| Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies. | |
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MedLine Citation:
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PMID: 21558388 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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-γ 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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Authors:
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Harjeet Singh; Matthew J Figliola; Margaret J Dawson; Helen Huls; Simon Olivares; Kirsten Switzer; Tiejuan Mi; Sourindra Maiti; Partow Kebriaei; Dean A Lee; Richard E Champlin; Laurence J N Cooper |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-05-10 |
Journal Detail:
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Title: Cancer research Volume: 71 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-17 Completed Date: 2011-07-22 Revised Date: 2012-05-18 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3516-27 Citation Subset: IM |
Copyright Information:
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©2011 AACR |
Affiliation:
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Division of Pediatrics, Children's Cancer Hospital, Houston, Texas, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, CD19 / biosynthesis*, metabolism Antigens, CD28 / metabolism B-Lymphocytes / cytology* Cell Lineage Coculture Techniques Hematologic Neoplasms / metabolism* Humans Immunotherapy, Adoptive / methods* Interferon-gamma / metabolism Interleukin-12 / metabolism* Interleukins / metabolism K562 Cells L-Selectin / metabolism Mice Mice, Inbred NOD STAT3 Transcription Factor / metabolism Signal Transduction T-Lymphocytes / immunology*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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5P30CA016672-32/CA/NCI NIH HHS; CA100265/CA/NCI NIH HHS; CA116127/CA/NCI NIH HHS; CA120956/CA/NCI NIH HHS; CA124782/CA/NCI NIH HHS; CA141303/CA/NCI NIH HHS; CA16672/CA/NCI NIH HHS; R01 CA120956-01A1/CA/NCI NIH HHS; R01 CA124782-01A1/CA/NCI NIH HHS; R01 CA124782-05/CA/NCI NIH HHS; R01 CA141303-01A1/CA/NCI NIH HHS; R01 CA141303-02/CA/NCI NIH HHS; R01 CA141303-03/CA/NCI NIH HHS; R33 CA116127-03/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD19; 0/Antigens, CD28; 0/Interleukins; 0/STAT3 Transcription Factor; 0/interleukin-21; 126880-86-2/L-Selectin; 187348-17-0/Interleukin-12; 82115-62-6/Interferon-gamma |
| Comments/Corrections | |
Erratum In:
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Cancer Res. 2011 Jul 1;71(13):4734 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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