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Updated: May 24, 2026
Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells
David M Davies1, Julie Foster, Sjoukje J C Van Der Stegen
1King's College London, King's Health Partners Integrated Cancer Center, Department of Research Oncology, Guy's Hospital Campus, London, UK.
Abstract:
Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbB-engineered 32D hematopoietic cells, we found that human T1E28z⁺ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28⁺ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.
Insights
This study introduces a novel immunotherapy targeting the ErbB network, a common driver of cancer. Engineered T cells (T1E28z) effectively target diverse tumor cells and reduce tumor growth in mice, offering a promising new cancer treatment strategy.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Pharmacological targeting of individual ErbB receptors shows antitumor activity but is often limited by resistance.
- Aberrant upregulation of the ErbB network is a fundamental mechanism driving tumorigenesis.
Purpose of the Study:
- To develop and evaluate a novel immunotherapeutic approach targeting the ErbB network.
- To engineer a chimeric antigen receptor (CAR) for broad ErbB targeting.
Main Methods:
- Engineered a CAR, T1E28z, fusing the ErbB ligand T1E to a CD28 + CD3ζ endodomain.
- Tested T1E28z CAR T cells against ErbB-engineered hematopoietic cells and diverse tumor cell lines in vitro.
- Evaluated antitumor activity in mice with established xenografts overexpressing ErbB receptors.
Main Results:
- T1E28z CAR T cells selectively activated by ErbB1-based dimers and the ErbB2/3 heterodimer.
- Demonstrated in vitro recognition and destruction of tumor cell lines with diverse ErbB profiles.
- Observed significant antitumor activity in mice against xenografts with ErbB1/2 or ErbB2/3 overexpression.
Conclusions:
- The T1E28z CAR T cell therapy exhibits broad applicability for targeting solid tumors with dysregulated ErbB networks.
- This approach offers a promising strategy for overcoming resistance to individual ErbB-targeted therapies.
- Supports the clinical development of this broadly applicable immunotherapeutic approach for various cancer types.
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