Establishment of new MRI technologies to monitor efficacy of glioma virotherapy

描述(申请人提供)：恶性胶质瘤患者的平均预后只有15个月，而且目前还没有有效的治疗方法。治疗胶质瘤遇到的一个主要困难是药物输送效率低下。可以在肿瘤细胞中选择性复制的病毒[溶瘤病毒(OV)是克服这一问题的有希望的工具，但临床试验的结果到目前为止还没有提供预期的结果。我们最近已经证明，OVS在体内通过肿瘤扩散的能力被肿瘤内吞噬细胞的小胶质细胞和外周巨噬细胞的侵袭所抑制，这些巨噬细胞呈现髓过氧化物酶(MPO)活性，并迅速清除注入的OVS。我们还表明，通过使用免疫抑制药物来调节肿瘤内OV扩散、吞噬细胞的渗透和肿瘤大小之间存在的动态平衡，有可能提高脑瘤病毒治疗的疗效。因此，OV治疗与免疫抑制药物相结合似乎是提高脑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OV在肿瘤内的扩散和吞噬细胞浸润的手段构成了在临床环境下评估这种治疗策略的结果的一个重要限制。我们假设，对联合免疫抑制药物进行的胶质瘤病毒治疗的全面评估将需要开发无创的体内成像技术，在整个治疗过程中监测卵泡的扩散、吞噬细胞的浸润和肿瘤的大小。我们的目标是通过应用两种新的磁共振成像(MRI)技术来开发这样的成像系统，以检测OV在肿瘤内的扩散和吞噬细胞的渗透。其中一项技术是由我们的合作者Chen博士和Weissleder博士发明的，它通过MPO活性的磁性增强来成像吞噬细胞的存在。由于这项技术使用的磁性增强剂是基于Gd的，它还提供了关于肿瘤大小的信息。第二项技术涉及开发一种OV，它配备了一种人造报告基因，可以呈现频率感应的磁对比度。这种病毒将从我们科室开发的单纯疱疹病毒(HSV)衍生的卵子病毒中培育出来，具有足够的安全性和有效性，可用于临床试验。这两种技术可以组合使用，以实现并发映像。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，并将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磁共振成像技术来监测胶质瘤病毒治疗的结果，这种病毒可以在肿瘤细胞中选择性复制。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，并量化病毒在癌症中的扩散。这三个因素之间的关系对胶质瘤病毒治疗的结果至关重要，在临床试验中应用这些新的诊断技术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.