title: A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.
abstract: 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.
  
  
  METHODS
  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).
  
  
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00626015.
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America. john.sampson@duke.edu
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmittling
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Congdon
authors.forename: Smita K
authors.initials: SK
authors.lastname: Nair
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Reap
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: April
authors.initials: A
authors.lastname: Coan
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D000077561:Daclizumab; D005260:Female; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008231:Lymphopenia / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D000077561:Daclizumab