The immune system has the potential to eliminate altered neoplastic cells with incredible specificity. A consistent in-frame deletion in the extra-cellular domain of the epidermal growth factor receptor (EGFRvIII) represents a truly tumor-specific target amenable to immunotherapeutic attack. Our multi-institutional Phase II study demonstrated that vaccination with an EGFRvIII-specific peptide in patients with newly-diagnosed glioblastoma multiforme (GBM) induces potent T- and B-cell immunity, produces nearly complete radiographic responses in all patients with residual tumor, and universally eliminates EGFRvIII-expressing cells. Recurrent tumors, however, continue to express wild-type EGFR suggesting that the immune response is specific, but productive intra-molecular cross-priming against other potential tumor-associated antigens is incomplete. We believe that productive extension of such secondary immune responses is hindered by the presence of regulatory T-cells (TRegs). We have recently shown that TRegs are disproportionately represented within the peripheral blood and tumors of patients with GBM and serve to induce a state of profound, but reversible, immunosuppression. TRegs are characterized by constitutive expression of the high affinity interleukin (IL)-2 receptor (IL-2R1)(CD25) and are uniquely dependent on IL- 2R1 signaling for their function and survival. Using our spontaneous murine glioma model, we have demonstrated that treatment with an antibody that blocks IL-2R1 signaling functionally inactivates and eliminates TRegs without inducing autoimmune toxicity. Our pre-clinical studies have shown that these unarmed IL-2R1-specific antibodies when given in vivo to mice during recovery from lymphopenia induced by therapeutic temozolomide (TMZ) are capable of not only functionally inactivating TRegs, but also dramatically enhance vaccine-induced immune responses. Daclizumab, an existing, humanized, unarmed IL-2R1-specific antibody, functions identically to the antibody used for TReg inactivation studies in mice. We hypothesize that daclizumab therapy during the recovery from therapeutic TMZ-induced lymphopenia in patients with newly-diagnosed GBM will inhibit the functional recovery of TRegs, enhance immune responses against an EGFRvIII-targeted vaccine, and promote productive cross-priming without the induction of deleterious autoimmunity. Because NK cells also express CD25 and may be potent activators or inhibitors of innate and antigen-specific immune responses, the effect of daclizumab on NK cells will also be assessed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA132891-02
Application #
7548590
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (06))
Program Officer
Timmer, William C
Project Start
2008-01-04
Project End
2009-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
2
Fiscal Year
2009
Total Cost
$175,500
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Yang, Shicheng; Archer, Gary E; Flores, Catherine E et al. (2013) A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model. Cancer Immunol Immunother 62:1649-62
Sampson, John H; Schmittling, Robert J; Archer, Gary E et al. (2012) A pilot study of IL-2R? blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One 7:e31046
Sampson, John H; Aldape, Kenneth D; Archer, Gary E et al. (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 13:324-33
Heimberger, Amy B; Sampson, John H (2011) Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma? Neuro Oncol 13:3-13
Sampson, John H; Archer, Gary E; Mitchell, Duane A et al. (2008) Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 20:267-275