Aurora kinase A-specific T-cell receptor gene transfer redirects T lymphocytes to display effective antileukemia reactivity.
Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201-restricted AURKA(207-215)-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors. In addition, AURKA(207-215)-specific TCR-transduced CD4(+) T cells displayed target-responsive Th1 cytokine production. Finally, AURKA(207-215)-specific TCR-transduced CD8(+) T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell-based AURKA-specific immunotherapy for the treatment of human leukemia.
Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Japan.
Kozo
K
Nagai
Toshiki
T
Ochi
Hiroshi
H
Fujiwara
Jun
J
An
Toshiaki
T
Shirakata
Junichi
J
Mineno
Kiyotaka
K
Kuzushima
Hiroshi
H
Shiku
J Joseph
JJ
Melenhorst
Emma
E
Gostick
David A
DA
Price
Eiichi
E
Ishii
Masaki
M
Yasukawa
D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015153:Blotting, Western; D016022:Case-Control Studies; D005240:Feasibility Studies; D005434:Flow Cytometry; D019672:Genes, T-Cell Receptor / Q000235:genetics*; D015316:Genetic Therapy; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015375:Receptors, Interleukin-2 / Q000502:physiology; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D008156:Luciferases; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases