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: 7361420
• 负责人: JOHN H. SAMPSON
• 金额: $ 21.06万
• 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/7361420
• 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; 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; Standards of Weights and Measures; T-Lymphocyte; Therapeutic; Therapeutic immunosuppression; Toxic effect; Toxin; Toxin Conjugates; Tumor Antigens; Tyrosine; Vaccination; Vaccines; brain tissue; cell growth; chemotherapy; cytokine; cytotoxicity; epidermal growth factor receptor VIII; human study; 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）：免疫系统具有消除改变的肿瘤细胞的潜力，具有令人难以置信的特异性。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受到调节性t细胞（TRegs）存在的阻碍。我们最近的研究表明，treg在GBM患者的外周血和肿瘤中不成比例地存在，并有助于诱导一种深刻但可逆的免疫抑制状态。TRegs的特点是高亲和力的白细胞介素(IL)-2受体（IL-2R1）（CD25）的组成性表达，并且独特地依赖于IL-2R1信号来维持其功能和生存。使用我们的自发性小鼠胶质瘤模型，我们已经证明了用阻断IL-2R1信号的抗体治疗在不诱导自身免疫毒性的情况下功能性地失活和消除treg。我们的临床前研究表明，在治疗性替莫唑胺（TMZ）诱导的淋巴细胞减少症的恢复过程中，给小鼠体内这些非杀伤的il - 2r1特异性抗体不仅能够在功能上灭活treg，而且能够显著增强疫苗诱导的免疫应答。Daclizumab是一种现有的、人源化的、非武装的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中恢复期间，daclizumab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，并促进生产性交叉启动，而不会诱导有害的自身免疫。由于NK细胞也表达CD25，并且可能是先天和抗原特异性免疫反应的有效激活剂或抑制剂，因此也将评估daclizumab对NK细胞的影响。