The infusion of tumor-specific T cells has been shown to be an effective therapeutic approach resulting in cancer eradication in animals with large tumor burdens. However, in human clinical trials, adoptive T cell therapy has elicited mostly partial responses with few cures. Some of the reasons for the difficulty in clinically implementing adoptive T cell therapy have been that current methods to expand T cells ex vivo are not optimized to generate antigen specific T cells with long-lived function and once infused, T cells fail to elicit tumor destruction and, in some cases, do not persist in vivo. For the past decade our group has been studying the HER-2/neu (HER2) oncoprotein as a tumor antigen in breast cancer. We have found that breast cancer patients immunized with HER2 T helper (Th) peptide vaccines show an increase in the number of circulating HER2-specific CD4+ Th1 cells and their T cells are more readily expanded ex vivo than those of non-immunized patients. We hypothesize HER2 specific Th1 CD4+ T cell lines derived from vaccinated patients would be ideally suited for use in adoptive T cell therapy in patients with advanced stage HER2 overexpressing breast cancer. First, tumor antigen-specific CD4+ Th1 cells may home to the tumor and the inflammatory cytokines they secrete, such as IFN-g, may modulate the tumor microenvironment. Th1 cytokines enhance the function of local antigen presenting cells (APCs) and augment endogenous antigen presentation. In addition, by providing a robust CD4+ Th1 T cell response, tumor-specific CD8+ T cells will be elicited and proliferate endogenously. Finally, antigen specific CD4+ T cells would provide the environment needed to enhance and sustain tumor specific T cell immune responses over time. In this proposal we will treat patients with HER2+ advanced stage breast cancer, who have been primed with a HER2 Th vaccine, with autologous HER2 specific Th cells that have been expanded in vitro. We will also administer booster vaccinations after T cell infusions have been completed to enhance the in vivo proliferation and persistence of the antigen specific T cells.
The specific aims of this proposal are to: (1) evaluate the safety of infusing escalating doses of HER2 specific T cells into patients with advanced HER2+ breast cancer using ex vivo expanded autologous T cells, (2) evaluate to what extent HER2 specific T cell immunity can be boosted and maintained in individuals after infusion of HER2 specific T cells, and, (3) investigate the potential anti-tumor effect of HER2 specific T cells in patients with HER2+ advanced stage breast cancer.

Public Health Relevance

The infusion of tumor-specific T cells has been shown to be an effective therapy resulting in cancer eradication in animals with large tumor burdens. However, in human clinical trials, adoptive T cell therapy has met with limited success. The proposed work will evaluate the safety of the infusion of HER-2/neu (HER2) specific Type I T helper cells in patients with advanced stage breast cancer after priming patients with a HER2 vaccine. Experiments proposed will assess the magnitude of immunity achieved in vivo, the persistence of the immune response, and the potential therapeutic efficacy of the approach.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Song, Min-Kyung H
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Disis, Mary L (2010) Immune regulation of cancer. J Clin Oncol 28:4531-8