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A Transgenic mouse tolerant to syngeneic cancer cells expressing truncated human epidermal growth factor receptor

Theresa Barberi1, Rahila Khuroo1, Alan D Friedman1

  • 1Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Plos One
|August 7, 2026
PubMed

Insights

Researchers developed genetically modified mice expressing a truncated human Epidermal Growth Factor Receptor (hEGFRt) to overcome immunotherapy challenges. These mice demonstrate tolerance to hEGFRt, enabling the development of novel cancer immunotherapies targeting EGFR-expressing tumors.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Epidermal Growth Factor Receptor (EGFR) is a target in various human cancers, including non-small-cell lung cancer (NSCLC), glioblastoma (GBM), pancreatic ductal carcinoma (PDC), and castration-resistant prostate cancer (CRPC).
  • Murine intolerance to human EGFR hinders the development of effective EGFR-targeted immunotherapies.

Purpose of the Study:

  • To create a mouse model that overcomes murine intolerance to human EGFR for advancing immunotherapy research.
  • To develop a tool for preclinical testing of immunotherapies targeting human EGFR.

Main Methods:

  • Generation of C57BL/6 mice expressing a truncated human EGFR (hEGFRt) variant under the CAG regulatory elements.
  • Utilized a floxed transgene (CAG-hEGFRt(f/f)) allowing for inducible excision via Mx1-Cre.
  • Validated antibody binding (Cetuximab) and transgene expression in various tissues and cell types.

Main Results:

  • The developed CAG-hEGFRt(f/f) mice exhibit tolerance to syngeneic tumors expressing hEGFRt.
  • Transgene expression is widespread, with high levels in hematopoietic cells and lower levels in non-hematopoietic tissues.
  • Mx1-Cre mediated excision significantly reduced hEGFRt expression in adult mice, and tolerance was maintained post-excision.

Conclusions:

  • CAG-hEGFRt(f/f) mice provide a valuable preclinical model for developing and testing immunotherapies targeting human EGFR.
  • This model facilitates the study of EGFR-targeted therapies in the context of various malignancies, including NSCLC, GBM, PDC, and CRPC.
  • The ability to delete the transgene offers a method to mitigate potential off-target effects of immunotherapies in normal tissues.

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