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

John H Sampson, Robert J Schmittling, Gary E Archer, Kendra L Congdon, Smita K Nair, Elizabeth A Reap, Annick Desjardins, Allan H Friedman, Henry S Friedman, James E Herndon 2nd, April Coan, Roger E McLendon, David A Reardon, James J Vredenburgh, Darell D Bigner, Duane A Mitchell, John H Sampson, Robert J Schmittling, Gary E Archer, Kendra L Congdon, Smita K Nair, Elizabeth A Reap, Annick Desjardins, Allan H Friedman, Henry S Friedman, James E Herndon 2nd, April Coan, Roger E McLendon, David A Reardon, James J Vredenburgh, Darell D Bigner, Duane A Mitchell

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.

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.

Conflict of interest statement

Competing Interests: Consultant or Advisory Role: JHS, Celldex Therapeutics (C); DDB, Celldex Therapeutics (C) Honoraria: JHS, Celldex Therapeutics; DDB, Celldex Therapeutics Research Funding: JHS. The designation (C) indicates a compensated position. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. CDX-110 is a Celldex product. There are no patents, products in development or other marketed products to declare.

Figures

Figure 1. CONSORT 2010 Flow Diagram.
Figure 1. CONSORT 2010 Flow Diagram.
Flow diagram of enrollment, allocation, follow-up and analysis of the Zenapax® Activated Peptide Immunotherapy (ZAP IT) Clinical Trial.
Figure 2. In vitro effects of IL2Rα…
Figure 2. In vitro effects of IL2Rα inhibition on CD4+, CD8+ and regulatory T-cells.
Normal donor peripheral blood mononuclear cells (PBMCs) were cultured for 48 hours with increasing concentrations of daclizumab followed by an additional 14 days stimulation/expansion with CMV pp65 RNA-pulsed DCs along with IL-2 or IL-15. PBMC were then isolated and stimulated for 6 hours with SEB or pp65 peptide mix in the presence of CD28/CD49d costimulation and Brefeldin A. The IFN-γ secretion of (A) CD3+CD4+CD69+ or (B) CD3+CD8+CD69+ T-cells was determined by flow cytometry.
Figure 3. Schema of ZAP IT Trial.
Figure 3. Schema of ZAP IT Trial.
Figure 4. Regulatory T-cells are significantly depleted…
Figure 4. Regulatory T-cells are significantly depleted by a single infusion of daclizumab.
The frequency of CD4+Foxp3+ TRegs was determined by FACS analysis of peripheral blood samples drawn prior to vaccination (V) or leukapheresis (LP). Percent change was calculated in comparison to baseline (vaccine 1). For each follow-up assessment, percent change from baseline (vaccine 1) was computed. For statistical comparisons of the daclizumab and saline groups, the average percent change at vaccine 2 (V-2), vaccine 3 (V-3), and leukapheresis (LP) was computed for each patient. Daclizumab showed a significantly greater reduction in CD4+Foxp3+ regulatory T-cells (p = 0.0464).
Figure 5. In vivo effects of daclizumab…
Figure 5. In vivo effects of daclizumab on the effector T-cell to regulatory T-cell ratio.
(A–B) Effector T-cells (CD4+ or CD8+) to TReg ratios were derived by dividing the absolute number of effector T-cells by the absolute number of TRegs at the indicated time-points; the absolute number of cells was determined by a combination of CBC and FACS analysis. The ratios of effector T-cells to TRegs as compared to baseline were generated by dividing the individual patient CD4+∶TReg or CD8+∶TReg ratio at every time point by the ratio at vaccine 1 (V-1 = baseline). A two sample t-test averaged over the V-2, V-3 and LP time-points was utilized to examine the difference between the daclizumab and saline groups in the CD4+∶TReg (p = 0.0757) and CD8+∶TReg (p = 0.0153) ratios.
Figure 6. Daclizumab remains bound to T…
Figure 6. Daclizumab remains bound to TRegs a month after administration.
(A) CD4+Foxp3+ TRegs from day 35±2 leukapheresis samples (saline n = 3, daclizumab n = 3) were determined by flow cytometry and were additionally stained with anti-CD25 antibodies that bind the same CD25 eptiope as daclizumab (competing clone 2A3) or bind a separate epitope (non-competing clone MA251). The ratio of the frequency of CD4+CD25+Foxp3+ TRegs as determined by MA251 or 2A3 binding was used as an indirect indicator of surface daclizumab expression. The percent change in the ratio was calculated from ratios determined from baseline (vaccine 1) samples, unpaired t-test *p = 0.0353. (B) CD4+CD25+Foxp3+ TRegs were determined by FACS analysis of PBMC and examined for human antibody expression as a direct indicator of daclizumab binding to the surface of TRegs. PBMCs from a saline and a daclizumab treated patient from vaccine 1 (Pre-Daclizumab) and leukapheresis at day 35±2 (Post-Daclizumab) time-points were assessed.
Figure 7. The frequency of T Regs…
Figure 7. The frequency of TRegs and anti-PEPvIII humoral responses are inversely correlated.
Patient sera from peripheral blood (vaccine 4) and leukapheresis samples were analyzed for levels of anti-PEPvIII antibodies and humoral responses were plotted against the frequency of TRegs (Foxp3+ of CD4+). Assuming the assessments within individuals are independent, the Spearman correlation coefficient for both saline and daclizumab treated patients overall is (R = −0.93, p<0.0001).

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