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A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma

BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are compli...

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Autores principales: Sampson, John H., Schmittling, Robert J., Archer, Gary E., Congdon, Kendra L., Nair, Smita K., Reap, Elizabeth A., Desjardins, Annick, Friedman, Allan H., Friedman, Henry S., Herndon, James E., Coan, April, McLendon, Roger E., Reardon, David A., Vredenburgh, James J., Bigner, Darell D., Mitchell, Duane A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288003/
https://www.ncbi.nlm.nih.gov/pubmed/22383993
http://dx.doi.org/10.1371/journal.pone.0031046
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author Sampson, John H.
Schmittling, Robert J.
Archer, Gary E.
Congdon, Kendra L.
Nair, Smita K.
Reap, Elizabeth A.
Desjardins, Annick
Friedman, Allan H.
Friedman, Henry S.
Herndon, James E.
Coan, April
McLendon, Roger E.
Reardon, David A.
Vredenburgh, James J.
Bigner, Darell D.
Mitchell, Duane A.
author_facet Sampson, John H.
Schmittling, Robert J.
Archer, Gary E.
Congdon, Kendra L.
Nair, Smita K.
Reap, Elizabeth A.
Desjardins, Annick
Friedman, Allan H.
Friedman, Henry S.
Herndon, James E.
Coan, April
McLendon, Roger E.
Reardon, David A.
Vredenburgh, James J.
Bigner, Darell D.
Mitchell, Duane A.
author_sort Sampson, John H.
collection PubMed
description BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015
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spelling pubmed-32880032012-03-01 A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma Sampson, John H. Schmittling, Robert J. Archer, Gary E. Congdon, Kendra L. Nair, Smita K. Reap, Elizabeth A. Desjardins, Annick Friedman, Allan H. Friedman, Henry S. Herndon, James E. Coan, April McLendon, Roger E. Reardon, David A. Vredenburgh, James J. Bigner, Darell D. Mitchell, Duane A. PLoS One Research Article BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015 Public Library of Science 2012-02-27 /pmc/articles/PMC3288003/ /pubmed/22383993 http://dx.doi.org/10.1371/journal.pone.0031046 Text en Sampson et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sampson, John H.
Schmittling, Robert J.
Archer, Gary E.
Congdon, Kendra L.
Nair, Smita K.
Reap, Elizabeth A.
Desjardins, Annick
Friedman, Allan H.
Friedman, Henry S.
Herndon, James E.
Coan, April
McLendon, Roger E.
Reardon, David A.
Vredenburgh, James J.
Bigner, Darell D.
Mitchell, Duane A.
A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma
title A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma
title_full A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma
title_fullStr A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma
title_full_unstemmed A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma
title_short A Pilot Study of IL-2Rα Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma
title_sort pilot study of il-2rα blockade during lymphopenia depletes regulatory t-cells and correlates with enhanced immunity in patients with glioblastoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288003/
https://www.ncbi.nlm.nih.gov/pubmed/22383993
http://dx.doi.org/10.1371/journal.pone.0031046
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