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In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study

INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of...

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Autores principales: Pressey, Joseph G., Adams, Julia, Harkins, Lualhati, Kelly, David, You, Zhiying, Lamb, Lawrence S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer Health 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5265919/
https://www.ncbi.nlm.nih.gov/pubmed/27684826
http://dx.doi.org/10.1097/MD.0000000000004909
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author Pressey, Joseph G.
Adams, Julia
Harkins, Lualhati
Kelly, David
You, Zhiying
Lamb, Lawrence S.
author_facet Pressey, Joseph G.
Adams, Julia
Harkins, Lualhati
Kelly, David
You, Zhiying
Lamb, Lawrence S.
author_sort Pressey, Joseph G.
collection PubMed
description INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa(®)]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB. METHODS: Patients 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options received ZOL on day 1, and IL-2 on days 1 to 5 and 15 to 19 of each 28-day cycle (n = 4). Lymphocyte immunophenotyping was assessed weekly. Immunophenotyping studies from the treatment group were compared with healthy pediatric controls (n = 16; range, 5y–15y) and of untreated NB disease controls (n = 9; range, 4m–18y). RESULTS: Treatment was well tolerated with no unexpected grade 3 and 4 toxicities. Lymphocyte subset counts did not differ significantly between volunteers and disease controls with the exception of γδ+ T cell counts that were significantly higher in healthy volunteers (212 + 93 vs. 89 + 42, P = 0.05). Study patients showed increases in circulating γδ+ T cell count (3–10 fold) after the first week, increasing into the range seen in healthy volunteers (125 + 37, P = 0.1940). Interestingly, all ZOL + IL-2 treated patients showed significant increases in CD3+CD4+CD27(hi)CD127(dim) T cells that rose weekly in 2 patients throughout the 4 weeks of observation (maximum 41% and 24% of total CD3+CD4+ T cells, respectively). CONCLUSIONS: In summary, combined ZOL and IL-2 is well tolerated and restored γδ+ T cell counts to the normal range with a moderate expansion of Natural Killer cells. Progressive increases in circulating CD4+ T cells with a regulatory phenotype cells may offset beneficial effects of this therapy.
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spelling pubmed-52659192017-02-06 In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study Pressey, Joseph G. Adams, Julia Harkins, Lualhati Kelly, David You, Zhiying Lamb, Lawrence S. Medicine (Baltimore) 5700 INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa(®)]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB. METHODS: Patients 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options received ZOL on day 1, and IL-2 on days 1 to 5 and 15 to 19 of each 28-day cycle (n = 4). Lymphocyte immunophenotyping was assessed weekly. Immunophenotyping studies from the treatment group were compared with healthy pediatric controls (n = 16; range, 5y–15y) and of untreated NB disease controls (n = 9; range, 4m–18y). RESULTS: Treatment was well tolerated with no unexpected grade 3 and 4 toxicities. Lymphocyte subset counts did not differ significantly between volunteers and disease controls with the exception of γδ+ T cell counts that were significantly higher in healthy volunteers (212 + 93 vs. 89 + 42, P = 0.05). Study patients showed increases in circulating γδ+ T cell count (3–10 fold) after the first week, increasing into the range seen in healthy volunteers (125 + 37, P = 0.1940). Interestingly, all ZOL + IL-2 treated patients showed significant increases in CD3+CD4+CD27(hi)CD127(dim) T cells that rose weekly in 2 patients throughout the 4 weeks of observation (maximum 41% and 24% of total CD3+CD4+ T cells, respectively). CONCLUSIONS: In summary, combined ZOL and IL-2 is well tolerated and restored γδ+ T cell counts to the normal range with a moderate expansion of Natural Killer cells. Progressive increases in circulating CD4+ T cells with a regulatory phenotype cells may offset beneficial effects of this therapy. Wolters Kluwer Health 2016-09-30 /pmc/articles/PMC5265919/ /pubmed/27684826 http://dx.doi.org/10.1097/MD.0000000000004909 Text en Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved. http://creativecommons.org/licenses/by-nc-nd/4.0 This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0
spellingShingle 5700
Pressey, Joseph G.
Adams, Julia
Harkins, Lualhati
Kelly, David
You, Zhiying
Lamb, Lawrence S.
In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study
title In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study
title_full In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study
title_fullStr In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study
title_full_unstemmed In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study
title_short In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study
title_sort in vivo expansion and activation of γδ t cells as immunotherapy for refractory neuroblastoma: a phase 1 study
topic 5700
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5265919/
https://www.ncbi.nlm.nih.gov/pubmed/27684826
http://dx.doi.org/10.1097/MD.0000000000004909
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