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 (TRegs) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Ra/CD25) can enhance antitumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Ra 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-2Ra monoclonal antibody (MAbs) to selectively deplete TRegs while permitting vaccine-stimulated immune responses. Methodology: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Ra MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete TRegs 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.