The applicant's efforts to produce an effective cancer therapy are focused on methods to restore tumor antigen presentation. Dendritic cells (DC) are bone marrow-derived leukocytes characterized by the high level expression of major histocompatibility (MHC) and co-stimulatory molecules as well as the capacity of take-up, process and present antigens. These powerful capacities facilitate activation and expansion of antigen-specific T cells. Recent murine studies and clinical trials have shown that DC, when appropriately armed with a tumor antigen (Ag) can promote antitumor immunity and significant tumor regression. In this application the applicant hypothesizes that autologous DC, when transduced with an adenoviral vector expressing the IL-7 gene (DC-AdIL-7), can be used to stimulate specific and therapeutic anti-tumor immunity without the need for priming with a tumor antigen ex vivo. In preliminary studies, the intratumoral injection of these gene-modified DC into established murine tumors induced specific antitumor response both locally and at metastatic sites. Animals treated in this manner not only experienced complete tumor regression, but also were protected from subsequent tumor challenge. He hypothesizes that the autologous tumor provides access to the entire repertoire of available antigens, both increasing the likelihood of a response and reducing the potential for phenotypic modulation. The overall goal of this application is to use murine models to determine the immunologic mechanisms by which DC-AdIL-7 mediate tumor eradication.
The specific aims are: 1) to identify the mechanisms of antitumor responses in DC-AdIL-7 intratumoral therapy and 2) to determine the features of transferred DC effective antitumor response. A unique focus of this work is the emphasis on a DC-based approach to stimulate specific immune responses that does not exclude patients on the basis of HLA phenotype or because of lack of expression of a particular tumor antigen. Thus, this therapy would be available to all lung cancer patients in the appropriate clinical setting. He anticipates that the studies described in the current application will enhance our understanding of the complex interactions between tumor cells and DC and thus lead to more effective therapy for lung cancer. His priority is to determine the mechanisms of antitumor responses in DC-AdIL-7 intratumoral therapy and the features of transferred DC responsible for mediating an effective antitumor response. Elucidation of the antitumor pathways in this model will ultimately allow him to define optimal conditions for therapeutic application of intratumoral DC-AdIL-7.
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