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

Lesniak, Maciej S

United States

2018-03-01T14:24:46Z

2018-03-01T14:24:46Z

2012

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.

https://www.ncbi.nlm.nih.gov/pubmed/22383993

PONE-D-11-20574

1932-6203

https://hdl.handle.net/10161/16110

eng

Public Library of Science (PLoS)

PLoS One

10.1371/journal.pone.0031046

Adult

Aged

Antibodies, Monoclonal, Humanized

Brain Neoplasms

CD4-Positive T-Lymphocytes

CD8-Positive T-Lymphocytes

Female

Glioblastoma

Humans

Immune System

Immunoglobulin G

Immunosuppressive Agents

Interleukin-2 Receptor alpha Subunit

Lymphopenia

Male

Middle Aged

Pilot Projects

T-Lymphocytes

T-Lymphocytes, Regulatory

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

Journal article

Sampson, John H|0000-0002-0104-7658

Nair, Smita K|0000-0001-7019-1912

Friedman, Henry S|0000-0001-7588-032X

McLendon, Roger E|0000-0001-6682-4588

Bigner, Darell D|0000-0001-5548-4899

https://www.ncbi.nlm.nih.gov/pubmed/22383993

e31046

2

Basic Science Departments

Biostatistics & Bioinformatics

Clinical Science Departments

Duke

Duke Cancer Institute

Faculty

Immunology

Institutes and Centers

Medicine

Medicine, Medical Oncology

Neurology

Neurology, General & Community Neurology

Neurosurgery

Orthopaedics

Pathology

Pediatrics

Radiation Oncology

School of Medicine

Surgery

Surgery, Surgical Sciences

Published

7