VACCINE THERAPY OF PEDIATRIC MALIGNANCIES UTILIZING DENDRITIC CELLS

人类癌症的免疫治疗主要局限于黑色素瘤和肾细胞癌，这两种肿瘤主要局限于成年人群。 在制定疫苗策略时，儿童癌症通常被忽视，尽管免疫系统在其中一些恶性肿瘤中具有潜在的重要性，尽管儿童在许多病理状态下表现出免疫系统的反应性增强。 我们建议在神经母细胞瘤、软组织肉瘤、骨尤因肉瘤和肾母细胞瘤患者中研究新的疫苗策略，这些肿瘤代表了困难的儿科肿瘤，但存在关于细胞表面抗原（可被免疫系统识别的肿瘤蛋白）表达的大量信息。 疫苗的组成将利用有关树突细胞（DC）生物学的快速发展的知识和技术。 DC是有效的抗原呈递细胞，其可以在培养物中用抗原脉冲并随后用于刺激T细胞中的初级免疫应答。 在实验室研究和早期临床研究中，DC已被证明在产生对肿瘤的特异性免疫应答方面非常有效，导致肿瘤消退。 这些研究为DC在晚期癌症儿科患者中的研究提供了理论基础。 DC将从患者的外周血中产生，并用自体（患者自己的）肿瘤脉冲以产生疫苗试剂。 此外，一半的免疫细胞将暴露于匙孔血蓝蛋白（KLH）。KLH是一种刺激免疫反应的物质，将用作对照，以验证免疫技术是否有效。在一系列免疫接种期间和之后，将进行血液测试、皮肤测试、X射线和扫描，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.