Abstract LB-278: In vivo evaluation model of human T cell activation by immune checkpoint inhibitors using human PBMC-transferred NOG mouse

Abstract

Abstract Within the past decade, immune checkpoint inhibitors, such as anti-programmed death (PD)-1 antibodies (e.g. pembrolizumab; Keytruda and Nivolumab: OPDIVO), treatment has become one of the most advancing therapeutic options in oncology. The PD-1/PD-L1 pathway plays a crucial role in mediating self tolerance and controlling self damage to suppress effector/self-reactive T cells and protects against autoimmune reactions. Therapeutic treatment of anti-PD-1 antibodies clearly suppresses tumor growth and induces T cell activation in cancer patients by blockade of the PD-1/PD-L1 pathway, but over activation of T cells exhibits immune-related adverse effects with exacerbation of autoimmune reactions. A human peripheral blood mononuclear cells (hPBMC) transferred humanized NOG mouse has been used to evaluate the efficacy and safety of therapeutic antibodies due to the efficient engraftment of human T cells in the mice. The human T cells were spontaneously activated in the mice because of xenogenic-reaction and the mice frequently died of graft-versus-host disease (GVHD) (Ito R et al., Transplantation, 2009). In the present study, we evaluate the potential adverse effects of 2 therapeutic antibodies, Keytruda and OPDIVO by using conventional NOG mice transferred with hPBMC. These mice showed a weight loss, wasting, rough fur, and skin thickening suggesting of GVHD symptoms. These changes exacerbated in either antibody treated hPBMC-NOG mice with increase of activation marker for T cells, and they died earlier than saline-treated group. By immune-cytoloical analysis, human T cells was significantly decreased in number in hPBMC-NOG mice even though the antibodies were treated. These results demonstrated the hPBMC-NOG mice might become powerful preclinical tools to analyze human T cells activated by therapeutic immune checkpoint inhibitors. Citation Format: Chiyoko Nishime, Ikumi Katano, Eiko Nishinaka, Kenji Kawai, Ryoji Ito, Jun-ichi Hata, Taichi Yamamoto. In vivo evaluation model of human T cell activation by immune checkpoint inhibitors using human PBMC-transferred NOG mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-278.