VACCINE THERAPY OF PEDIATRIC MALIGNANCIES UTILIZING DENDRITIC CELLS

人类癌症的免疫治疗在很大程度上局限于黑色素瘤和肾细胞癌的应用，这两种肿瘤在很大程度上局限于成年人。尽管免疫系统在某些恶性肿瘤中具有潜在的重要性，尽管在许多病理状态下儿童免疫系统表现出增强的反应性，但在制定疫苗策略时，儿童癌症通常被忽视。我们建议在神经母细胞瘤、软组织肉瘤、骨尤因肉瘤和Wilms肿瘤患者中研究新的疫苗策略，这些肿瘤代表着困难的儿童肿瘤，但存在大量关于细胞表面抗原（可被免疫系统识别的肿瘤蛋白）表达的信息。疫苗的组成将利用树突状细胞（DC）生物学方面迅速发展的知识和技术。DC是一种有效的抗原呈递细胞，可以在培养物中与抗原脉冲，随后用于刺激T细胞的初级免疫反应。在实验室研究和早期临床研究中，DC已被证明在对肿瘤产生特异性免疫反应导致肿瘤消退方面非常有效。这些研究为研究DC在小儿晚期癌症患者中的应用提供了理论依据。DC将从患者的外周血中产生，并与自体（患者自身）肿瘤脉冲产生疫苗试剂。此外，一半的免疫细胞将暴露在锁眼帽贝血青素（KLH）中。KLH是一种刺激免疫反应的物质，它将被用作验证免疫技术是否有效的对照物。在一系列免疫接种期间和之后，将进行血液检查、皮肤检查、x光检查和扫描，以评估患者对免疫接种的反应（肿瘤缩小、反应性t细胞增加等），并监测副作用。

Immunotherapy of human cancers has largely been restricted to applications in melanoma and renal cell cancer, two tumors that are largely confined to the adult population. Pediatric cancers have been generally neglected when developing vaccine strategies, despite the potential importance of the immune system in some of these malignancies and despite the enhanced responsiveness of the immune system demonstrated by children in many pathologic states. We propose to investigate new vaccine strategies in patients with neuroblastoma, soft tissue sarcomas, Ewings sarcomas of bone, and Wilms tumors which represent difficult pediatric tumors, and yet for which considerable information about cell surface antigen (tumor proteins which can be recognized by the immune system) expression exist. The composition of the vaccines will take advantage of rapidly developing knowledge and technology regarding the biology of dendritic cells (DC). DC are potent antigen-presenting cells which can be pulsed with antigens in culture and subsequently used to stimulate primary immune responses in T cells. In laboratory studies and early clinical studies, DC have been shown to be highly effective at generating specific immune responses to tumors leading to tumor regression. These studies serve as rationale for the study of DC in pediatric patients with advanced cancer. DC will be generated from the patient+s peripheral blood and pulsed with autologous (the patient's own) tumor to generate vaccine reagents. In addition, one half of the immune cells will be exposed Keyhole Limpet Hemocyanin (KLH). KLH is a substance which stimulates an immune response and which will be used as a control to verify whether the immunization technique has worked. During and after the series of immunizations, blood tests, skin tests, x-rays, and scans will be done to assess the patients response to the immunizations (tumor shrinkage, increase in reactive T-cells, etc.), and to monitor for side effects.