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

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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 CD3\(\zeta\) 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.

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Data availability

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author. All data will be made available to interested parties upon reasonable request.

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Funding

This work was funded by the University of Kansas Cancer Center.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Kansas Cancer Center, Kansas City, KS, USA

    Siddharth Subham, John D. Jeppson, Colette Worcester, Bruce F. Kimler, Ronald C. Chen, Shane R. Stecklein & David Akhavan

  2. Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, KS, USA

    Siddharth Subham, Jie Zhao, Shane R. Stecklein & David Akhavan

  3. BioEngineering Program, University of Kansas, Lawrence, KS, USA

    Siddharth Subham & David Akhavan

  4. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    Colette Worcester, Rashna Madan, Nelli S. Lakis & Shane R. Stecklein

  5. Department of Neurosurgery, University of Kansas Medical Center, Kansas City, KS, USA

    Bryan Schatmeyer

  6. Department of Hematology and Stem Cell Transplantation, University of Kansas Medical Center, Kansas City, KS, USA

    Joseph P. McGuirk

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  1. Siddharth Subham
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by DA, SS, SS, JJ, and CW, BS, and JZ. The first draft of the manuscript was written by DA and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to David Akhavan.

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Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki and its later amendments or comparable ethical standards. Ethical approval of this study was granted by the University of Kansas Medical Center Institutional Review Board (IRB) and IACUC on September 21, 2021.

Informed consent

Informed consent was obtained from all University of Kansas Medical Center Biorepository Core Facility for all patient tissue presented in this study.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for de-identified immunohistochemistry in Fig. 1A.

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Subham, S., Jeppson, J.D., Worcester, C. et al. EGFR as a potent CAR T target in triple negative breast cancer brain metastases. Breast Cancer Res Treat 197, 57–69 (2023). https://doi.org/10.1007/s10549-022-06783-1

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