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rdf:type |
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lifeskim:mentions |
umls-concept:C0006826,
umls-concept:C0037083,
umls-concept:C0039194,
umls-concept:C0079613,
umls-concept:C0332161,
umls-concept:C0962190,
umls-concept:C1149231,
umls-concept:C1334107,
umls-concept:C1367171,
umls-concept:C1416406,
umls-concept:C1423038,
umls-concept:C1710082,
umls-concept:C1831593
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pubmed:issue |
10
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pubmed:dateCreated |
2011-5-17
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pubmed:abstractText |
Improving the therapeutic efficacy of T cells expressing a chimeric antigen receptor (CAR) represents an important goal in efforts to control B-cell malignancies. Recently an intrinsic strategy has been developed to modify the CAR itself to improve T-cell signaling. Here we report a second extrinsic approach based on altering the culture milieu to numerically expand CAR(+) T cells with a desired phenotype, for the addition of interleukin (IL)-21 to tissue culture improves CAR-dependent T-cell effector functions. We used electrotransfer of Sleeping Beauty system to introduce a CAR transposon and selectively propagate CAR(+) T cells on CD19(+) artificial antigen-presenting cells (aAPC). When IL-21 was present, there was preferential numeric expansion of CD19-specific T cells which lysed and produced IFN-? in response to CD19. Populations of these numerically expanded CAR(+) T cells displayed an early memory surface phenotype characterized as CD62L(+)CD28(+) and a transcriptional profile of naïve T cells. In contrast, T cells propagated with only exogenous IL-2 tended to result in an overgrowth of CD19-specific CD4(+) T cells. Furthermore, adoptive transfer of CAR(+) T cells cultured with IL-21 exhibited improved control of CD19(+) B-cell malignancy in mice. To provide coordinated signaling to propagate CAR(+) T cells, we developed a novel mutein of IL-21 bound to the cell surface of aAPC that replaced the need for soluble IL-21. Our findings show that IL-21 can provide an extrinsic reprogramming signal to generate desired CAR(+) T cells for effective immunotherapy.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1538-7445
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pubmed:author |
pubmed-author:ChamplinRichard ERE,
pubmed-author:CooperLaurence J NLJ,
pubmed-author:DawsonMargaret JMJ,
pubmed-author:FigliolaMatthew JMJ,
pubmed-author:HulsHelenH,
pubmed-author:KebriaeiPartowP,
pubmed-author:LeeDean ADA,
pubmed-author:MaitiSourindraS,
pubmed-author:MiTiejuanT,
pubmed-author:OlivaresSimonS,
pubmed-author:SinghHarjeetH,
pubmed-author:SwitzerKirstenK
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pubmed:copyrightInfo |
©2011 AACR
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
71
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3516-27
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pubmed:dateRevised |
2011-8-18
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pubmed:meshHeading |
pubmed-meshheading:21558388-Animals,
pubmed-meshheading:21558388-Antigens, CD19,
pubmed-meshheading:21558388-Antigens, CD28,
pubmed-meshheading:21558388-B-Lymphocytes,
pubmed-meshheading:21558388-Cell Lineage,
pubmed-meshheading:21558388-Coculture Techniques,
pubmed-meshheading:21558388-Hematologic Neoplasms,
pubmed-meshheading:21558388-Humans,
pubmed-meshheading:21558388-Immunotherapy, Adoptive,
pubmed-meshheading:21558388-Interferon-gamma,
pubmed-meshheading:21558388-Interleukin-12,
pubmed-meshheading:21558388-Interleukins,
pubmed-meshheading:21558388-K562 Cells,
pubmed-meshheading:21558388-L-Selectin,
pubmed-meshheading:21558388-Mice,
pubmed-meshheading:21558388-Mice, Inbred NOD,
pubmed-meshheading:21558388-STAT3 Transcription Factor,
pubmed-meshheading:21558388-Signal Transduction,
pubmed-meshheading:21558388-T-Lymphocytes
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pubmed:year |
2011
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pubmed:articleTitle |
Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies.
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pubmed:affiliation |
Division of Pediatrics, Children's Cancer Hospital, Houston, Texas, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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