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(PD-1) Blockade in Humanized the NOG-Major Histocompatibility Complex (MHC) Double Knockout Mouse

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(PD-1) Blockade in Humanized the NOG-Major Histocompatibility Complex (MHC) Double Knockout Mouse Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Antitumor effect of programmed death-1 (PD-1) blockade in humanized the NOG-major histocompatibility complex (MHC) double knockout mouse Tadashi Ashizawa1, Akira Iizuka1, Chizu Nonomura1, Ryota Kondo1, Chie Maeda1, Haruo Miyata1, Takashi Sugino4, Koichi Mitsuya3, Nakamasa Hayashi3, Yoko Nakasu3, Kouji Maruyama2, Ken Yamaguchi5, Ikumi Katano6, Mamoru Ito6, Yasuto Akiyama1, 3* 1Immunotherapy Division, 2Experimental Animal Facility, Shizuoka Cancer Center Research Institute, 3Division of Neurosurgery, 4Division of Pathology, 5Office of the President, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan 6Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan Running title; Antitumor effect of anti-PD-1 antibody in NOG-MHC dKO mice Keywords; Immune checkpoint antibody, anti-PD-1 antibody, humanized NOG mouse, NOG-MHC dKO mouse, autologous immunotherapy model Financial support; This work was supported by a grant to Akira Iizuka from JSPS KAKENHI (Grant Number 26430178), Japan. Address correspondence to: Yasuto Akiyama, M.D., Immunotherapy Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Sunto-gun, Shizuoka 411-8777, Japan. Tel: (+81) 559895222 (Ext. 5330), Fax: (+81) 559896085, e-mail; [email protected] Conflict of interest The authors declare that they have no conflict of interest. The word count of manuscript: 4967 The total number of figures and tables; 6 Quantity of supplementary materials; 6 Translational relevance Despite the clinical success with immune checkpoint antibody therapy against advanced cancers, there are still difficulties associated with predicting precisely the clinical responses prior to the treatment. Biomarker studies are also performed intensively, however these are not enough potent for the precise prediction. In the current study, we developed and used a novel NOG-MHC dKO mouse model. We found that this humanized mouse model exhibited no obvious signs of GVHD and that the injection of anti-PD-1 antibody inhibited PD-L1 positive SCC-3 tumor growth and induced tumor-specific immune responses. Therefore, in vivo investigation of anti-PD-1 antibody effect using humanized NOG-dKO mouse can contribute to the profiling of patients to predict the efficacy of anti-PD-1 antibody prior to the clinical treatment. These observations indicate that the NOG-dKO mouse might be a good tool giving a promising future to a translational research of immune checkpoint antibody therapy. 2 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Purpose: 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 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 3 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. to the clinical treatment. INTRODUCTION With the recent success of immune checkpoint antibodies, such as ipilimumab and nivolumab, reported in metastatic melanoma patients, many ongoing clinical trials are underway to evaluate their efficacy in various solid cancers other than melanomas (1-5). Specifically, a promising combination therapy of ipilimumab and nivolumab has demonstrated a very high response rate and long-term survival benefit in patients with advanced cancers, including non-small cell lung cancer (6-8). Despite these promising results, the response rate associated with single antibody treatment is approximately 20-40%. Furthermore, it is difficult to accurately predict the responders to antibody therapy based on the results of preclinical studies (9-10). Multiple types of humanized mice have been developed and used as a therapeutic model in preclinical studies of new cancer treatments. The severely immunodeficient mouse strains, such as NOD/Shi-scid-IL2rγnull (NOG) (11-12), NOD/LtSz-scid IL2rγnull (NSG) (13) and BALB/c Rag2 null IL2rγnull (14) are ideal in vivo platforms for reconstituting the human hemato-lymphoid system due to their lack of an endogenous mouse immune system. Several researchers demonstrated these humanized mouse models are capable of temporary antigen-specific immune responses, such as cytotoxic T lymphocyte (CTL) activation (15) and human antibody production (16-17). In addition, humanized mouse models transplanted with both human peripheral blood mononuclear cell (PBMC) and cancer cells have been used in some pre-clinical studies to evaluate antibody-based therapies (18-20). These mouse models are amenable to 4 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. hematopoietic stem cell transplantation; however they cannot undergo human PBMC transplantation due to a severe xeno-graft versus host disease (xeno-GVHD) response (21-22). In the present study, we used major histocompatibility (MHC) gene-double knockout NOG mice, deficient in both the murine MHC class I and class II genes. MHC double- knockout NOG mice were generated by knockout of the gene encoding β2-microglobulin, a component of the MHC class I molecule, and the gene encoding IAβ, the light chain of the MHC class II molecule (referred to as NOG-dKO or NOG-β2m, IAβ double KO mice). Yaguchi et al. reported for the first time that NOG-dKO mice that had undergone transplantation with human PBMCs exhibited a much milder xeno-GVHD response, with less weight loss and a longer survival period, compared with control NOG mice (23). Consistent with these results, we were able to successfully transplant PBMCs into NOG-dKO mice whereas transplanted PBMCs were rejected by regular NOG mice. Based on these observations, we established humanized NOG-dKO mice transplanted with both PBMCs and human cancer cells as a model to evaluate cancer immunotherapy. We used this therapeutic in vivo model to evaluate antitumor activity of anti-PD-1 antibody with respect to the immunological response of human origin. MATERIALS AND METHODS Antibodies and flow cytometry The following antibodies were used for a flow cytometric analysis. The anti-mouse CD45 antibody used to label mouse cells was purchased from BD Pharmingen (San 5 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 25, 2016; DOI: 10.1158/1078-0432.CCR-16-0122 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Jose, CA, USA). The anti-CD3-biotin (HIT3a), anti-CD4-PE (RPA-T4), anti-CD8-FITC (HIT8a), anti-CD11b-PE-Cy7 (ICRF44), anti-CD14-PerCP (MΦP9), anti-CD19-FITC (HIB19), anti-CD25-FITC (M-A251), anti-CD33-PE (WM53), anti-CD45-FITC (2D1), anti-CD45RA-FITC (HI100), anti-CD45RO-APC (UCHL1), anti-CD56-PE (B159), anti-CD127-PE-Cy7
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