IMMUNOTHERAPY OF BREAST CANCER WITH TUMOR ANTIGEN SPECIFIC CYTOTOXIC T CELLS

点击翻译按钮获取中文摘要

The studies contained in Project 5 are based on the hypothesis that breast cancer patients mount detectable, albeit ineffective, cellular immune responses against well-conserved TAA expressed by their actively-growing tumors and that specific augmentation of these activities may provide improved host control of tumor outgrowth. The overall objective of Project 5 is, therefore, to characterize potential anti-TAA reactivities present in TIL and PBMC populations from breast cancer patients with tumors having well-defined TAA expression, and to use these pre-clinical findings as a framework for constructing rational Phase I immune-based therapeutic approaches. The scientific endeavors of the previous years have, in close collaboration with Core 4, focused on the establishment of a bank of paired tumor/Til/PBMC specimens from women who have had surgical intervention for treatment of their breast cancer. This specimen bank currently contains clinical material from over 80 patients. Using combined molecular and immunohistochemical techniques, disaggregated tumor specimens are assessed for specific TAA expression and, based on the mosaic of TAA expressed by an individual tumor, TIL and PBMC are analyzed for the presence of immune reactivities against those specific antigens. Assays aimed at detecting both helper T cell and precursor CTL (CTL/p) activities form the basis for these immunologic analyses. Major efforts in Years 4&5 will be focused on completion of the analyses. In addition, a Phase I clinical trial involving direct administration of a recombinant canary pox-MAGE-1/3 minigene vector to HLA-A1 patients with MAGE-1 and/or MAGE-3 expressing tumors will begin in mid-Year 3 and, most likely, carry through Year 4 and part of Year 5. Although the principal goals of this trial are safety and toxicity, major laboratory emphasis will be placed on monitoring enrolled patients for development and enhancement of responses to the specific minigenes. Assays aimed at measuring and quantitating helper T cell and CTL precursors activities will serve as the mainstay of the immunologic assessments. Collectively, these approaches are designed to expand our current working knowledge of host responses against autologous breast tumors and to utilize these findings in formulating rational, antigen-specific, immune-based therapies. The studies in Years 4&5 will allow us to test these concepts in the context of a Phase I clinical trial and to further build a foundation for future trials.