Abstract
The major limiting factor in the successful application of adjuvant therapy for metastatic disease is the lack of adjuvant specificity that leads to severe side effects. Reasoning that T cells of the immune system are highly specific, we generated tumor-specific T cells by genetic modification of mouse primary T cells with a chimeric receptor reactive with the human breast cancer-associated Ag erbB-2. These T cells killed breast cancer cells and secreted IFN-gamma in an Ag-specific manner in vitro. We investigated their use against metastatic breast cancer in mice in an adjuvant setting, and compared their effectiveness with the commonly applied adjuvants doxorubicin, 5-fluorouracil, and herceptin. Mice were inoculated orthotopically with the human erbB-2-expressing spontaneously metastatic mouse breast cancer 4T1.2 in mammary tissue, and the primary tumor was surgically removed 8 days later. Significant metastatic disease was demonstrated in lung and liver at the time of surgery on day 8 with increased tumor burden at later time points. T cell adjuvant treatment of day 8 metastatic disease resulted in dramatic increases in survival of mice, and this survival was significantly greater than that afforded by either doxorubicin, 5-fluorouracil, or herceptin.
Publication types
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Evaluation Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / therapeutic use
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antimetabolites, Antineoplastic / therapeutic use
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Antineoplastic Agents / therapeutic use
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Carcinoma / drug therapy
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Carcinoma / pathology
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Carcinoma / secondary*
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Carcinoma / surgery
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Carcinoma / therapy
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Chemotherapy, Adjuvant
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Combined Modality Therapy
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Doxorubicin / therapeutic use
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Drug Resistance, Neoplasm
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Female
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Fluorouracil / therapeutic use
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Genetic Engineering
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Humans
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Immunotherapy, Adoptive*
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Interferon-gamma / metabolism
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Liver Neoplasms / drug therapy
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Liver Neoplasms / secondary
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Liver Neoplasms / therapy
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Lung Neoplasms / drug therapy
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Lung Neoplasms / secondary
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Lung Neoplasms / therapy
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / pathology
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Mammary Neoplasms, Experimental / surgery
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Mammary Neoplasms, Experimental / therapy*
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Membrane Proteins / genetics*
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Membrane Proteins / immunology
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Mice
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Mice, Inbred BALB C
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Mice, SCID
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Neoplasm Proteins / immunology*
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Neoplasm Transplantation
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Receptor, ErbB-2 / immunology*
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Receptors, Antigen, T-Cell / genetics*
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Receptors, Antigen, T-Cell / immunology
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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T-Cell Antigen Receptor Specificity / genetics*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / transplantation*
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Trastuzumab
Substances
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Antibiotics, Antineoplastic
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antimetabolites, Antineoplastic
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Antineoplastic Agents
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Membrane Proteins
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Neoplasm Proteins
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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antigen T cell receptor, zeta chain
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Doxorubicin
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Interferon-gamma
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Receptor, ErbB-2
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Trastuzumab
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Fluorouracil