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，这两种肿瘤免疫原性较弱，并且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，尽管其中一些恶性肿瘤具有免疫原性潜力，尽管儿童在许多病理状态下表现出增强的免疫反应性。 我们建议在神经母细胞瘤、软组织肉瘤、骨尤文氏肉瘤和肾母细胞瘤患者中研究新的疫苗策略，这些肿瘤代表令人烦恼的肿瘤实体，但存在大量关于细胞表面抗原表达的数据。 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是一种有效的抗原提呈细胞，可以在体外用抗原脉冲并随后用于刺激初始T细胞中的初级免疫应答。 在临床前研究中，DC已被证明在对免疫原性差的肿瘤产生特异性免疫应答方面非常有效，导致肿瘤消退。 这些临床前研究为DC在晚期癌症儿科患者中的研究提供了依据。 将从患者的外周血中分离DC，并用自体肿瘤脉冲以产生疫苗试剂。 拟定的临床研究将在FDA批准的IND（BB-IND #6958，Mule博士，已获得允许治疗儿童的修订IND）下进行。

Immunotherapy of human cancers has largely been restricted to applications in melanoma and renal cell cancer, two weakly immunogenic tumors and two that are largely confined to the adult population. Pediatric cancers have been generally neglected when developing vaccine strategies, despite the immunogenic potential of some of these malignancies and despite the enhanced immunoreactivity demonstrated by children in many pathologic states. We propose to investigate novel vaccine strategies in patients with neuroblastoma, soft tissue sarcomas, Ewing's sarcomas of bone, and Wilm's tumors which represent vexing neoplastic entities, and yet for which considerable data regarding cell surface antigen 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 vitro and subsequently used to stimulate primary immune responsed in naive T cells. In pre-clinical studies, DC have been shown to be highly effective at generating specific immune responses to poorly immunogenic-tumors leading to tumor regression. These pre-clinical studies serve as rationale for the study of DC in pediatric patients with advanced cancer. DC will be isolated from patient's peripheral blood and pulsed with autologous tumor to generate vaccine reagents. The clinical studies proposed will be conducted under an FDA-approved IND (BB-IND #6958 to Dr. Mule, an amended IND to allow the treatment of children has been obtained.)