Development of a novel humanized mouse model for improved evaluation of in vivo anti-cancer effects of anti-PD-1 antibody

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer in the clinic. Further discovery of novel drugs or therapeutic protocols that enhance efficacy requires reliable animal models that recapitulate human immune responses to ICI treatment in vivo. In this study, we utilized an immunodeficient NOG mouse substrain deficient for mouse FcγR genes, NOG-FcγR−/− mice, to evaluate the anti-cancer effects of nivolumab, an anti-programmed cell death-1 (PD-1) antibody. After reconstitution of human immune systems by human hematopoietic stem cell transplantation (huNOG-FcγR−/− mice), four different programmed death-ligand 1 (PD-L1)-positive human cancer cell lines were tested. Among them, the growth of three cell lines was strongly suppressed by nivolumab in huNOG-FcγR−/− mice, but not in conventional huNOG mice. Accordingly, immunohistochemistry demonstrated the enhanced infiltration of human T cells into tumor parenchyma in only nivolumab-treated huNOG-FcγR−/− mice. Consistently, the number of human T cells was increased in the spleen in huNOG-FcγR−/− mice by nivolumab but not in huNOG mice. Furthermore, human PD-L1 expression was strongly induced in the spleen of huNOG-FcγR−/− mice. Collectively, our results suggest that the anti-cancer effects of anti-PD-1 antibodies can be detected more clearly in NOG-FcγR−/− mice than in NOG mice.

Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice

“…In recent years, significant progress has been made in the development and application of Hu-mouse xenograft models. The most common methods for testing cancer immunotherapy involve the subcutaneous implantation of established cell lines and patient-derived tissues [16, 18, 35, 41]. However, these models may not always accurately reflect the characteristics of the primary tumor, as they lack interaction with the TME, and do not provide the conditions necessary for metastasis.…”

A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR+ cells during antibody‐mediated immune responses

“…FcR-γ-deficient HIS mice may be useful in defining the contribution of human FcγR + cells to effects mediated by exogenously delivered Tx mAbs or other immunomodulators that can bind FcRs (e.g., Fc-fusion proteins [49]). Katano et al [48] used an adoptive cell transfer model in IL-15Tg FcR-γ-deficient NOG mice to suggest that human NK cells could be involved in the elimination of human tumor xenografts, although the precise mechanism remained unclear. Here, we showed in fully reconstituted FcRγ-deficient BRGSA2DR2 HIS mice that NK cells were important effectors of rituximab and that boosting human CD16 + NK cells (via exogenous IL-15) could amplify B-cell depletion elicited by the IgG1_KA rituximab variant.…”

“…One consistent finding observed in these different FcR‐γ‐deficient HIS models is the important role played by residual mouse FcR + cells in mediating effects of Tx mAbs. This was first shown in immunocompetent and immunodeficient mouse models [43–46] and subsequently in HIS mice [23, 24, 47, 48] in the context of tumor rejection. The differential effects mediated by hIgG1 and hIgG4 isotypes in HIS mice were initially revealed in FcR‐γ‐deficient HIS mice using human B cell or mouse platelet‐depleting antibodies [23, 47]; results we confirm here using B‐cell‐depleting Rituximab.…”

A Comparative Study of Patient-Derived Tumor Models of Pancreatic Ductal Adenocarcinoma Involving Orthotopic Implantation

“…Recently, Katano et al [63] transplanted human hematopoietic stem cells into immunodeficient NOG mice lacking the mouse FcγR gene (NOG-FcγR −/− ) to reconstruct the human immune system (huNOG-FcγR −/− mice). They implanted cancer cells into this humanized mouse and succeeded in evaluating the anticancer effect of nivolumab, an anti-programmed cell death-1 antibody [63]. The development of such humanized mice is progressing, and they are considered to eventually be established as an evaluation model for immunotherapy.…”

“…First, the SCID mice described in the present study cannot be used for immunological therapy, and an animal model that reproduces the human immune response is essential. Recently, Katano et al [63] transplanted human hematopoietic stem cells into immunodeficient NOG mice lacking the mouse FcγR gene (NOG-FcγR −/− ) to reconstruct the human immune system (huNOG-FcγR −/− mice). They implanted cancer cells into this humanized mouse and succeeded in evaluating the anticancer effect of nivolumab, an anti-programmed cell death-1 antibody [63].…”