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

描述（由申请人提供）：no - od -09-058: NIH宣布恢复法案基金可用于竞争性修订申请免疫系统具有以令人难以置信的特异性消除改变的肿瘤细胞的潜力。表皮生长因子受体（EGFRvIII）胞外结构域的一致框内缺失代表了一个真正的肿瘤特异性靶标，可接受免疫治疗攻击。我们的多机构II期研究表明，在新诊断的多形性胶质母细胞瘤（GBM）患者中接种egfrviii特异性肽可诱导有效的T细胞和b细胞免疫，在所有残留肿瘤患者中产生几乎完全的放射学应答，并普遍消除表达egfrviii的细胞。然而，复发肿瘤继续表达野生型EGFR，这表明免疫反应是特异性的，但针对其他潜在肿瘤相关抗原的分子内交叉启动是不完整的。我们认为，这种次生免疫反应的生产性延伸被调节性T细胞(T)的存在所阻碍，调节性T细胞在Regs患者的外周血和肿瘤中不成比例地代表着GBM。T细胞的特点是组成性表达高亲和力的白细胞介素(IL)-2 Regs受体（IL- 2r1）（CD25），并且独特地依赖于IL- 2r1信号来维持其功能和生存。在现有拨款的背景下，我们进行了一项随机试验，证明il - 2r1阻断抗体daclizumab可显着降低GBM患者的TReg水平，在5周时达到最低点，而不会降低总体CD8+或CD4+ t细胞计数。初步分析还表明，与生理盐水治疗组相比，daclizumab增强了egfrviii特异性细胞（P=0.01）和体液（P=0.003）免疫应答。单剂量daclizumab的效果在与已知半衰期一致的12周后减弱，然而treg恢复。有了这个补充，我们试图通过检查在同一患者队列中连续给药daclizumab的效果来扩展我们的结果。我们假设，在新诊断的GBM患者中，连续剂量的daclizumab治疗将延长功能性treg抑制的持续时间，并进一步增强疫苗诱导的免疫反应。与《美国复苏与再投资法案》的目标一致，这一补充将加快我们在这一领域的研究节奏，并允许创造和保留就业机会。

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