Mouse models for immune-oncology

The preclinical models play a critical role in the field of cancer immunotherapy for advancing the candidate drugs from bench to clinic. These models contribute massively to basic research, translational studies and immune-oncology research. Over the years, cell line xenografts (CDX) and syngeneic models were widely used to study the tumour growth and drug response pattern. However, these models fail to capture the complexity of human heterogeneity and thus genetically engineered mouse models and humanized mice have been at the forefront of the immune-oncology research. This review in the field of immunotherapy.

Objectives

• • Mouse models in the field of immune-oncology
• • Discusses the advantages, limitations of existing mouse models
• • Focusses on innovation such as CRISPR technology and humanized models
• • Explore critical parameters for improving translational relevance

Key Insights

The contribution of mouse models to immune-oncology

• • CDX models: Human cancer cells (immortalised cancer cell lines) are inoculated into the immunocompromised mice. They are widely used for their reproducibility and are highly valuable for drug screening.
• • PDX models: Human tumour tissue/ cells are transplanted into immunocompromised mice. This model offers the advantage of tumour heterogeneity.
• • Syngeneic models: Tumour cells transplanted into immunocompetent mice with same genetic background. These models are simple and ideal for studying immune responses but do lack tumour heterogeneity.
• • Genetically engineered mouse models: Tumours develop spontaneously due to engineered mutations, allowing tumour related studies in an intact immune system (Bosenberg et al., 2023).
• • Humanized mice: Immunodeficient mice engrafted with immune cells or tissues, enabling evaluation of human specific immunotherapies, such as checkpoint inhibitors and CAR-T cells.

Applications in Immuno-oncology

• - Car-T cell therapy: Humanised mice have proven to be an excellent model to evaluate engineered T cells against tumour antigens.
• - Checkpoint inhibitors: Syngeneic models have been at the forefront for testing PD-1 and CTLA-4 inhibitors, through the translatability is still limited.
• - Tumour microenvironment studies: GEMMs and humanised mice allow exploration of stromal and immune interaction during tumour progression.

Strengths

• Comprehensive coverage: The review gives a detailed description of the different types of mouse models- Syngeneic, GEMMs, PDX, CDX and humanized mice.
• Non-biased views: Each model is discussed with its advantages and disadvantages, which helps researchers to understand the pitfalls and choose the correct model for their project.
• Emerging technologies and clinical relevance: Application of technologies such as CRISPR, multi-omics and spatial transcriptomics to refine the mouse models. The review bridges the gap between laboratory models and patient outcomes.

Limitations

• Tumour model limitations: Some tumour models such as syngeneic or CDX, may not mimic the tumour heterogeneity and microenvironment.
• Species differences: The murine immune system differs in various parameters compared to human counterpart such as cytokine profile, tumour-immune population interactions.
• Humanisation constraints: Humanised models bridge the species gap but still has its own caveat such as graft-versus-host issues,
• Reproducibility issues: Even after reasonable success, better rigorous design, validation and refined models will increase the success rate to the clinic. The review does not address the PDX or novel organoids-based models which are emerging but have their own limitations.

Implications for Translational Research and CROs

For Contract Research Organizations (CROs) and translational researchers, mouse models remain central to immuno‑oncology pipelines as it allows:

• • Early efficacy testing of immunotherapies.
• • Mechanistic studies of tumour–immune interactions.
• • Resistance profiling to guide combination strategies.
• • Data packages supporting regulatory submissions.

References:

• 1. Bosenberg, M., Liu, E.T., Yu, C.I., & Palucka, K. (2023). Mouse models for immuno oncology. Trends in Cancer, 9(7), 578–590.


• 2. Day, C.P., Merlino, G., & Van Dyke, T. (2015). Preclinical mouse cancer models: a maze of opportunities and challenges. Cell, 163(1), 39–53.


• 3. Rongvaux, A., et al. (2014). Humanized mice for studying human immune responses and immunotherapy. Immunological Reviews, 254(1), 220–233.