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.
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. ? ? ?
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| Disis, Mary L (2011) Immunologic biomarkers as correlates of clinical response to cancer immunotherapy. Cancer Immunol Immunother 60:433-42 |
| Disis, Mary L (2010) Immune regulation of cancer. J Clin Oncol 28:4531-8 |
