Antitumor effect of anti-PD-1 antibody in NOG-MHC dKO mice

Purpose:Humanized mouse models using NOD/Shi-scid-IL2r gammanull (NOG) and NOD/LtSz-scid IL2r gamma null (NSG) mouse are associated with several limitations, such as long incubation time for stem cell engraftment and the development of xeno-graft versus host disease (xeno-GVHD) in mice injected with peripheral blood mononuclear cells (PBMCs). To solve problems, we used humanized major histocompatibility (MHC) class I and class II-deficient NOG mice (referred to as NOG-dKO) to evaluate the anti-tumor effect of anti-programmed death-1 (PD-1) antibody. Experimental Design: 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 monoclonal antibody generated in our lab 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 cytotoxic T lymphocytes (CTL) against SCC-3 cells and upregulation of natural killer (NK) cell activity was observed in the antibody-treated group. Tumor-infiltrating lymphocyte (TIL) 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.

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