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Dendritic cells are highly efficient antigen-presenting cells distributed throughout lymphoid and non-lymphoid tissues. Dendritic cells have been identified infiltrating a variety of human carcinomas, and several observations suggest an important role in antitumor immunity. The objective of this proposal is to examine the possibility that the infusion of dendritic cells pulsed ex vivo with a tumor-associated antigen will initiate an antitumor immune response in vivo. A method of expanding autologous dendritic cells for clinical use has been developed that is based on the capacity of granulocyte-macrophage colony stimulating factor (GM-CSF) to mobilize peripheral blood CD34+ hematopoietic progenitors and on the synergistic action of GM-CSF and tumor necrosis factor (TNF) on dendritic cell growth and differentiation. Patients receive a short course of GM-CSF and then undergo leukapheresis. CD34+ cells are enriched from the leukapheresis product. Dendritic cells are then expanded from the enriched CD34+ cell population in ir porous, plastic bags. The expanded dendritic cells can then be pulsed with tumor-associated antigens. A phase Ib clinical trial in patients with metastatic carcinoma will be performed to determine the phenotypic and functional characteristics of dendritic cells expanded from mobilized peripheral blood CD34+ progenitors in vitro, the nature and severity of toxicities associated with the infusion escalating doses of antigen-pulsed dendritic cells in vivo, and the capacity of dendritic cells pulsed with an oligopeptide antigen in vitro to induce an antigen-specific response in vivo. In these initial studies dendritic cells will be pulsed with a synthetic oligopeptide corresponding to an activating mutation of the p21 ras proto-oncogene. The results of these may provide a new approach to immunization in situ, a goal that previously could be approached only empirically with adjuvants; lead to a highly specific, non-toxic form of cancer immunotherapy; and help improve our understanding of the role of dendritic cells in antitumor immunity.
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