Flexible Targeting of ErbB Dimers That Drive Tumorigenesis by Using Genetically Engineered T Cells
| Autor: | Vincent Kao, David M. Davies, May C I van Schalkwyk, Sjoukje J. C. van der Stegen, Zhe Liu, Ana C. Parente-Pereira, Laura Chiapero-Stanke, Carol Box, Sophie Burbridge, George J. Delinassios, Leticia Bosshard-Carter, Suzanne A. Eccles, Julie Foster, John Maher, Scott Wilkie, Stephen J. Mather |
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| Rok vydání: | 2012 |
| Předmět: |
Receptor
ErbB-2 Recombinant Fusion Proteins T-Lymphocytes Breast Neoplasms Mice SCID Biology medicine.disease_cause Mice ErbB Receptors Downregulation and upregulation Transduction Genetic ErbB Cell Line Tumor Genetics medicine Animals Humans skin and connective tissue diseases Receptor Molecular Biology Genetics (clinical) Interleukin 4 CD28 Articles Xenograft Model Antitumor Assays Molecular biology Chimeric antigen receptor Receptors Antigen Cell Transformation Neoplastic Head and Neck Neoplasms Cancer research Molecular Medicine Female Interleukin-4 Protein Multimerization Genetic Engineering Carcinogenesis |
| Zdroj: | Molecular Medicine. 18:565-576 |
| ISSN: | 1528-3658 1076-1551 |
| DOI: | 10.2119/molmed.2011.00493 |
| Popis: | 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 T1E28z+ 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. |
| Databáze: | OpenAIRE |
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