Immunotherapy Division, Shizuoka Cancer Center Research Institute, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
Division of Pathology, Shizuoka Cancer Center Hospital, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
Clin Cancer Res. 2017 Jan 1;23(1):149-158. doi: 10.1158/1078-0432.CCR-16-0122. Epub 2016 Jul 25.
Humanized mouse models using NOD/Shi-scid-IL2rγ (NOG) and NOD/LtSz-scid IL2rγ (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.
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.
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 (PD1TIM3LAG3) 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.
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.
利用 NOD/Shi-scid-IL2rγ（NOG）和 NOD/LtSz-scid IL2rγ（NSG）小鼠建立的人源化小鼠模型存在一些局限性，例如干细胞植入的潜伏期长，以及注入外周血单核细胞（PBMCs）的小鼠中会出现异种移植物抗宿主病。为了解决这些问题，我们使用了人源化主要组织相容性复合体 I 和 II 缺陷型 NOG 小鼠（简称 NOG-dKO）来评估抗程序性死亡-1（PD-1）抗体的抗肿瘤作用。
我们将移植了人 PBMC 和人淋巴瘤细胞系 SCC-3 或胶质母细胞瘤细胞系 U87 的人源化 NOG-dKO 小鼠用作免疫治疗模型，以研究抗 PD-1 抗体的作用。我们实验室制备的一种 PD-1 抗体生物类似药用于移植肿瘤的人源化 NOG-dKO 小鼠。
移植后 4 周内，抗体治疗组小鼠脾脏中 CD45 细胞约占 70%。抗 PD-1 抗体的注射使 SCC-3 和 U87 肿瘤的大小减少了 50%以上。此外，在抗体治疗组中观察到针对 SCC-3 细胞的 CTL 诱导和自然杀伤细胞活性上调。肿瘤浸润淋巴细胞分析显示，在抗 PD-1 抗体治疗的肿瘤中，更多的衰竭标志物（PD1TIM3LAG3）阳性 T 细胞得以维持。在接受抗 PD-1 抗体治疗的小鼠中，更多的 CD8 和颗粒酶产生的 T 细胞浸润肿瘤。
这些结果表明，NOG-dKO 小鼠可能成为一种很好的人源化免疫治疗模型，可在临床治疗前评估抗 PD-1 抗体的疗效。临床癌症研究；23(1)；149-58. ©2016 AACR.
