title: Antitumor Effect of Programmed Death-1 (PD-1) Blockade in Humanized the NOG-MHC Double Knockout Mouse.
abstract: OBJECTIVE
  Humanized mouse models using NOD/Shi-scid-IL2rγnull(NOG) and NOD/LtSz-scid IL2rγnull(NSG) mouse are associated with several limitations, such as long incubation time for stem cell engraftment and the development of xenograft versus host disease in mice injected with peripheral blood mononuclear cells (PBMCs). To solve problems, we used humanized major histocompatibility class I- and class II-deficient NOG mice (referred to as NOG-dKO) to evaluate the antitumor effect of anti-programmed death-1 (PD-1) antibody.
  
  
  METHODS
  Humanized NOG-dKO mice, in which human PBMCs and human lymphoma cell line SCC-3, or glioblastoma cell line U87 were transplanted, were used as an immunotherapy model to investigate the effect of anti-PD-1 antibody. A biosimilar anti-PD-1 mAb generated in our laboratory was administered to humanized NOG-dKO mice transplanted with tumors.
  
  
  RESULTS
  Within 4 weeks after transplantation, human CD45+cells in antibody-treated mice constituted approximately 70% of spleen cells. The injection of anti-PD-1 antibody reduced by more 50% the size of SCC-3 and U87 tumors. In addition, induction of CTLs against SCC-3 cells and upregulation of natural killer cell activity was observed in the antibody-treated group. Tumor-infiltrating lymphocyte profiling showed that more exhausted marker (PD1+TIM3+LAG3+) positive T cells maintained in anti-PD-1 antibody-treated tumor. A greater number of CD8+and granzyme-producing T cells infiltrated the tumor in mice treated with the anti-PD-1 antibody.
  
  
  CONCLUSIONS
  These results suggest that NOG-dKO mice might serve as a good humanized immunotherapy model to evaluate the efficacy of anti-PD-1 antibody prior to the clinical treatment. Clin Cancer Res; 23(1); 149-58. ©2016 AACR.
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ashizawa
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Iizuka
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Chizu
authors.initials: C
authors.lastname: Nonomura
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kondou
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Maeda
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Miyata
authors.affiliation: Division of Pathology, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugino
authors.affiliation: Division of Neurosurgery, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Mitsuya
authors.affiliation: Division of Neurosurgery, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Nakamasa
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: Division of Neurosurgery, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakasu
authors.affiliation: Experimental Animal Facility, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki, Kanagawa, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Katano
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki, Kanagawa, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan. y.akiyama@scchr.jp.|Division of Neurosurgery, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000074322:Antineoplastic Agents, Immunological; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D061026:Programmed Cell Death 1 Receptor