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.
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.
| Farrar, Christian T; Buhrman, Jason S; Liu, Guanshu et al. (2015) Establishing the Lysine-rich Protein CEST Reporter Gene as a CEST MR Imaging Detector for Oncolytic Virotherapy. Radiology 275:746-54 |
| Kleijn, Anne; Chen, John W; Buhrman, Jason S et al. (2011) Distinguishing inflammation from tumor and peritumoral edema by myeloperoxidase magnetic resonance imaging. Clin Cancer Res 17:4484-93 |
