A wide range of mouse models are currently available to researchers working on the preclinical development of oncology therapeutics. Syngeneic mouse models, also known as allograft mouse tumor models, are mice engrafted with mouse-derived cancer cell lines. These mice have an intact murine immune system and thus are appealing for proof-of-concept immuno-oncology studies. However, one limitation of traditional syngeneic models is that they are not suitable for human-specific therapies. To overcome this, scientists have developed genetically engineered mice that express human immune targets, such as PD-1, PD-L1, CTLA4 and OX40, in an otherwise immunocompetent model. Tumor cell lines have been developed that also express immune checkpoint molecules, which can have a significant effect on the efficacy of potential immune checkpoint inhibitors being evaluated.
Consider the pros and cons of using syngeneic models expressing human targets (huSyn):
- The screening of anti-tumor responses in an immunocompetent mouse allows for a more physiologically relevant readout of potential clinical responses. This model system can be used to assess the effect of the tumor microenvironment on immune checkpoint blockade and can be also used to assess the effect of tumor metastasis on checkpoint blockade or therapeutic intervention.
- HuSyn mice are a more affordable model compared with humanized mice that must be irradiated and then engrafted with CD34+ hematopoietic stem cells or peripheral blood mononuclear cells before usage.
- HuSyn mice are more homogeneous compared with humanized mice that exhibit different levels of engraftment and more variable immune responses. This helps reduce mouse-to-mouse variability and helps in the comparison of different drugs or therapeutics under preclinical development
- HuSyn mice can only use syngeneic mouse-derived tumor cell lines and not patient tumor biopsies (patient-derived xenograft model). Preclinical findings in HuSyn mice may not account for the effects of genetic and tumor microenvironment heterogeneity in tumors from patients.
- HuSyn mice typically use tumor cell lines with a higher neoantigen load relative to human tumors, which influences the immune responses to these tumors. Differences in neoantigen expression makes it difficult to evaluate the efficacy of therapies that are specific to patient-derived tumor neoantigens such as adoptive cell transfer-based therapies
- HuSyn mice have an intact murine immune system, which differs both qualitatively and quantitatively from the human immune system and can lead to discordant findings. These differences are reflected in systemic T cell responses as well as the frequency of immunosuppressive cell subsets found in the tumor microenvironment.
HuSyn mice are considered a good choice for preliminary evaluations of novel drugs or biologics that target known human molecules. As potential therapeutic targets are identified, new mouse models expressing these molecules can be generated. Consider using HuSyn models for the preclinical evaluation of new immune checkpoint inhibitors or other novel therapeutics.