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Updated: May 9, 2026
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for
Erik M Alcantar-Orozco1, Hannah Gornall, Vania Baldan
1Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, The Institute of Cancer Sciences, Manchester Academic Healthcare Science Centre, The University of Manchester , Manchester M20 4BX, United Kingdom .
Abstract:
The genetic modification of peripheral blood lymphocytes using retroviral vectors to redirect T cells against tumor cells has been recently used as a means to generate large numbers of antigen-specific T cells for adoptive cell therapy protocols. However, commonly used retroviral vector-based genetic modification requires T cells to be driven into cell division; this potent mitogenic stimulus is associated with the development of an effector phenotype that may adversely impact upon the long-term engraftment potential and subsequent antitumor effects of T cells. To investigate whether the cytokines used during culture impact upon the engraftment potential of gene-modified T cells, a humanized model employing T cells engrafted with a MART-1-specific T cell receptor adoptively transferred into NOD/Shi-scid IL-2rγ(-/-) (NSG) immune-deficient mice bearing established melanoma tumors was used to compare the effects of the common γ chain cytokines IL-2, IL-7, and IL-15 upon gene-modified T cell activity. MART-1-specific T cells cultured in IL-7 and IL-15 demonstrated greater relative in vitro proliferation and viability of T cells compared with the extensively used IL-2. Moreover, the IL-15 culture prolonged the survival of animals bearing melanoma tumors after adoptive transfer. However, the combination of IL-7 and IL-15 produced T cells with improved engraftment potential compared with IL-15 alone; however, a high rate of xenogeneic graft-versus-host disease prevented the identification of a clear improvement in antitumor effect of these T cells. These results clearly demonstrate modulation of gene-modified T cell engraftment in the NSG mouse, which supports the future testing of the combination of IL-7 and IL-15 in adoptive cell therapy protocols; however, this improved engraftment is also associated with the long-term maintenance of xenoreactive T cells, which limits the ultimate usefulness of the NSG mouse model in this situation.
Insights
Cytokines IL-7 and IL-15 enhance T cell proliferation and survival for adoptive cell therapy. Combining IL-7 and IL-15 improves T cell engraftment in mice, but xenogeneic graft-versus-host disease complicates antitumor effect assessment.
Area of Science:
- Immunology
- Cell Biology
- Cancer Therapy
Background:
- Adoptive cell therapy utilizes genetically modified T cells to target tumors.
- Current methods often induce T cell effector phenotypes, potentially limiting long-term efficacy.
- Cytokine selection during T cell culture influences their function and engraftment potential.
Purpose of the Study:
- To investigate the impact of common gamma chain cytokines (IL-2, IL-7, IL-15) on gene-modified T cell engraftment and antitumor activity.
- To compare the effects of IL-2, IL-7, and IL-15 on T cells engineered with a MART-1-specific T cell receptor.
- To evaluate the potential of IL-7 and IL-15 combinations for improving T cell-based cancer therapies.
Main Methods:
- Genetic modification of peripheral blood lymphocytes with retroviral vectors to express a MART-1-specific T cell receptor.
- Culture of gene-modified T cells with IL-2, IL-7, or IL-15.
- Adoptive transfer of T cells into NOD/Shi-scid IL-2rγ(-/-) (NSG) mice bearing established melanoma tumors.
- Assessment of T cell proliferation, viability, engraftment, animal survival, and antitumor effects.
Main Results:
- T cells cultured with IL-7 and IL-15 showed superior in vitro proliferation and viability compared to those cultured with IL-2.
- IL-15 culture alone prolonged survival in tumor-bearing mice post-adoptive transfer.
- Combined IL-7 and IL-15 culture enhanced T cell engraftment potential compared to IL-15 alone, but high rates of xenogeneic graft-versus-host disease (xGvHD) hindered clear assessment of improved antitumor effects.
Conclusions:
- Cytokines IL-7 and IL-15 modulate gene-modified T cell engraftment in the NSG mouse model.
- The combination of IL-7 and IL-15 shows promise for improving T cell engraftment in adoptive cell therapy protocols.
- Long-term maintenance of xenoreactive T cells in NSG mice presents a limitation for evaluating ultimate antitumor efficacy, necessitating further model refinement.
