The administration of large numbers of tumor specific T cells has been shown to be an effective method of eradicating tumors in animal models and in treating established infectious disease in immunocompromised patients. Obstacles to the development of successful T cell therapy for human malignancy, to date, have been the lack of (1) defined tumor antigens which would allow expansion of antigen specific T cells, (2) a detailed understanding of the in vitro expansion requirements of T cells which would allow the generation of maximal numbers while retaining optimal antigen specific function and (3) understanding the in vivo environment necessary for the sustained in vivo expansion needed for tumor eradication. Recent advances in molecular immunology providing the scientific technology needed to define tumor-specific antigens and an understanding of how T cells recognize antigen have made it possible to consider strategies using antigen-specific adoptive T cell therapy as a cancer therapeutic. For the last several years her group has been studying the HER-2/neu (HER2) oncoprotein as a tumor antigen in several solid tumors. The development of vaccine strategies targeting HER2 has led to Phase I clinical trials of peptide based vaccines which have been effective in significantly increasing the HER2 specific T cell precursor frequency in immunized patients. As a result of the increased number of circulating HER2 specific T cells, we have been able to isolate HER2 specific T cell clones and grow T cell lines ex vivo more readily from the immunized than the naive patient. This proposal will outline the pre-clinical studies needed to establish the role of T cell infusion in the eradication of neu overexpressing tumors in a murine model and will identify the culture conditions most effective in expanding HER2 specific T cells while retaining antigen specific function. Pre-clinical experiments will translate to a pilot trial of infusion of HER2 specific T cells in patients with relapsed HER2 overexpressing cancer.
The aims of this proposal are to, (a) determine the immune effector arm most effective in the eradication of rat neu overexpressing tumors in neu-tg mice using adoptive immunotherapy of rat neu specific CD8+ and CD4+ T cells, (b) monitor the trafficking and functionality of neu specific cells in vivo in the neu-tg mouse using imaging techniques, (c) determine the feasibility of the expansion of HER2 specific CD4+ and CD8+ T cell lines from patients previously immunized with a HER2 peptide based vaccine, and, (d) determine, in a pilot clinical trial, the feasibility of the infusion of HER2 specific T cells, in patients with HER2 overexpressing tumors, for the treatment of advanced stage cancer.
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