Effects of Irradiated Tumor Vaccine and Continuous Localized Infusion of Granulocyte-Macrophage Colony-Stimulating Factor on Neuroblastomas in Mice

Abstract

Background/Purpose: Immunomodulatory treatment has been proposed as a feasible strategy for neuroblastoma treatment. In this study, the antitumor effects of a continuous localized subcutaneous infusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) into the injection site of irradiated tumor vaccine used as a source of tumor antigens on mouse neuroblastoma were investigated. Methods: A/J mice were inoculated subcutaneously with wild type neuro -2a neuroblastoma cells and then treated with 5 doses of irradiated tumor vaccine or continuous localized infusion of GM-CSF (1 ng/d or 10 ng/d) via an osmotic minipump. Survival rates and survival times were compared among the groups. Tumor growth rates and animal survival times were followed and compared among different groups. Histologic and immunohistochemical analyses were performed to observe the immune response induced by various treatment strategies. Results: Tumor growth rates were reduced significantly and survival times prolonged significantly by the treatment using tumorvaccine and continuous infusion of 10 ng/d of GM- CSF when compared with the control group (P < .05). One mouse treated with tumor vaccine and a 10 ng/ d infusion of GM-CSF showed tumor regression and long-term survival, and no tumor growth was noted after rechallenge with wild-type neuro-2a cells. In contrast, using tumor vaccine only, or tumor vaccine combined with a 1 ng/d infusion of GM-CSF was less effective than tumor vaccine combined with a 10 ng/d infusion of GM-CSF (P < .05). Infusion of GM-CSF alone had no antitumor effects. Immunohistologic analyses showed significant CD4+ and CD8+ T cell infiltration of the tumor in the mice treated with tumor vaccine and a 10 ng/d infusion of GM-CSF. Conclusions: The results suggest that an irradiated tumor vaccine combined with continuous localized infusion of GM-CSF may induce a tumor-specific antitumor immune response that can suppress tumor growth and prolong survival. Such a treatment strategy deserves consideration as a possible adjuvant treatment for neuroblastoma. Copyright 2002, Elsevier Science (USA). All rights reserved .