Dendritic cell-based approaches for the immunotherapy of malignant diseases
Ko, Eric C.
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The overall goal of this thesis is to develop and evaluate the immunogenicity and therapeutic efficacy of several interrelated strategies for the active specific immunotherapy of malignant diseases. The primary focal point is the development of dendritic cell (DC)-based immunization approaches, as DC have been shown to be highly effective in the induction of self-antigen-specific immune responses in the context of cancer immunotherapy. We have investigated the ability of DC-based immunotherapy to elicit immunity to antigens expressed in the tumor vasculature, and to a model tumor-associated antigen. In the first study, we have focused on targeting self-antigens expressed by endothelial cells associated with the tumor vasculature. A somatic fusion strategy, in which DC are hybridized with syngeneic endothelial cells, was utilized to load DC with endothelial cell antigens, and the hybrid cell was utilized to elicit immune responses to inhibit tumor angiogenesis. In the second study, we have focused on targeting the high molecular weight-melanoma associated antigen (HMW-MAA), a tumor-associated antigen expressed by melanoma cells. DC were transfected with a vector encoding HMW-MAA to elicit HMW-MAA-specific cellular immunity. A secondary focal point of this thesis is to evaluate related immunization approaches that also target HMW-MAA. To this end, we have evaluated the immunogenicity and characterized the immune responses elicited by a variant of an anti-idiotype mAb and two peptides, all of which were selected on the basis of their in vitro mimicry of HMW-MAA. Collectively, the studies described in this thesis extend the current approaches for the immunotherapy of malignant diseases by describing a novel DC approach to elicit immune responses targeting the tumor vasculature, and by offering alternative immunization approaches that can be utilized to elicit HMW-MAA-specific immune responses.