Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation

Abstract

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife PerfexionTM and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4 to 12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P<0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P<0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.

Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth

“…Nonirradiated glioblastoma tumor cells (DBT) were implanted in the ipsilateral hemisphere 6 weeks postirradiation (13). Anatomic MRI and histology (hemotoxylin and eosin [H&E] staining) showed no evidence of frank radiation necrosis or structural changes at these irradiation doses (14, 15). (We note that laboratory mice are roughly half as radiation sensitive [re LD 50 ] as humans.…”

Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy

“…We have developed a novel, Gamma Knife ® (GK) enabled, focal (hemispheric) brain-irradiation mouse model ( 10 ), termed the Radiation-Induced Immunosuppressive Microenvironment (RI 2 M) model, that provides a powerful platform for investigation into the late effects of irradiation on the brain parenchyma microenvironment. Earlier studies of GK-enabled focal-irradiation of mouse brain from this laboratory employed substantially greater radiation doses and were purposefully designed to reliably elicit late-time-to-onset radiation necrosis in an experimentally tractable time frame, with radiation necrosis consistently appearing approximately four to eight weeks post-irradiation ( 11 – 17 ). Importantly, the resultant radiation necrosis in the mouse brain recapitulated all of the key histologic hallmarks of the clinically observed pathology, giving strong confidence regarding the platform’s clinical relevance.…”

Ionizing radiation-induced risks to the central nervous system and countermeasures in cellular and rodent models

“…Thus, VEGF expression inhibitor bevacizumab (AvastinV R , Genentech) has been used to treat radiation-induced brain necrosis in 15 patients (Gonzalez et al 2007), and has efficiently decreased it in 50-60 Gy gamma ray ('gamma knife' model) irradiated mice . However, bevacizumab treatment has been reported to cause side effects during prolonged administration, including vessel overpruning, deep vein thrombosis and focal mineralization (Jeyaretna et al 2011;Levin et al 2011;Duan et al 2017). Moreover, other studies have demonstrated the recurrence of radiation necrosis after stopping bevacizumab treatment and drugresistance for re-treatment after discontinuation (Furuse et al 2011;Zhuang et al 2016).…”