Vaccination with Regulatory T Cell Depletion

描述（由申请人提供）：有效的癌症免疫治疗一直是一个长期追求的目标，因为免疫系统可以被利用来精确地靶向肿瘤细胞，而保持正常组织完整。激活、增殖和维持高频抗原特异性T细胞对于成功的细胞免疫应答肿瘤至关重要。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细胞溶解T细胞反应，但它们的强度低且持久性有限。事实上，在一项基于树突状细胞（DC）的免疫平台的I期研究中，用痘载体修饰树突状细胞（DC）来超表达肿瘤抗原CEA和三联共刺激分子（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细胞的频率在接种4剂疫苗后达到峰值，此后没有增加，在某些情况下下降。CD4+CD25+调节性T细胞（Treg）已成为抗原特异性T细胞有限激活的可能原因，因为它们在控制自身反应性T细胞中的作用。该建议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细胞来实现更大程度的肿瘤抗原特异性免疫反应。在体外消除调节性T细胞允许激活频率更高的抗原特异性T细胞反应。Treg在体内可以通过IL-2和一种毒素（denileukin didititox）的融合分子来消耗，这种毒素通过CD25与细胞结合并传递致命毒素。因此，我们提出了一项I期临床试验，以探讨在使用rF-CEA(6D)-TRICOM修饰的自体DC免疫前，用脱白素消耗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细胞反应的大小。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的临床益处。

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.