TMOD-48. F18-FET PET/ Ferumoxytol MRI To Distinguish Progression From Pseudoprogression in Mouse Models of High-Grade Glioma

Abstract The current standard of care for high grade glioma (HGG) – resection followed by radiotherapy and concurrent chemotherapy with temozolomide – causes inflammation called pseudoprogression (PsP), which appears as abnormal MRI signals at the site of the original tumor within 2-6 months. None of the existing imaging protocols can reliably distinguish PS from true progression in HGG. The goal of this study was, using iron oxide Ferumoxytol, taken up uniquely by inflammatory macrophages, and F18-flurotyrosine (FET), taken up by glioma cells, to develop a reliable MRI/PET protocol for PsP and HGG progression, respectively. Glioma cells (106) were inoculated orthotopically into female nude athymic (U251) or wild-type (GL261) mice. Once the tumors reached a size of ca. 50 mm3 mice were treated with oral temozolomide (TMZ) and 2 Gy radiation therapy (RT) daily for 5 days. 7 days after, T2 maps were acquired followed by injection of ferumoxytol (SPIONs) as a T2 contrast agent. 24 hours later, 0.1 mCi of F18-FET were injected and a PET/ T2 MRI was acquired. If macrophages take up iron uniquely compared with tumor cells, we expect the SPION T2 signal reduction to be greater with PS which is induced by chemo-radiation therapy. Indeed, untreated fast-growing tumors shows no changes in T2 relaxation times after injection of ferumoxytol with a high uptake of 18F-FET. The irradiated tumors (10 Gy)+TMZ treated tumors showed a significant decrease in T2 (up to -15 msec) in the GL261 wild type mice; while U251 immunocompromised animals exhibited a high F18-FET uptake. In conclusion, immunocompromised mice with xenograft U251 GBM showed less PsP profiling with a higher level of disease progression. SPION contrast in MRI for PsP, combined with F18-FET for true progression, showed a promising discernment of PsP from tumor progression non-invasively for HGG.