Gene-Engineered T Cells as a Superior Adjuvant Therapy for Metastatic Cancer

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 mo...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2004-08, Vol.173 (3), p.2143-2150
Main Authors: Kershaw, Michael H, Jackson, Jacob T, Haynes, Nicole M, Teng, Michele W. L, Moeller, Maria, Hayakawa, Yoshihiro, Street, Shayna E, Cameron, Rachel, Tanner, Jane E, Trapani, Joseph A, Smyth, Mark J, Darcy, Phillip K
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - therapeutic use
Antibodies, Monoclonal - therapeutic use
Antibodies, Monoclonal, Humanized
Antimetabolites, Antineoplastic - therapeutic use
Antineoplastic Agents - therapeutic use
Carcinoma - drug therapy
Carcinoma - pathology
Carcinoma - secondary
Carcinoma - surgery
Carcinoma - therapy
Chemotherapy, Adjuvant
Combined Modality Therapy
Doxorubicin - therapeutic use
Drug Resistance, Neoplasm
Female
Fluorouracil - therapeutic use
Genetic Engineering
Humans
Immunotherapy, Adoptive
Interferon-gamma - metabolism
Liver Neoplasms - drug therapy
Liver Neoplasms - secondary
Liver Neoplasms - therapy
Lung Neoplasms - drug therapy
Lung Neoplasms - secondary
Lung Neoplasms - therapy
Mammary Neoplasms, Experimental - drug therapy
Mammary Neoplasms, Experimental - pathology
Mammary Neoplasms, Experimental - surgery
Mammary Neoplasms, Experimental - therapy
Membrane Proteins - genetics
Membrane Proteins - immunology
Mice
Mice, Inbred BALB C
Mice, SCID
Neoplasm Proteins - immunology
Neoplasm Transplantation
Receptor, ErbB-2 - immunology
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - immunology
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - immunology
T-Cell Antigen Receptor Specificity - genetics
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
T-Lymphocyte Subsets - transplantation
Trastuzumab
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.173.3.2143