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

IL-2R抗体对恶性胶质瘤患者调节性T细胞的影响

• 批准号: 7548590
• 负责人: JOHN H. SAMPSON
• 金额: $ 17.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-04 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7548590
• 关键词: Accounting; Adult; Affinity; Alkylating Agents; Antibodies; Antigens; Attenuated; Autoimmune Process; Autoimmunity; B-Lymphocytes; Blocking Antibodies; Blood - brain barrier anatomy; Bypass; CD3 Antigens; Cause of Death; Cell Death; Cells; Cessation of life; Child; Clinical; Cross-Priming; Daclizumab; Environment; Epidermal Growth Factor Receptor; Glioblastoma; Glioma; Human; IL2RA gene; Immune response; Immune system; Immunity; Immunologic Memory; Immunologics; Immunosuppression; Immunotherapeutic agent; In Vitro; Infusion procedures; Interleukin 2 Receptor; Interleukin-2; Interleukins; Invaded; Lymphopenia; Malignant Glioma; Malignant neoplasm of brain; Memory; Modeling; Molecular; Mus; Natural Killer Cells; Newly Diagnosed; Normal tissue morphology; Patients; Peptides; Phase II Clinical Trials; Phenotype; Physiological; Radiation; Radiosurgery; Recombinants; Recovery; Recovery of Function; Recurrent tumor; Residual Tumors; Resistance; Signal Transduction; Specificity; T-Lymphocyte; Therapeutic; Toxic effect; Toxin; Toxin Conjugates; Tumor Antigens; Tyrosine; Vaccination; Vaccines; brain tissue; cell growth; chemotherapy; conventional therapy; cytokine; cytotoxicity; epidermal growth factor receptor VIII; in vivo; inhibitor/antagonist; neoplastic cell; novel; peripheral blood; preclinical study; reconstitution; response; temozolomide; tumor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：免疫系统有潜力以令人难以置信的特异性消除改变的肿瘤细胞。表皮生长因子受体（EGFRvIII）胞外域中一致的框内缺失代表了真正的肿瘤特异性靶点，易于免疫治疗攻击。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 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反应，并普遍消除 EGFRvIII 表达细胞。然而，复发性肿瘤继续表达野生型 EGFR，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有效分子内交叉引发是不完整的。我们认为，调节性 T 细胞 (TReg) 的存在阻碍了此类二次免疫反应的有效延伸。我们最近发现，TRegs 在 GBM 患者的外周血和肿瘤中比例过高，并可诱导一种深刻但可逆的免疫抑制状态。 TReg 的特征是高亲和力白细胞介素 (IL)-2 受体 (IL-2R1)(CD25) 的组成型表达，并且其功能和存活独特地依赖于 IL-2R1 信号传导。使用我们的自发性小鼠神经胶质瘤模型，我们已经证明，用阻断 IL-2R1 信号传导的抗体进行治疗可以功能性地灭活并消除 TRegs，而不会诱导自身免疫毒性。我们的临床前研究表明，这些非武装的 IL-2R1 特异性抗体在治疗性替莫唑胺 (TMZ) 诱导的淋巴细胞减少症恢复期间给予小鼠体内，不仅能够在功能上灭活 TRegs，而且能够显着增强疫苗诱导的免疫反应。 Daclizumab 是一种现有的人源化非武装 IL-2R1 特异性抗体，其功能与用于小鼠 TReg 失活研究的抗体相同。我们假设，在新诊断的 GBM 患者从治疗性 TMZ 诱导的淋巴细胞减少症恢复期间，达珠单抗治疗将抑制 TReg 的功能恢复，增强针对 EGFRvIII 靶向疫苗的免疫反应，并促进有效的交叉引发，而不诱导有害的自身免疫。由于 NK 细胞也表达 CD25，并且可能是先天性和抗原特异性免疫反应的有效激活剂或抑制剂，因此还将评估达珠单抗对 NK 细胞的影响。