Humanized Immune System Mice: An Effective Preclinical Model for Reproducing Human Immune-Tumor Interactions

Humanized Immune System Mice (HIS mice) are developed by transplanting human immune system components into mice, resulting in animal models that partially or fully replicate human immune system functions. HIS mouse models are constructed through various methods, including transplantation of human hematopoietic stem cells (HSCs), human peripheral blood mononuclear cells (PBMCs), human thymus tissue transplantation, and human spleen or lymph node tissues.

In preclinical research situations where direct experimentation on humans is not possible, HIS mice offer the advantage of simulating the complexity and diversity of the human immune system. This enables researchers to study human immune responses within a living organism. As such, HIS mouse models are crucial for understanding the role of the immune system in health and disease, developing new immunotherapies, and assessing the immunotoxicity and efficacy of drugs.

Applications of HIS Mice in Drug Development

The utilization of Human Immune System Mice (HIS mice) in drug development has provided significant insights into various therapeutic approaches. HIS mice have been proven as invaluable research tools across key immunotherapy research applications, including immune checkpoint inhibitor (ICI) therapy, bispecific antibodies, cancer vaccines, and combination therapies.

1. Functional Validation Of Immune Checkpoint Inhibitor (ICI) Therapy

Research has shown that although Nivolumab (an anti-PD-1 antibody) does not significantly affect tumor growth in PBMC-humanized mice with transplanted osteosarcoma tumors, it partially inhibits the formation of lung metastases by increasing CD4+ and CD8+ T cells and enhancing CD8+ T cell cytotoxicity. This finding paves the way for anti-PD1 therapy in patients with metastatic osteosarcoma.

Studies have shown that tumor growth of triple negative breast cancer (TNBC) CDX as well as TNBC and non-small cell lung cancer (NSCLC) PDX – after being transplanted into HIS mice and treated with another anti-PD-1 antibody, Pembrolizumab (Keytruda) – was significantly delayed, mirroring clinical observations. The effect of Pembrolizumab is mediated by CD8+ T cells, and the tumor's response to Pembrolizumab depends on the HSC donor. This finding is consistent with the clinical observation of varying patient responses to anti-PD1 antibodies.

2. T-Cell-Engaging Bispecific Antibodies

T-cell-engaging bispecific (TCB) antibody therapy has demonstrated reduced tumor growth and increased tumor-infiltrating T cells in similar humanized B-cell lymphoma, gastric cancer, and pancreatic cancer mouse models. In HIS mice transplanted with human B-cell lymphoma, the antitumor effect of the bispecific antibody CD20-TCB (T cell bispecific) was observed. This effect is mediated by the rapid formation of T cell-tumor cell synapses, inducing tumor cell cytotoxicity and cytokine synthesis. TCB can upregulate PD-1 expression on T cells and PD-L1 expression on both cancer and T cells. Compared to monotherapy, TCB shows a stronger antitumor effect when used in combination with anti-PD-L1 than as an individual treatment.

3. Therapeutic Cancer Vaccines

The carcinogenicity of human papillomavirus (HPV) is associated with the persistent expression of HPV proteins E6 and E7 in tumors. Numerous clinical trials have explored the efficacy of therapeutic vaccines targeting E6 and E7, but none have been approved for clinical use so far. A novel therapeutic gorilla adenovirus HPV vaccine, PRGN-2009, has shown promise in HIS mice carrying human HPV16+ cervical tumors, as it reduces tumor growth and increases levels of CD8+ and CD4+ T cells in the tumor microenvironment, supporting its application in clinical trials.

In Cyagen's self-developed fully humanized immune system mice, huHSC-NKG-ProF, A375 melanoma cells were inoculated and treated with a therapeutic cancer vaccine three times. After 21 days, the tumor inhibition rate reached 38% (p<0.01). In vitro experiments showed that huHSC-NKG-ProF mice could produce antigen-specific T cells, with increased detection of IFN-γ and tetramers.

Figure 1. mRNA cancer vaccine treatment of A375 melanoma in huHSC-NKG-ProF mice.

huHSC-NKG-ProF Mouse Model

• Product Name: huHSC-NKG-ProF  
• Product Number: C001543  
• Model Highlights: Fully humanized immune system reconstitution
• Immune Reconstitution Details: Reconstitution of lymphoid lineage T cells, B cells, NK cells, and myeloid lineage dendritic cells (DC), monocytes, macrophages, and granulocytes
• Reconstitution Time: Humanization ratio reaches 40-60% within 8 weeks

4. Combination Therapy

HIS mice can be used to evaluate the functional effects of oncolytic virus therapy targeting cancer cells and inducing immunogenic cell death. Studies have shown that IL-21 is an excellent candidate as an immunomodulator. Whether used alone or in combination with chimeric antigen receptor T (CAR-T) cell therapy or invariant natural killer T (iNKT) cell therapy, Torque Teno oncolytic virus (TTV) has demonstrated efficacy in the treatment of lung cancer tumors in Humanized Immune System Mice. This study not only indicates a significant synergistic effect between the two combination therapies but also suggests potential synergistic effects when other immunotherapies are combined with IL-21-carrying TTV.

Recommended Humanized Immune System Mouse Models

It is increasingly recognized that simple immunocompetent mice are not the best preclinical models, especially in the development of immunotherapies and combination therapies. Therefore, implementing an animal model that can replicate human immune-tumor interactions is of increasing research value.

Cyagen has developed a humanized immune system mouse model by transplanting human peripheral blood mononuclear cells and hematopoietic stem cells into our proprietary NKG severely immunodeficient mice. The huHSC-NKG mice are a result of several upgrades, including our advanced neonatal mouse techniques that allow the development of various human immune cells. Notably, the fully humanized immune system mouse model, huHSC-NKG-ProF, can reconstitute lymphoid lineage cells (T, B, NK cells) and myeloid lineage cells (dendritic cells (DC), monocytes, macrophages, and granulocytes).

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References:

[1] Zheng, Bingxin., Zheng, Bingxin., Ren, Tingting., Ren, Tingting.,  and Huang, Yi.. "PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse." Journal of hematology & oncology 11.1(2018):16.

[2] Wang, Minan., Yao, Li-Chin., Cheng, Mingshan., Cai, Danying.,  and Martinek, Jan.. "Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32.3(2018):1537-1549.

[3] Sam, Johannes., Colombetti, Sara., Fauti, Tanja., Roller, Andreas.,  and Biehl, Marlene.. "Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity." Frontiers in oncology 10:575737.

[4] Smalley Rumfield, Claire., Roller, Nicholas., Pellom, Samuel Troy., Schlom, Jeffrey.,  and Jochems, Caroline.. "Therapeutic Vaccines for HPV-Associated Malignancies." ImmunoTargets and therapy 9.