COMPLETE REGRESSION OF HUMAN NEUROBLASTOMA XENOGRAFTS IN ATHYMIC MICEAFTER LOCAL NEWCASTLE-DISEASE VIRUS THERAPY

Background: Neuroblastoma is the most common pediatric extra-cranial s olid cancer. Using conventional therapies, children older than 1 year of age with advanced neuroblastoma have a poor prognosis. The developm ent of new approaches for treating such children with neuroblastoma co ntinues to be one of the most important goals today in pediatric oncol ogy. Despite numerous anecdotal reports of human tumor regression duri ng viral infections, the use of viruses to directly lyse neuroblastoma cells has never been reported as a potential therapy. Newcastle disea se 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 neuro blastoma (IMR-32) cells is maintained during the in vivo treatment of established tumors. Methods: Two experiments mere performed using NDV strain 73-T. Athymic mice with subcutaneous IMR-32 human neuroblastoma xenografts (6-12 mm) were treated intralesionally with live NDV, UV-i nactivated NDV, or phosphate-buffered saline (PBS). To study virus rep lication in situ, mice were given intratumoral or intramuscular inject ions of NDV. These mice were then killed at various times, and the amo unt of infectious virus present in tumor or muscle was determined. Res ults: After one injection of live NDV, 17 of 18 tumors regressed compl etely, whereas rapid tumor growth occurred in all 18 mice treated with PBS and in all nine mice treated with UV-inactivated NDV (P<.0001). T he one tumor that showed only a partial response to a single injection regressed completely after a second NDV treatment. Six months followi ng virus-induced regression, only one tumor had recurred. No significa nt acute or chronic side effects of live NDV were noted in athymic mic e given doses up to 500 times that used in this study. Virus levels in creased more than 80-fold between 5 and 24 hours in virus-injected tum ors (P<.04), while no infectious virus was produced in NDV-injected mu scle tissue. Conclusions: NDV 73-T appears to replicate selectively in human IMR-32 neuroblastoma xenografts, leading directly to a potent a ntitumor effect as demonstrated by long-lasting, complete tumor regres sion occurring after a single local injection of virus. Implication: T hese experiments may provide an important step in the development of n ew therapeutic approaches to challenging cancers such as neuroblastoma .