Lymphoid infiltration of mammary tumors has been considered evidence of a host anti-tumor immune response. The progression of tumor despite the presence of these immune cells has been attributed to the production of immunosuppressive substances such as transforming growth factor-beta (TGF-beta) within the tumor. In breast cancer patients, the presence of tumor-derived TGF-beta-1 directly correlates with disease progression, metastases and disease recurrence. Transforming growth factor is a cytokine produced by many cell types including malignant cells and is a potent inhibitor of immune functions. A potentially effective form of tumor-specific immunotherapy of cancer is one in which tumor vaccines consisting of tumor cells deprived of the ability to synthesize TGF-beta are used. The objective of this study is to inhibit the production of TGF-beta in mammary tumor cells by genetic manipulation and to employ these gene modified cells as vaccines to treat established tumors and eradicate residual metastatic disease. TGF-beta synthesis will be blocked by inserting an antisense TGF-beta transcriptional cassette in mammary tumor cells to produce complementary RNA that binds endogenous messenger TGF-beta RNA to prevent its translation to protein.
The specific aims of this research are to determine: (1a) The efficacy of antisense TGF-beta tumor cell vaccines in eliminating established primary tumors and residual metastatic disease. (1b) The ability of IFN-gamma or B7.1 gene transfer to improve the effectiveness of antisense TGF-beta tumor vaccines. (2) The mechanism by which antisense TGF-beta gene expression inhibits tumorigenicity. The results from this study will demonstrate the effectiveness of antisense TGF-beta tumor vaccines in treating established tumors and eradicating metastatic disease and the ability of IFN-gamma and B7.1 to potentiate antitumor activity. These studies will lead to the development of a novel and effective approach of treating metastatic breast cancer which has immediate application in the clinic. In the long term, it is expected that this approach of genetically eliminating tumor-derived immunosuppression in order to trigger an effective antitumor response will find widespread use in treating other forms of cancer.
