Differentiation of Glioma from Radiation Injury Using Cellular MRI

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DESCRIPTION (provided by applicant): Despite extensive treatment strategies and investigations, the prognosis of glioblastoma multiforme is still poor. The main reason is the inability to delineate the margin of the tumor during routine investigations or during surgery. Moreover, current imaging modalities fail to differentiate, conclusively, the recurrent or left over tumor from radiation necrosis or necrotic tissues. For proper management and follow up it is utmost important to detect recurrent tumor as early as possible. Recently dendritic cell based vaccination and cytotoxic T-lymphocytes (CTL) are being considered for the treatment of recurrent glioma. In the animal models as well as in the early phases of clinical trials, CTL has been shown to accumulate in the glioma. By tracking the migration and homing of CTL it may be possible to differentiate recurrent glioma from radiation necrosis. Recently, using two FDA-approved agents, we formed ferumoxides-protamine sulfate complex and labeled any kind of mammalian cells. To examine whether labeled cells can be used as cellular probes to detect and differentiate physiological and/or pathological conditions, we have selected glioma and radiation injury models. It is hypothesized that in vivo magnetic resonance imaging (MRI) tracking of magnetically labeled CTLs will enable us to identify different patterns of accumulation and incorporation of labeled injected CTLs, thus allowing for differentiation between recurrent glioma and radiation injury. The goals of this study will be achieved by making glioma as well as radiation injury models in tumor bearing or control nude rats. Nude rats will be used to implant human U-251 glioma cell lines. In these rats we will test whether CTLs produced in vitro by U-251 cell lysate-pulsed dendritic cells can recognize the implanted human glioma and differentiate it from radiation injury. CTLs produced in vitro will be magnetically labeled using feridex- protamine sulfate complexes and the labeled cells will be injected into tail vein of the rats at different stages of their disease processes. These labeled cells, once incorporated into the tumors or areas of injury, can be detected as low signal intensity areas on in vivo and ex vivo MRI because of the susceptibility effects of iron oxides inside the cells. Serial MRI of tumors and radiation injured areas after injecting labeled cells at different time points will be obtained by a 7 tesla MRI system. The findings of MRI will be correlated with histology, and immuonohistochemical detection of CTLs. The results will also be compared among the animals of all groups. Early detection of recurrent or metastatic glioma as well as early differentiation of glioma from radiation necrosis will help clinician to tackle this devastating neurological malignant tumor. Early detection and differentiation of recurrent glioma from radiation injury/necrosis by noninvasive imaging technique is essential for the proper management of this devastating malignant disease. If these studies are successfully completed, the results can easily be translated into a clinical trial, where patients' own dendritic cells (differentiated from autologous monocytes and/or hematopoietic stem cells separated from peripheral blood mononuclear cells [PBMC]), can be used to produce cytotoxic T-lymphocytes (CTL) to target tumor cells for detection and differentiation of tumor from radiation injury/necrosis. Genetically engineered CTL can also be used. This magnetic labeling technique will also help investigators to track the injected CTL in the body as well as in the targeted areas by magnetic resonance imaging (MRI).