@article {MORISAKI4529, author = {TAKASHI MORISAKI and TATSUYA HIRANO and NORIHIRO KOYA and AKIFUMI KIYOTA and HIROTO TANAKA and MASAYO UMEBAYASHI and HIDEYA ONISHI and MITSUO KATANO}, title = {NKG2D-directed Cytokine-activated Killer Lymphocyte Therapy Combined with Gemcitabine for Patients with Chemoresistant Metastatic Solid Tumors}, volume = {34}, number = {8}, pages = {4529--4538}, year = {2014}, publisher = {International Institute of Anticancer Research}, 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{\textendash}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.}, issn = {0250-7005}, URL = {https://ar.iiarjournals.org/content/34/8/4529}, eprint = {https://ar.iiarjournals.org/content/34/8/4529.full.pdf}, journal = {Anticancer Research} }