Effect on IL-2R Antibody on Regulatory T-cells in Patients with Malignant Gliomas

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DESCRIPTION (provided by applicant): NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application 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 (T ) which are disproportionately represented within the peripheral blood and tumors of Regs patients with GBM. T are characterized by constitutive expression of the high affinity interleukin (IL)-2 Regs receptor (IL-2R1)(CD25) and are uniquely dependent on IL-2R1 signaling for their function and survival. In the context of the existing grant, we conducted a randomized trial demonstrating that an IL-2R1-blocking antibody, daclizumab, significantly reduces TReg levels in patients with GBM with a nadir at 5 weeks without reducing overall CD8+ or CD4+ T-cell counts. Preliminary analysis also suggests that daclizumab enhances EGFRvIII-specific cellular (P=0.01) and humoral (P=0.003) immune responses compared to the saline treated group. The effect of a single dose of daclizumab wanes after 12 weeks consistent with its known half-life, and TRegs recover, however. With this supplement, we seek to extend our results by examining the effects of serial administration of daclizumab in this same patient cohort. We HYPOTHESIZE that serial doses of daclizumab therapy in patients with newly-diagnosed GBM will extend the duration of functional TRegs inhibition and further enhance vaccine-induced immune responses. Consistent with the goals of the American Recovery and Reinvestment Act, this Supplement would accelerate the tempo of our research in this area and allow for job creation and retention. PUBLIC HEALTH RELEVANCE: Treatment for malignant primary brain tumors, which are the most common cause of death among children and account for more deaths in adults than melanoma, currently represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. We have developed a vaccine that eliminates tumor cells containing a tumor-specific protein (EGFRvIII) in patients, but tumor cells that express related normal proteins survive. In this proposal, we will see if prolonged elimination of immunosuppressive "regulatory" T-cells that inhibit immune responses to these related normal proteins will enhance the effectiveness of the vaccine without inducing deleterious autoimmunity. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page