Document Detail


Bispecific T-cells expressing polyclonal repertoire of endogenous γδ T-cell receptors and introduced CD19-specific chimeric antigen receptor.
MedLine Citation:
PMID:  23295945     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Even though other γδ T-cell subsets exhibit antitumor activity, adoptive transfer of γδ Tcells is currently limited to one subset (expressing Vγ9Vδ2 T-cell receptor (TCR)) due to dependence on aminobisphosphonates as the only clinically appealing reagent for propagating γδ T cells. Therefore, we developed an approach to propagate polyclonal γδ T cells and rendered them bispecific through expression of a CD19-specific chimeric antigen receptor (CAR). Peripheral blood mononuclear cells (PBMC) were electroporated with Sleeping Beauty (SB) transposon and transposase to enforce expression of CAR in multiple γδ T-cell subsets. CAR(+)γδ T cells were expanded on CD19(+) artificial antigen-presenting cells (aAPC), which resulted in >10(9) CAR(+)γδ T cells from <10(6) total cells. Digital multiplex assay detected TCR mRNA coding for Vδ1, Vδ2, and Vδ3 with Vγ2, Vγ7, Vγ8, Vγ9, and Vγ10 alleles. Polyclonal CAR(+)γδ T cells were functional when TCRγδ and CAR were stimulated and displayed enhanced killing of CD19(+) tumor cell lines compared with CAR(neg)γδ T cells. CD19(+) leukemia xenografts in mice were reduced with CAR(+)γδ T cells compared with control mice. Since CAR, SB, and aAPC have been adapted for human application, clinical trials can now focus on the therapeutic potential of polyclonal γδ T cells.
Authors:
Drew C Deniger; Kirsten Switzer; Tiejuan Mi; Sourindra Maiti; Lenka Hurton; Harjeet Singh; Helen Huls; Simon Olivares; Dean A Lee; Richard E Champlin; Laurence J N Cooper
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-08
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-10-22     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  638-47     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigen-Presenting Cells / immunology,  metabolism
Antigens, CD19 / immunology*,  metabolism
Cell Line, Tumor
Electroporation
Humans
Immunotherapy, Adoptive / methods*
Leukemia / therapy
Leukocytes, Mononuclear / immunology,  metabolism
Lymphocyte Activation / immunology
Mice
Mice, Knockout
Receptors, Antigen, T-Cell, gamma-delta / immunology*
T-Lymphocytes / immunology*
Transposases / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA100632/CA/NCI NIH HHS; CA120956/CA/NCI NIH HHS; CA124782/CA/NCI NIH HHS; CA136411/CA/NCI NIH HHS; CA141303/CA/NCI NIH HHS; CA163587/CA/NCI NIH HHS; CA16672/CA/NCI NIH HHS; P01 CA148600/CA/NCI NIH HHS; P30 CA016672/CA/NCI NIH HHS; R33 CA116127/CA/NCI NIH HHS; S10RR026916/RR/NCRR NIH HHS; TL1 RR024147/RR/NCRR NIH HHS; UL1 RR024148/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD19; 0/Receptors, Antigen, T-Cell, gamma-delta; EC 2.7.7.-/Transposases; EC 2.7.7.-/sleeping beauty transposase, human
Comments/Corrections

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