Document Detail


Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer.
MedLine Citation:
PMID:  22466705     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The transfer of high-avidity T cell receptor (TCR) genes isolated from rare tumor-specific lymphocytes into polyclonal T cells is an attractive cancer immunotherapy strategy. However, TCR gene transfer results in competition for surface expression and inappropriate pairing between the exogenous and endogenous TCR chains, resulting in suboptimal activity and potentially harmful unpredicted antigen specificities of the resultant TCRs. We designed zinc-finger nucleases (ZFNs) that promoted the disruption of endogenous TCR β- and α-chain genes. Lymphocytes treated with ZFNs lacked surface expression of CD3-TCR and expanded with the addition of interleukin-7 (IL-7) and IL-15. After lentiviral transfer of a TCR specific for the Wilms tumor 1 (WT1) antigen, these TCR-edited cells expressed the new TCR at high levels, were easily expanded to near purity and were superior at specific antigen recognition compared to donor-matched, unedited TCR-transferred cells. In contrast to unedited TCR-transferred cells, the TCR-edited lymphocytes did not mediate off-target reactivity while maintaining their anti-tumor activity in vivo, thus showing that complete editing of T cell specificity generates tumor-specific lymphocytes with improved biosafety profiles.
Authors:
Elena Provasi; Pietro Genovese; Angelo Lombardo; Zulma Magnani; Pei-Qi Liu; Andreas Reik; Victoria Chu; David E Paschon; Lei Zhang; Jurgen Kuball; Barbara Camisa; Attilio Bondanza; Giulia Casorati; Maurilio Ponzoni; Fabio Ciceri; Claudio Bordignon; Philip D Greenberg; Michael C Holmes; Philip D Gregory; Luigi Naldini; Chiara Bonini
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nature medicine     Volume:  18     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-06-18     Completed Date:  2012-07-27     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  807-15     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Deoxyribonucleases, Type II Site-Specific / pharmacology*
Gene Transfer Techniques
Humans
Jurkat Cells
Lentivirus / genetics*
Leukemia / immunology*
Molecular Sequence Data
Receptors, Antigen, T-Cell / genetics*
T-Cell Antigen Receptor Specificity*
T-Lymphocytes / immunology
WT1 Proteins / genetics
Zinc Fingers*
Grant Support
ID/Acronym/Agency:
TGT11D02//Telethon
Chemical
Reg. No./Substance:
0/Receptors, Antigen, T-Cell; 0/WT1 Proteins; EC 3.1.21.4/Deoxyribonucleases, Type II Site-Specific

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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