Chemical-induced lung tumor in Tg-rasH2 mice: a novel mouse tumor model to assess immune checkpoint inhibitors combined with a chemotherapy drug

• Published in: Journal of Toxicologic Pathology 2022, Vol.35(4), pp.321-331
• Main Authors: Hagiwara, Teruaki, Numano, Takamasa, Hara, Tomomi, Sugiyama, Taiki, Mera, Yukinori, Tamano, Seiko, Miyata, Hiroto
• Format: Article
• Language: English
• Subjects: Animal models; Antibodies; Anticancer properties; Antitumor activity; Carcinogenesis; Carcinogens; chemically-induced lung carcinogenesis; Chemotherapy; Combined treatment; Effectiveness; Experiments; Gemcitabine; Genetic modification; ICI therapy model; Immune checkpoint; immune checkpoint inhibitors (ICI); Immunotherapy; Lung cancer; Lung carcinoma; Lungs; Non-small cell lung carcinoma; Original; PD-1; PD-1 protein; rasH2 mice; Statistical analysis; Tumor microenvironment; Tumors
• ISSN: 0914-9198; 1881-915X; 1347-7404
• DOI: 10.1293/tox.2022-0040

In subcutaneous tumor models, changes in the tumor microenvironment can lead to differences in therapeutic treatment responses between the subcutaneous and parent tumors. Accordingly, we generated a lung carcinogenesis model that combines genetically modified mice (Tg-rasH2 mice) with two-stage chemical carcinogenesis as an alternative to the subcutaneous tumor model. In this model, Tg-rasH2 mice were treated with 1-ethyl-1-nitrosourea, followed by butylhydroxytoluene. Mice developed lung adenomas five weeks after treatment initiation. Subsequently, anti-mouse PD-1 antibody (α-mPD-1) or isotype control was administered intraperitoneally twice a week for 4 weeks. Tumor growth was examined by measuring the relative tumor area in serially sliced lung histopathological specimens. No statistically significant differences were observed in the relative lung tumor areas between treated and control groups. A second experiment then examined the antitumor efficacy of α-mPD-1 combined with gemcitabine in a mouse model. Mice were treated identically as in Experiment 1, except that the treated group received once-weekly intraperitoneal injections of 10 mg/kg gemcitabine. In contrast to Experiment 1, the combined treatment significantly reduced the relative tumor areas in the lungs. This result also resembles that of a phase III clinical trial (ORIENT-12), showing that patients with non-small-cell lung carcinoma benefited from combination treatment with gemcitabine and the anti-human PD-1 antibody sintilimab. Thus, this mouse model could be a feasible means to preclinically evaluate the antitumor efficacy of different immunotherapy and chemotherapy drug combinations.