Document Detail


Interleukin 15 provides relief to CTLs from regulatory T cell-mediated inhibition: implications for adoptive T cell-based therapies for lymphoma.
MedLine Citation:
PMID:  23149818     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs. We used the model of adoptive transfer of Epstein-Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients.
EXPERIMENTAL DESIGN: Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored.
RESULTS: We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs.
CONCLUSIONS: IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies.
Authors:
Serena K Perna; Biagio De Angelis; Daria Pagliara; Sayyeda T Hasan; Lan Zhang; Aruna Mahendravada; Helen E Heslop; Malcolm K Brenner; Cliona M Rooney; Gianpietro Dotti; Barbara Savoldo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-13
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  19     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-06-18     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  106-17     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Cell Death / drug effects,  immunology
Cells, Cultured
Herpesvirus 4, Human / immunology
Hodgkin Disease / immunology,  therapy
Humans
Immunophenotyping
Immunotherapy, Adoptive
Interleukin-15 / pharmacology*
Lymphocyte Activation / drug effects,  immunology
Lymphoma / immunology,  therapy
T-Lymphocytes, Cytotoxic / drug effects*,  immunology*
T-Lymphocytes, Regulatory / immunology*
Grant Support
ID/Acronym/Agency:
P01 CA094237/CA/NCI NIH HHS; P30 CA125123/CA/NCI NIH HHS; P50 CA126752/CA/NCI NIH HHS; P50CA126752/CA/NCI NIH HHS; R01 CA131027/CA/NCI NIH HHS; R01 CA131027/CA/NCI NIH HHS; R01 CA142636/CA/NCI NIH HHS; R01 CA142636/CA/NCI NIH HHS; R01CA131027/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Interleukin-15
Comments/Corrections

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