Complete Regression of Human Neuroblastoma Xenografts in Athymic Mice After Local Newcastle Disease Virus Therapy

Abstract

Background : Neuroblastoma is the most common pediatric extra-cranial solid cancer. Using conventional ther apies, Children older than 1 year of age with advanced neuroblastoma have a poor progrnosis. The development of new approaches for treating such children with neuroblastoma continues to be one of the most important goals today in pediatric oncology. Despite numerous anecdotal reports of human tumor regression during viral infections, the use of viruses to directly lyse neuroblastoma cells has never been reported as a potential therapy.New-castle disease virus(NDV) has been shown to replicate in and kill cultured human and rat neuroblastoma cells but not normal human fibroblasts. Purpose : Our purpose was to determine if this selective killing of human neuroblastoma (IMR-32) cells is maintained during the in vivo treatment of established tumors. Mothods : Two experiments were performed using NDV strain 73-T Athymic mice with subcutaneous IMR-32 human neuriblastoma xenografts (6–12 mm) were treated intralesionally with live NDV, UV-inacivated NDV, or phosphate-buffered saline (PBS). To study vrius replication in situ, mice were given intraumoral or intramuscular injections of NDV. These mice were then killed at various times, and the amount of infectious viurs present in tumor or muscle was determined. Results : after one injection of live NDV, 17 of 18 tumorsregressed completely, Whereas rapid tumor growth occured in all 18 mice treated with PBS and in all nine mice treated with UV-inactivated NDV (P<.0001). The one tumor that showed only a partial response to asingle injection regressed completely after a second NDV treatment, six months following virus-induced regression, only one tumor had recurred.Nosignificant acute or chronic side effects of live NDV were noted in athymic mice given doses up to 500 times that used in this study. Virus levels increased more than 80-fold between 5 and 24 hours in virus-injected tumors(P<.04), while no infectious virus was produced in NDV-injected muscle tissue. Conclusions: NDv 73-T appears to replcate selectively in human IMR-32 neuroblastoma xenografts, leading directly to a potent antitumor effect as demonstrated by long-lasting, complete tumor regression occuring after a single local injection of virus. Implication: These experiments may proveide an important step in the development af new therapeutic approaches to challenging cancers such as neuroblastoma. [J Natl Cancer Inst 86: 1228–1233, 1994]