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 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.
Kershaw
Michael H
MH
Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Jackson
Jacob T
JT
Haynes
Nicole M
NM
Teng
Michele W L
MW
Moeller
Maria
M
Hayakawa
Yoshihiro
Y
Street
Shayna E
SE
Cameron
Rachel
R
Tanner
Jane E
JE
Trapani
Joseph A
JA
Smyth
Mark J
MJ
Darcy
Phillip K
PK
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
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