RESUMEN
Monoclonal antibodies have the potential to target therapy for high-grade gliomas. Monoclonal antibody 8H9 is specific for membrane protein B7H3 and is reactive with most human high-grade gliomas. We tested the 8H9scFv-PE38 recombinant Pseudomonas immunotoxin in a preclinical model of high-grade glioma. The half maximal inhibitory concentration (IC(50)) of 8H9scFv-PE38 in vitro was determined using glioblastoma cell lines U87 and U251. Maximum tolerated infusion dose of 8H9scFv-PE38 following interstitial infusion to the striatum and pons was defined using athymic rats. Maximum tolerated infusion dose of 8H9scFv-PE38 or PBS control were interstitially delivered to athymic rats xenografted with U87 in the striatum or brain stem. Radiographic response and survivals were measured and compared between treatment groups. The in vitro IC(50) of 8H9scFv-PE38 for U87 was 1,265 ng/mL and, for U251, 91 ng/mL. The maximum tolerated infusion doses of interstitially infused 8H9scFv-PE38 to the striatum and brain stem were 0.75 and 1.8 mug, respectively. For rats harboring intracranial U87 xenografts, infusion of 8H9scFv-PE38 increased mean survival (striatum, 43.4 versus 24.6 days; brain stem, 80.6 versus 45.5 days; n = 28 total) and produced three long-term survivors past 120 days. None of the 14 placebo-treated animals survived >54 days. Tumors also showed volumetric response to infusion of 8H9scFv-PE38 by magnetic resonance imaging. Interstitial infusion of 8H9scFv-PE38 shows potential for the treatment of hemispherical and brain stem glioma. Mol Cancer Ther; 9(4); 1039-46. (c)2010 AACR.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Glioma/tratamiento farmacológico , Inmunotoxinas/uso terapéutico , Infusiones Intralesiones , Proteínas Recombinantes/uso terapéutico , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Tronco Encefálico/efectos de los fármacos , Tronco Encefálico/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glioma/diagnóstico por imagen , Glioma/patología , Humanos , Inmunotoxinas/administración & dosificación , Inmunotoxinas/efectos adversos , Inmunotoxinas/farmacología , Estimación de Kaplan-Meier , Dosis Máxima Tolerada , Radiografía , Ratas , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A critical need exists for the development of novel forms of treatment for high-grade glioma. Molecular characterization of high-grade glioma has shown overexpression of the epidermal growth factor receptor, antagonists to which, including erlotinib, may prevent tumor growth. Interstitial infusion is a mode of local delivery which bypasses the blood-brain barrier and utilizes a pressure-dependent gradient to enhance drug uniformity and volume of distribution. Interstitial infusion of erlotinib was performed to the striatum of 12 rats in increasing, therapeutic doses. No evidence of clinical or histopathologic toxicity was found. In this experimental study we demonstrate that interstitial infusion of erlotinib is safe in the rodent brain, and may have potential applicability for the treatment of high-grade glioma.