title: Gene-engineered T cells as a superior adjuvant therapy for metastatic cancer.
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.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Jackson
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Maria
authors.initials: M
authors.lastname: Moeller
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Shayna E
authors.initials: SE
authors.lastname: Street
authors.forename: Rachel
authors.initials: R
authors.lastname: Cameron
authors.forename: Jane E
authors.initials: JE
authors.lastname: Tanner
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary* / Q000601:surgery / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005818:Genetic Engineering; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000628:therapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000628:therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000276:immunology*; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D000068878:Trastuzumab
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004317:Doxorubicin; D005472:Fluorouracil; D007371:Interferon-gamma; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab; C054979:antigen T cell receptor, zeta chain