A number of recent studies suggest that one of the reasons that tumors do not provoke protective immune responses in the host is that tumors do not induce effective """"""""help"""""""" for the generation of cytotoxic T lymphocytes (CTL). The basis for this failure may be that tumors lack the signals necessary for activation of T cells. It has been demonstrated that T cells require two signals for activation, an antigen-specific signal generated via the antigen receptor, and a second costimulatory signal. Without the second signal, Tcells not only fail to respond, but enter a long-lived stated of antigen-specific anergy. Recent studies have strongly implicated the T cell surface molecule CD28 as the costimulatory receptor, and the B7 molecule as its ligand on the antigen presenting cell. Expression of the costimulatory ligand is largely restricted to B cells, macrophages, and dendritic cells. Many solid tumors appear to lack B7 expression and thus may have a poor capacity to directly activate T cell responses and may even induce specific non-responsiveness. We propose a novel approach to immunotherapy which will exploit the costimulatory receptor and its ligand to enhance the immunogenicity of tumors in a mouse model. A monoclonal antibody to the costimulatory receptor CD28 will be used to provide costimulation systemically, and the gene for the costimulatory ligand B7 will be used to provide costimulation specifically by the tumor. The effectiveness of the antibody and gene therapy approaches in preventing the growth of primary tumors, established tumors, and in eliciting immunity to subsequent tumor challenge will be assessed in vivo. The mechanism of protection will be determined by analyzing helper and killer T cells in treated mice. We will also determine whether the costimulatory approach can be used in the long term propagation of tumor specific T cells in vitro for use in adoptive immunotherapy and the identification of tumor-specific antigens. Since reagents are currently available for the human costimulatory receptor and ligand, the results of this study can be rapidly transferred to treatment of human cancer.
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