Expansion of HER2/ neu-Specific T Cells Ex Vivo Following Immunization with a HER2/ neu Peptide-Based Vaccine

Abstract

The identification and characterization of tumor antigens has facilitated the development of immune-based cancer prophylaxis and therapy. Cancer vaccines, like viral vaccines, may be effective in cancer prevention. Adoptive T-cell therapy, in contrast, may be more efficacious for the eradication of existing malignancies. Our group is examining the feasibility of antigen-specific adoptive T-cell therapy for the treatment of established cancer in the HER2/ neu model. Transgenic mice overexpressing rat neu in mammary tissue develop malignancy, histologically similar to human HER2/ neu-overexpressing breast cancer. These mice can be effectively immunized against a challenge with neu-positive tumor cells. Adoptive transfer of neu-specific T cells into tumor-bearing mice eradicates malignancy. Effective T-cell therapy relies on optimization of the ex vivo expansion of antigen-specific T cells. Two important elements of ex vivo antigen-specific T-cell growth that have been identified are (1) the preexisting levels of antigen-specific T cells and (2) the cytokine milieu used during ex vivo expansion of the T cells. Phase I clinical trials of HER2/ neu-based peptide vaccination in human cancer patients have demonstrated that increased levels of HER2/ neu-specific T cells can be elicited after active immunization. Initiating cultures with greater numbers of antigen-specific T cells facilitates expansion. In addition, cytokines, such as interleukin-12, when added during ex vivo culturing along with interleukin-2 can selectively expand antigen-specific T cells. Interleukin-12 also enhances antigen-specific functional measurements such as interferon-gamma and tumor necrosis factor-alpha release. Refinements in ex vivo expansion techniques may greatly improve the feasibility of tumor-antigen T-cell–based therapy for the treatment of advanced-stage HER2/ neu-overexpressing breast malignancy.