Journal
PLOS ONE
Volume 7, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0031046
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Funding
- National Institutes of Health (NIH) [RO1-CA097222, R21-NS067980, R21-CA132891]
- NIH/National Institute of Neurological Disorders and Stroke SRC on Primary and Metastatic Tumors of the Central Nervous System [P50-NS020023]
- Specialized Program of Research Excellence in Brain Cancer [P50-CA108786]
- Duke University from National Center for Research Resources/NIH [1UL2-RR024128]
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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-2R alpha/CD25) can enhance antitumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2R alpha 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-2R alpha 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-2R alpha 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:
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