OV armed with an artificial reporter gene that presents frequency induced magnetic contrast. Such virus will be engineered from a Herpes Simplex virus (HSV)-derived OV that was developed in our department and is sufficiently safe and efficient to be used in clinical trials. These two technologies can be used in a combined fashion for concurrent imagine. Thus, they will strongly increase our capacity to monitor the outcome of glioma virotherapy and will provide new insights for more efficient therapeutic strategies. PUBLIC HEALTH RELEVANCE: With this project we plan to apply two novel MRI technologies for monitoring the outcome of glioma treatment with viruses that can selectively replicate in tumor cells. These technologies can image the presence of anti-viral immune responses, determine the size of the tumor, and quantify the spread of the virus within the cancer. The relation between these three factors is crucial for the outcome of glioma virotherapy and application of these new diagnostic technologies in clinical trials can help the design of more efficient therapies.