RESUMEN
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.
Asunto(s)
Anticuerpos/uso terapéutico , Antígenos de Diferenciación/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Antígeno CD47/inmunología , Fagocitosis , Receptores Inmunológicos/metabolismo , Animales , Anticuerpos/farmacología , Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Niño , Modelos Animales de Enfermedad , Humanos , Inmunocompetencia , Inyecciones Intraventriculares , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/patología , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/secundario , Ratones Endogámicos C57BL , Modelos Biológicos , Metástasis de la Neoplasia , Fagocitosis/efectos de los fármacos , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.