Abstract LB122: Establishment of an <i>in vivo</i> ICI evaluation system using lung adenocarcinoma-derived PDX inoculated PBMC-huNOG-ΔMHC mice

Abstract Immune checkpoint inhibitors (ICIs) such as anti-PD-1 antibodies have broadened the spectrum of cancer therapies. These inhibitors are under active development, focusing on identifying new targets and developing effective combination therapies. In addition to these advancements, novel in vivo systems are required to evaluate the efficacy of newly developed ICI therapies. Our goal was to establish an innovative novel ICI evaluation system using a new animal model replicating the interactions between human immune cells and human tumor cells. We established an animal model by transplanting lung adenocarcinoma patient-derived xenograft (PDX) generated in CIEM along with human peripheral blood mononuclear cells (PBMCs) into MHC class I and class II-deficient NOG mice (NOG-ΔMHC mice). These mice suppress graft-versus-host disease (GvHD) and allow long-term evaluation following human PBMC transplantation. Two lung adenocarcinoma-derived PDXs were prepared for inoculation. Using this model, we evaluated the efficacy of the anti-PD-1 antibody, either alone or in combination with a new compound, the IDO1/TDO2 dual inhibitor KYPS-80. Three weeks after PDX inoculation, anti-PD-1 antibody was injected twice a week for 2 weeks, and KYPS-80 was administered once a day for 14 days. Tumor size was measured, and the mice were subjected to immunological and pathological analyses the day after the final administration. We established two criteria for animal selection to evaluate the efficacy of the ICIs. The first criterion was the confirmation of human PBMC engraftment: maintaining a chimeric ratio of over 10% in the peripheral blood until the end of the test. The second criterion was the confirmation of PDX engraftment: no decrease in tumor volume from day 14 to 21 after PDX transplantation (before drug administration). When these criteria were applied, tumor growth was suppressed in mice treated with anti-PD-1 and/or KYPS-80 in both PDX-inoculated models. In the pathological analysis, regression of tumor nests with single cell necrosis of tumor cells and fibrosis were observed in the treated mice. Additionally, the frequency of human CD8+ T cells increases in regressed tumors. We established the criteria for animal selection to confirm human PBMC and PDX engraftment. When these criteria were applied, the efficacies of the anti-PD-1 antibody and the new compound were demonstrated using two models inoculated with different lung adenocarcinoma PDXs. In this study, we established new ICI evaluation systems that replicate human immune cell-tumor cell interactions. Citation Format: Asami Hanazawa, Seinosuke Sakai, Chiyoko Nishime, Naohisa Ogo, Masami Suzuki, Jun-ichi Hata, Akira Asai, Taichi Yamamoto. Establishment of an in vivo ICI evaluation system using lung adenocarcinoma-derived PDX inoculated PBMC-huNOG-ΔMHC mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB122.