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.
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| Kridel, Steven J; Sawai, Hisako; Ratnikov, Boris I et al. (2002) A unique substrate binding mode discriminates membrane type-1 matrix metalloproteinase from other matrix metalloproteinases. J Biol Chem 277:23788-93 |
| Geiger, J D; Hutchinson, R J; Hohenkirk, L F et al. (2001) Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res 61:8513-9 |
| Geiger, J; Hutchinson, R; Hohenkirk, L et al. (2000) Treatment of solid tumours in children with tumour-lysate-pulsed dendritic cells. Lancet 356:1163-5 |
