期刊
MOLECULAR MEDICINE
卷 18, 期 4, 页码 565-576出版社
FEINSTEIN INST MED RES
DOI: 10.2119/molmed.2011.00493
关键词
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资金
- Association for International Cancer Research [08-0419]
- Breast Cancer Campaign [2006NovPR18]
- Guy's and St Thomas' Charity
- Experimental Cancer Medicine Centre (King's College London)
- Moulton Charitable Foundation
- Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre
- King's College London
- ICR
- Cancer Research UK [CA309/A8274]
- NIHR
- Academy of Medical Sciences (AMS) [AMS-SGCL6-Papa] Funding Source: researchfish
- Cancer Research UK [11566] Funding Source: researchfish
- National Institute for Health Research [CL-2011-17-007] Funding Source: researchfish
- Worldwide Cancer Research [08-0419] Funding Source: researchfish
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 + CD3 zeta endodomain. Using a panel of ErbB-engineered 32D hernatopoietic 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. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00493
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