EGFR as a potent CAR T target in triple negative breast cancer brain metastases

Breast Cancer Res Treat. 2023 Jan;197(1):57-69. doi: 10.1007/s10549-022-06783-1. Epub 2022 Nov 1.

Abstract

Purpose: There is currently no curative treatment for patients diagnosed with triple-negative breast cancer brain metastases (TNBC-BM). CAR T cells hold potential for curative treatment given they retain the cytolytic activity of a T cell combined with the specificity of an antibody. In this proposal we evaluated the potential of EGFR re-directed CAR T cells as a therapeutic treatment against TNBC cells in vitro and in vivo.

Methods: We leveraged a TNBC-BM tissue microarray and a large panel of TNBC cell lines and identified elevated epidermal growth factor receptor (EGFR) expression. Next, we designed a second-generation anti-EGFR CAR T construct incorporating a clinically relevant mAb806 tumor specific single-chain variable fragment (scFv) and intracellular 4-1BB costimulatory domain and CD3ζ using a lentivirus system and evaluated in vitro and in vivo anti-tumor activity.

Results: We demonstrate EGFR is enriched in TNBC-BM patient tissue after neurosurgical resection, with six of 13 brain metastases demonstrating both membranous and cytoplasmic EGFR. Eleven of 13 TNBC cell lines have EGFR surface expression ≥ 85% by flow cytometry. EGFR806 CAR T treated mice effectively eradicated TNBC-BM and enhanced mouse survival (log rank p < 0.004).

Conclusion: Our results demonstrates anti-tumor activity of EGFR806 CAR T cells against TNBC cells in vitro and in vivo. Given EGFR806 CAR T cells are currently undergoing clinical trials in primary brain tumor patients without obvious toxicity, our results are immediately actionable against the TNBC-BM patient population.

Keywords: Brain metastases; Breast cancer; CAR T; EGFR; TNBC.

MeSH terms

  • Animals
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / secondary
  • Brain Neoplasms* / therapy
  • Cell Line, Tumor
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Mice
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / therapeutic use
  • Triple Negative Breast Neoplasms* / drug therapy
  • Triple Negative Breast Neoplasms* / therapy

Substances

  • Receptors, Chimeric Antigen
  • ErbB Receptors
  • EGFR protein, human