The proposed study investigates the development of a novel approach for a cancer vaccine. The strategy involves the fusion of dendritic cells (DC) with MUC1 expressing cancer cells to generate antitumor immunity in MUC1 transgenic mice (MUC1.Tg). Activation of T cells requires the antigenic peptide presented to the major histocompatibility complex (MHC) and costimulatory molecules from antigen presenting cells (APCs). The absence of MHC and costimulation, thereby functional activation of T cells can result in the induction of tolerance to tumor antigens. DC expresses the essential costimulatory ligands and exhibits the capacity to stimulate primary cytolytic T cell responses. The fusion of DC and tumor cells allows for the expression of multiple tumor antigens in the context of costimulation. MUC1, a tumor associated antigen, is a high molecular weight glycoprotein that is overexpressed in human breast, pancreatic and other carcinomas. They can serve as targets for active specific immunotherapy (ASI). The proposed work will study the development of ASI for MUC1 positive tumors using fusions of dendritic cells (DC) and carcinoma cells that express MUC1. Recent studies have demonstrated that fusion cells derived from DC and MUC1-positive carcinomas (FC/MUC1) induce immunity against MUC1 and rejection of established tumor metastases. The effectiveness of MUC1-positive fusion cells as antitumor vaccines will be studied in transgenic mice that express MUC1 and are unresponsive to MUC1 antigen. A syngeneic model of a MUC1 carcinoma in the transgenic strain will be used to evaluate reversal of tolerance and induction of antitumor activity. The MUC1 transgenic mice will be crossed with mice that express transforming genes and develop breast carcinoma spontaneously. In these models, MUC1-positive fusion cells will be evaluated in the prevention and treatment of spontaneous tumors.
The specific aims are: 1). To study the basis for reversal of unresponsiveness to MUC1 in MUC1 transgenic mice immunized with fusion vaccine of dendritic cells and MUC1-positive tumor cells. 2). To determine whether reversal of unresponsiveness to MUC1 by fusion cells is effective in the prevention and treatment of MUC1 -positive transplantable tumors in MUC1 transgenic mice. 3). To assess the effectiveness of fusion cell vaccines in the prevention and treatment of spontaneous breast carcinoma in transgenic mice.
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