NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors

Takashi Morisaki, Tatsuya Hirano, Norihiro Koya, Akifumi Kiyota, Hiroto Tanaka, Masayo Umebayashi, Hideya Ohnishi, Mitsuo Katano

研究成果: ジャーナルへの寄稿記事

20 引用 (Scopus)

抄録

Natural-killer group 2, member D (NKG2D) is an activating receptor found on activated natural killer cells and on activated T-cells, here termed cytokine-activated killer (CAK) cells. NKG2D ligands are expressed on various human cancer types. Gemcitabine is an anticancer drug which is a less immune-destructive agent than others. Herein, we investigated the clinical efficacy and the underlying mechanisms of a combination of CAK cell infusion therapy and gemcitabine. Twenty-three patients with disseminated carcinomas were treated with chemo-immunotherapy consisting of CAK cell infusion therapy following gemcitabine treatment. To investigate the underlying mechanisms by which CAK cells synergize with gemcitabine, we used enzyme-linked immunosorbent assay, Real-time reverse transcription polymerase chain reaction assay, calcein-release assay, and adherent target detachment assay. Using these assays we determined the NKG2D ligands such as major histocompatibility complex-class I-related chain (MIC)A/B expression in carcinoma cells and the level of cellular cytotoxicity generated by treatment with gemcitabine with/without CAK cells. The tumor responses differed among the patients (n=23). In vitro experiments revealed that MICA/B protein and mRNA expression were up-regulated in several carcinoma cell lines after gemcitabine treatment. Pre-treatment with gemcitabine and subsequent exposure to CAK cells induced greater cytotoxicity than either treatment alone. Inclusion of soluble MICB in CAK cell-mediated cytotoxicity assay significantly reduced cytotoxicity. Our clinical results of gemcitabine - CAK combinatorial therapy demonstrated long-term stable disease despite chemoresistance. In conclusion, the combination of gemcitabine and CAK cells may have clinical therapeutic significance for pancreatic, hepato-biliary tract, and urothelial tract cancer. Our study shows that combining CAK therapy with gemcitabine can lead to successful treatment of metastatic cancer.

元の言語英語
ページ(範囲)4529-4538
ページ数10
ジャーナルAnticancer research
34
発行部数8
出版物ステータス出版済み - 8 1 2014

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gemcitabine
Lymphocytes
Cytokines
Neoplasms
Therapeutics
Cell- and Tissue-Based Therapy
Carcinoma
Cytokine-Induced Killer Cells
Ligands
Biliary Tract

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Morisaki, T., Hirano, T., Koya, N., Kiyota, A., Tanaka, H., Umebayashi, M., ... Katano, M. (2014). NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors. Anticancer research, 34(8), 4529-4538.

NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors. / Morisaki, Takashi; Hirano, Tatsuya; Koya, Norihiro; Kiyota, Akifumi; Tanaka, Hiroto; Umebayashi, Masayo; Ohnishi, Hideya; Katano, Mitsuo.

:: Anticancer research, 巻 34, 番号 8, 01.08.2014, p. 4529-4538.

研究成果: ジャーナルへの寄稿記事

Morisaki, T, Hirano, T, Koya, N, Kiyota, A, Tanaka, H, Umebayashi, M, Ohnishi, H & Katano, M 2014, 'NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors', Anticancer research, 巻. 34, 番号 8, pp. 4529-4538.
Morisaki, Takashi ; Hirano, Tatsuya ; Koya, Norihiro ; Kiyota, Akifumi ; Tanaka, Hiroto ; Umebayashi, Masayo ; Ohnishi, Hideya ; Katano, Mitsuo. / NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors. :: Anticancer research. 2014 ; 巻 34, 番号 8. pp. 4529-4538.
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abstract = "Natural-killer group 2, member D (NKG2D) is an activating receptor found on activated natural killer cells and on activated T-cells, here termed cytokine-activated killer (CAK) cells. NKG2D ligands are expressed on various human cancer types. Gemcitabine is an anticancer drug which is a less immune-destructive agent than others. Herein, we investigated the clinical efficacy and the underlying mechanisms of a combination of CAK cell infusion therapy and gemcitabine. Twenty-three patients with disseminated carcinomas were treated with chemo-immunotherapy consisting of CAK cell infusion therapy following gemcitabine treatment. To investigate the underlying mechanisms by which CAK cells synergize with gemcitabine, we used enzyme-linked immunosorbent assay, Real-time reverse transcription polymerase chain reaction assay, calcein-release assay, and adherent target detachment assay. Using these assays we determined the NKG2D ligands such as major histocompatibility complex-class I-related chain (MIC)A/B expression in carcinoma cells and the level of cellular cytotoxicity generated by treatment with gemcitabine with/without CAK cells. The tumor responses differed among the patients (n=23). In vitro experiments revealed that MICA/B protein and mRNA expression were up-regulated in several carcinoma cell lines after gemcitabine treatment. Pre-treatment with gemcitabine and subsequent exposure to CAK cells induced greater cytotoxicity than either treatment alone. Inclusion of soluble MICB in CAK cell-mediated cytotoxicity assay significantly reduced cytotoxicity. Our clinical results of gemcitabine - CAK combinatorial therapy demonstrated long-term stable disease despite chemoresistance. In conclusion, the combination of gemcitabine and CAK cells may have clinical therapeutic significance for pancreatic, hepato-biliary tract, and urothelial tract cancer. Our study shows that combining CAK therapy with gemcitabine can lead to successful treatment of metastatic cancer.",
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AU - Morisaki, Takashi

AU - Hirano, Tatsuya

AU - Koya, Norihiro

AU - Kiyota, Akifumi

AU - Tanaka, Hiroto

AU - Umebayashi, Masayo

AU - Ohnishi, Hideya

AU - Katano, Mitsuo

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