title: NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors.
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.
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan tmorisaki@cancer-clinic.jp.
authors: Takashi
authors: T
authors: Morisaki
authors: Sada Hospital, Fukuoka, Japan.
authors: Tatsuya
authors: T
authors: Hirano
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Norihiro
authors: N
authors: Koya
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Akifumi
authors: A
authors: Kiyota
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Hiroto
authors: H
authors: Tanaka
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Masayo
authors: M
authors: Umebayashi
authors: Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Hideya
authors: H
authors: Onishi
authors: Departments of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Mitsuo
authors: M
authors: Katano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D055612:Cytokine-Induced Killer Cells / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000502:physiology*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D012189:Retrospective Studies; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D055655:NK Cell Lectin-Like Receptor Subfamily K; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: CAK; Gemcitabine; MICA/B; NKG2D; immunotherapy