Vaccination with Regulatory T Cell Depletion

消除调节性 T 细胞的疫苗接种

• 批准号: 7283963
• 负责人: MICHAEL A MORSE
• 金额: $ 21.45万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283963
• 关键词: Antigens; Autologous Dendritic Cells; Binding; CD58 gene; CD80 gene; CD8B1 gene; Cancer Vaccines; Carcinoembryonic Antigen; Cells; Cessation of life; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Denileukin Diftitox; Development; Dose; Flow Cytometry; Fowlpox vector; Frequencies; Future; Goals; Human; ICAM1 gene; IL2RA gene; Immune response; Immune system; Immunization; Immunologics; Immunotherapy; In Vitro; Interleukin 2 Receptor; Interleukin-2; Kinetics; Left; Maintenance; Malignant Neoplasms; Measures; Normal tissue morphology; Numbers; Outcome; Patients; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Phase II Clinical Trials; Purpose; Range; Recovery; Role; Safety; Solid Neoplasm; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Toxin; Translating; Triad Acrylic Resin; Tumor Antigens; Vaccination; Vaccines; anthrax lethal factor; base; cancer immunotherapy; clinical efficacy; cytokine; enzyme linked immunospot assay; in vivo; interleukin 2-diphtheria toxin; neoplastic cell; response; tumor; vector

DESCRIPTION (provided by applicant): Effective cancer immunotherapy has been a long sought goal because of the possibility that the immune system can be harnessed to precisely target tumor cells, leaving normal tissue intact. Activation, proliferation, and maintenance of high frequency antigen-specific T cells are essential for a successful cellular immune response against tumor. Although a number of cancer vaccines in development can activate detectable tumor antigen-specific cytolytic T cell responses, they have been of low magnitude and limited durability. Indeed, in a phase I study of an immunization platform based on dendritic cells (DC) modified with a pox vector to hyperexpress the tumor antigen CEA and a triad of costimulatory molecules (called DC-rF- CEA(6D)-TRICOM), potent activation of CEA specific T cell responses was observed; but, the frequency of CD4+ and CD8+ CEA-specific T cells peaked within 4 doses of the vaccine and did not increase thereafter and in some cases decreased. CD4+CD25+ regulatory T cells (Treg) have emerged as a likely cause of the limited activation of antigen-specific T cells because of their role in controlling auto-reactive T cells. The purpose of this proposal is to determine whether a greater magnitude of tumor antigen specific immune response can be achieved by eliminating regulatory T cells prior to administration of an anti-cancer vaccine. Eliminating regulatory T cells in vitro permits activation of a greater frequency of antigen-specific T cell responses. Treg may be depleted in vivo using a fusion molecule of IL-2 and a toxin (denileukin diftitox) which binds to cells via CD25 and delivers the lethal toxin. Therefore, a phase I clinical trial is proposed to explore the safety, feasibility, and clinical and immunologic activity of Treg depletion with denileukin diftitox prior to immunization with autologous DC modified with rF-CEA(6D)-TRICOM. The kinetics of the Treg depletion will be assessed. In addition, the magnitude of the CEA-specific T cell response will be measured. Preliminary data regarding clinical efficacy will be collected to plan for phase II studies. Future studies will assess whether the greater magnitude and durability of the CEA-specific immune responses will translate into a long-term clinical benefit.

描述（由申请人提供）：有效的癌症免疫疗法一直是人们长期追求的目标，因为可以利用免疫系统精确靶向肿瘤细胞，同时保持正常组织完好无损。高频抗原特异性 T 细胞的激活、增殖和维持对于成功对抗肿瘤的细胞免疫反应至关重要。尽管许多正在开发的癌症疫苗可以激活可检测的肿瘤抗原特异性溶细胞 T 细胞反应，但它们的强度较低且持久性有限。事实上，在基于树突状细胞 (DC) 的免疫平台的 I 期研究中，该平台经过痘载体修饰以超表达肿瘤抗原 CEA 和三联体共刺激分子（称为 DC-rF-CEA(6D)-TRICOM），观察到 CEA 特异性 T 细胞反应的有效激活；但是，CD4+ 和 CD8+ CEA 特异性 T 细胞的频率在 4 剂疫苗内达到峰值，此后不再增加，在某些情况下还下降。 CD4+CD25+调节性T细胞(Treg)因其在控制自身反应性T细胞中的作用而成为抗原特异性T细胞激活有限的可能原因。该提案的目的是确定是否可以通过在施用抗癌疫苗之前消除调节性 T 细胞来实现更大幅度的肿瘤抗原特异性免疫反应。体外消除调节性 T 细胞可以激活更频繁的抗原特异性 T 细胞反应。使用 IL-2 和毒素（denileukin diftitox）的融合分子可在体内消除 Treg，该融合分子通过 CD25 与细胞结合并递送致命毒素。因此，建议进行一项 I 期临床试验，以探索在用 rF-CEA(6D)-TRICOM 修饰的自体 DC 免疫之前用地尼白素 diftitox 消除 Treg 的安全性、可行性以及临床和免疫活性。将评估 Treg 耗竭的动力学。此外，还将测量 CEA 特异性 T 细胞反应的强度。将收集有关临床疗效的初步数据以规划 II 期研究。未来的研究将评估 CEA 特异性免疫反应的更大程度和持久性是否会转化为长期临床益处。