Vaccination with Regulatory T Cell Depletion

消除调节性 T 细胞的疫苗接种

• 批准号: 7111336
• 负责人: MICHAEL A MORSE
• 金额: $ 22.03万
• 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/7111336
• 关键词: active immunization; clinical research; immunization; tumor antigens

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.

有效的癌症免疫疗法一直是长期追求的目标，因为免疫系统可以被利用来精确靶向肿瘤细胞，而使正常组织保持完整。高频率抗原特异性T细胞的活化、增殖和维持对于针对肿瘤的成功细胞免疫应答是必需的。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细胞应答，但它们的数量很低，耐久性有限。事实上，在基于树突状细胞（DC）的免疫平台的I期研究中，树突状细胞（DC）用痘病毒载体修饰以过表达肿瘤抗原CEA和共刺激分子三联体。（称为DC-rF- CEA（6D）-TRICOM），观察到CEA特异性T细胞应答的有效活化;但是，CD 4+和CD 8 + CEA特异性T细胞的频率在疫苗的4个剂量内达到峰值，此后不增加，并且在某些情况下降低。CD 4 + CD 25+调节性T细胞（Treg）由于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细胞的有限活化的可能原因。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应答。在体外消除调节性T细胞允许激活更高频率的抗原特异性T细胞应答。可以使用IL-2和毒素（地尼白介素diftitox）的融合分子在体内耗尽Treg，所述毒素通过CD 25结合细胞并递送致死毒素。因此，提出了I期临床试验以探索在用rF-CEA（6D）-TRICOM修饰的自体DC免疫之前用地尼白介素diftitox去除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，将测量CEA特异性T细胞应答的幅度。将收集有关临床疗效的初步数据，以计划II期研究。未来的研究将评估CEA特异性免疫应答的更大幅度和持久性是否会转化为长期的临床益处。