Expansion of HER2/neu-specific T cells ex vivo following immunization with a HER2/neu peptide-based vaccine.
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.
Knutson
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Division of Oncology, University of Washington, 1959 NE Pacific Street, HSB BB1321, Box 356527, Seattle, WA 98195-6527, USA. kknutson@u.washington.edu
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D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007114:Immunization; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D019496:Cancer Vaccines; D016207:Cytokines; D010446:Peptide Fragments; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases