Strategies to enhance tumor regression by stimulating the immune response to malignant cells have shown limited efficacy in animal and human studies, but represent an important potential approach to the treatment of cancer. We have developed a gene transfer approach to the immunotherapy of malignancy by expression of cell surface antigens in tumors using direct gene transfer in vivo. We had previously shown that direct transfer of recombinant genes to tumors in vivo alters their immunogenicity. Preclinical studies had shown that introduction of a gene encoding a highly immunogenic protein, from an allogeneic class I major histocompatibility complex (MHC) gene, in transplantable mouse tumors induced specific cytolytic T cells against this protein and also elicited a response against unmodified tumor cells, causing tumor regression or cure in animals. Human studies of direct gene transfer with foreign MHC have also been performed with the support of this grant and applied to melanoma in tow independent human phase I clinical studies completed at The University of Michigan medical Center with encouraging preliminary results. In this proposal, delivery of a foreign histocompatibility gene directly into colon carcinoma metastatic to liver will be optimized, and gene expression and immune response in patients will be analyzed to understand the mechanisms which lead to successful responses. Expression of allogeneic MHC will be assessed, and the immunologic basis of antitumor responses. Expression of allogeneic MHC will be assessed, and the immunologic basis of antitumor responses will be characterized. Such analyses will also be used to develop systems which allow molecular cloning of immunologically relevant tumor- associated antigens in the future. Finally, we will develop modifications of the current protocol which will improve its efficacy in humans. To understand and improve upon this gene transfer strategy, we will: 1) perform catheter delivery of a foreign MHC gene, HLA- B7, into metastatic liver lesions of colon cancer utilizing improved vectors and liposomes, 2) analyze gene expression, define correlates of successful immune responses and delineate mechanisms of tumor rejection, and 3) develop novel gene transfer approaches using combination gene therapy of foreign MHC and the p21 cyclin- dependent kinase, which arrests cell proliferation and induces terminal differentiation which may promote further changes which induce immune recognition of tumors. These studies expand on the present technology of current human clinical trials to improve the efficacy of gene transfer approaches to cancer and will provide insight into the molecular basis of immune recognition in malignancy.
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