Regarding the therapeutic effects on liver cancer, Okrah et al from Genentech have reported the potential of suppressing liver cancer through the administration of a stroma-modifying drug (TGF-β neutralizing antibody, 1D11 antibody), which improves fibrosis in the tumor microenvironment. Administering the TGF-β neutralizing antibody to STAM™ mice in the liver cancer phase has been shown to decrease fibrotic areas, reduce the number and diameter of tumors in the liver, and increase the infiltration of CD8+ T cells into the tumors. This suggests therapeutic effects on liver cancer through changes in T cell localization mediated by the improvement of fibrosis (see Figure 1). The effectiveness of immune checkpoint inhibitors used in clinical settings has been reported to depend significantly on the tumor microenvironment. Targeting the immunosuppressive tumor microenvironment is believed to bring a new breakthrough in the research of liver cancer therapeutics.

Example studies

The anti-PD-L1 antibody (clone: 10F.9G2) used in clinical practice demonstrated a tumor growth inhibition at the rate of 75.1% in liver cancer treatment trials using STAM™ mice, with observed tumor shrinkage effects (see Figure 2).

Figure 2

The STAM™ mouse is currently the only model that allows the evaluation of the effects on tumors not only for immunotherapy, centered around immune checkpoint inhibitors, but also for therapeutics that modify the tumor microenvironment.

References

• Huang DQ et al,: Global epidemiology of NAFLD-related HCC: trends, predictions, rick factors and prevention, Nature Reviews Gastroenterology & Hepatology, vol 18, 223-238 (2021)
• Chen C et al,: Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma, frontiers inImmunology, vol 14, 1133308 (2023)
• Tan S et al,: Immune checkpoint inhibitor therapy in oncology: current uses and future directions, JACC: CardioOncology, vol 4, 579-597 (2022)
• Valero C et al,: Inappropriate use of the same cutoff by different sequencing panels for tumor mutation burdenas immunotherapy biomarker, JAMA Oncology, 7, 1245-1246 (2021)
• Fujii M et al,: A murine model for non-alcoholic steatohepatitis showing evidence of association betweendiabetes and hepatocellular carcinoma, Medical Molecular Morphology, vol. 46, 141-152 (2013).
• Takakura K et al,: Characterization of non-alcoholic steatohepatitis-derived hepatocellular carcinoma as ahuman stratification model in mice, Anticancer Research, vol.34, 4849-4855 (2014).
• Dow M et al,: Integrative genomic analysis of mouse and human hepatocellular carcinoma, PNAS, vol 115,E9879-E9888 (2018).
• Li E et al,: Mouse models for immunotherapy in hepatocellular carcinoma, Cancers, vol 11, 1800 (2019)
• Bresnahan E et al,: Mouse models of oncoimmunology in hepatocellular carcinoma, Clinical Cancer Research,vol 26, 5276-5286 (2020)
• Okrah K et al,: Transcriptomic analysis of hepatocellular carcinoma reveals molecular features of diseaseprogression and tumor immune biology, NPJ Precision Oncology, vol 25 (2018).

Current status of liver cancer

Treatment drugs and response rates for liver cancer

In addition to molecular targeted drugs such as lenvatinib and sorafenib, immune checkpoint inhibitors like atezolizumab + bevacizumab, nivolumab, and pembrolizumab have been used in clinical practice in recent years.

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Immune checkpoint inhibitors and response rate for various cancer

The response rate of immune checkpoint inhibitors for liver cancer is between 0-14%, which is lower compared to other cancers (for example, the response rate for melanoma is 35-70%). Due to this, there is an expectation for the development of novel therapeutic drugs. Additionally, there are many challenges in the models of mice used in the field of immuno-oncology, including a lack of diversity and heterogeneity in cancer cell lines, tumors not originating from normal cells, and the failure to reproduce the tumor microenvironment (see Table 2).

Table 2. Mouse models for immuno-oncology in hepatocellular carcinoma

*We searched for literature in PubMed using the keyword “syngeneic orthotopic”, “tumor microenvironment”, “HCC”, “stromal modifying agent”, but no literature was found as of October 2023.

There has been high anticipation for the development of new therapeutic drugs for liver cancer.

In response to this social background, we provide clinical efficacy evaluation services for novel hepatocellular carcinoma drugs, including immune checkpoint inhibitors, by utilizing various advantageous characteristics of STAM™ mouse, which develop hepatocarcinoma in a short period of time.