title: Development of a novel redirected T-cell-based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia.
abstract: Although adult T-cell leukemia (ATL) has a poor prognosis, successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) in some cases suggests that a cellular immune-mediated strategy can be effective. So far, however, no effective target for anti-ATL immunotherapy has been defined. Here we demonstrated for the first time that human telomerase reverse transcriptase (hTERT) is a promising therapeutic target for ATL, and we developed a novel redirected T-cell-based immunotherapy targeting hTERT. hTERT messenger RNA was produced abundantly in ATL tumor cells but not in steady-state normal cells. Rearranged human leukocyte antigen-A*24:02 (HLA-A*24:02) -restricted and hTERT461-469 nonameric peptide-specific T-cell receptor (TCR) α/β genes were cloned from our previously established cytotoxic T lymphocyte clone (K3-1) and inserted into a novel retroviral TCR expression vector encoding small interfering RNAs for endogenous TCR genes in redirected T cells (hTERT-siTCR vector). Consequently, allogeneic or autologous gene-modified CD8(+) T cells prepared using the hTERT-siTCR vector successfully killed ATL tumor cells, but not normal cells including steady-state hematopoietic progenitors, in an HLA-A*24:02-restricted manner both in vitro and in vivo. Our experimental observations support the development of a novel hTERT-targeting redirected T-cell-based adoptive immunotherapy for ATL patients, especially those for whom suitable allo-HSCT donors are lacking.
authors: Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Yukihiro
authors: Y
authors: Miyazaki
authors: Hiroshi
authors: H
authors: Fujiwara
authors: Hiroaki
authors: H
authors: Asai
authors: Fumihiro
authors: F
authors: Ochi
authors: Toshiki
authors: T
authors: Ochi
authors: Taichi
authors: T
authors: Azuma
authors: Takashi
authors: T
authors: Ishida
authors: Sachiko
authors: S
authors: Okamoto
authors: Junichi
authors: J
authors: Mineno
authors: Kiyotaka
authors: K
authors: Kuzushima
authors: Hiroshi
authors: H
authors: Shiku
authors: Masaki
authors: M
authors: Yasukawa
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002461:Cell Line, Transformed; D005260:Female; D059871:HLA-A24 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009368:Neoplasm Transplantation; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019098:Telomerase / Q000276:immunology* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D009363:Neoplasm Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C509186:TERT protein, human; D019098:Telomerase