VACCINE THERAPY OF PEDIATRIC MALIGNANCIES

描述：人类癌症的免疫治疗在很大程度上限于 在黑色素瘤和肾细胞癌中的应用， 肿瘤和两种主要局限于成年人群。 在开发疫苗时，儿童癌症通常被忽视 尽管这些恶性肿瘤中的一些具有免疫原性， 尽管许多儿童的免疫反应性增强， 病理状态提出研究新的疫苗策略， 神经母细胞瘤和软组织肉瘤患者，这代表了两个 令人烦恼的肿瘤实体，但其中两个相当多的数据 关于细胞表面抗原的表达存在。 的组成 疫苗将利用迅速发展的知识和技术 关于树突状细胞（DC）的生物学。 DC很强大 - 抗原呈递细胞，其可以在体外用肿瘤细胞脉冲， 随后用于刺激初始T细胞中的初级免疫应答。 DC将从患者的外周血中分离出来，并用 自体肿瘤以产生疫苗试剂。 此外，申请人 将检查使用趋化因子（化学引诱细胞因子）交付 在疫苗接种现场。 趋化因子是白细胞 贩运和煽动过程。 趋化因子似乎也能增强 DC功能。 他们计划通过以下方式将趋化因子输送到当地的疫苗接种点： 在接种前将DC与分泌趋化因子的成纤维细胞组合。 自体成纤维细胞将被遗传修饰以分泌趋化因子。 该项目的具体目标是：1。 为了在体外评价 用自体肿瘤脉冲的人树突状细胞（DC）检测 T细胞对自体神经母细胞瘤和肉瘤的特异性反应，2。 到 体外测定趋化因子分泌细胞与 DC用自体肿瘤脉冲以检测、吸引和增强特异性， 抗原反应性T细胞，3. 进行疫苗治疗的第一阶段试验 单独或与分泌趋化因子的 复发性神经母细胞瘤或肉瘤儿童的成纤维细胞。

DESCRIPTION: Immunotherapy of human cancers has largely been restricted to applications in melanoma and renal cell cancer, two weakly immunogenic tumors and two which 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 propose to investigate novel vaccine strategies in patients with neuroblastoma and soft tissue sarcomas, which represent two vexing neoplastic entities, and yet two 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 tumor cells in vitro and subsequently used to stimulate primary immune responses in naive T cells. DC will be isolated from patient's peripheral blood and pulsed with autologus tumor to generate vaccine reagents. In addition, the applicants will examine the use chemokines (chemoattractant cytokines) delivered locally at the site of the vaccine. Chemokines are essential for leukocyte trafficking and inflammatory processes. Chemokines also appear to enhance DC function. They plan to deliver chemokines to the local vaccine site by combining DC with chemokine-secreting fibroblasts prior to inoculation. Autologous fibroblast will be genetically modified to secrete the chemokine. The Specific Aims of this project are: 1. To evaluate in vitro the capacity of human dendritic cells (DC) pulsed with autologus tumor to detect T cells specific responses to autologus neuroblastoma and sarcoma, 2. To determine in vitro the capacity of chemokine-secreting cells combined with DC pulsed with autologus tumor to detect, attract, and augment specific, antigen-reactive T cells, 3. To conduct a Phase I trial of vaccine therapy utilizing tumor -pulsed DC alone or combined with chemokine-secreting fibroblast in children with recurrent neuroblastoma or sarcoma.