Project 2: A Novel Cellular Tumor Vaccine Strategy for Glioblastoma

项目摘要--项目2 胶质母细胞瘤(Gbm)是最常见的恶性脑肿瘤，预后极差。 总体生存时间为21个月。对于GBM的标准疗法基本上是无效的。基底膜的免疫治疗 似乎有最大的成功潜力，但受到基底膜肿瘤很差的事实的限制 免疫原性。因此，有效的治疗基底膜可能需要主动的免疫疗法，如 针对GBM抗原的疫苗接种。不幸的是，激发有效的抗肿瘤T细胞反应 事实证明，大多数患者都很困难。虽然标准的肿瘤疫苗策略刺激肿瘤特异性 细胞毒性T细胞(CTL)反应在大多数患者中，它们在肿瘤进展方面提供的益处很小 和病人的生存。我们推测，目前的肿瘤疫苗效果不佳可能是因为 它们并不针对产生内源性CTL反应的途径。使用鼠标模型， 我们确定了一种新的细胞疫苗策略，它利用了内源性Ag提呈途径。在这 策略：通过静脉注射负载抗原的方法原位负载抗原(AGS) 单核细胞。给药的单核细胞迁移到脾，将抗原转移到DC，然后呈递给T细胞， 刺激强大的T细胞增殖、CTL活性和抗肿瘤免疫反应 比目前的疫苗要好。我们的临床前数据表明，这一策略可能会作为一种 用于治疗人类癌症的简单有效的免疫治疗平台。在这里，我们将，为了 第一次，在人类身上测试这种新的细胞疫苗策略。在对我们的协议进行大规模优化后 人单核细胞的采集和载银，我们将进行一期安全性和剂量范围研究 银屑病患者的单核细胞疫苗接种。在这项研究中，增加载银的人单核细胞数量 将用于患者队列，以确定是否以及何时发生剂量限制毒性，并确定 刺激最大抗原特异性T细胞反应的单核细胞的剂量。一旦这些安全性和剂量 参数已经确定，我们将执行扩展的第一阶段研究，以确认我们的 最佳单核细胞剂量，并根据T细胞反应和潜在的临床益处确定其效果。这 该项目是一项首次人的研究，旨在为一种全新的细胞疫苗建立原理证明 策略。

PROJECT SUMMARY – Project 2 Glioblastoma (GBM), the most common malignant brain tumor, has an extremely poor prognosis with a median overall survival of <21 months. Standard therapies for GBM are largely ineffective. Immunotherapies for GBM appear to have the greatest potential for success, but are limited by the fact that GBM tumors are poorly immunogenic. For this reason, effective treatment of GBM will likely require an active immunotherapy such as vaccination against GBM antigens. Unfortunately, stimulating effective anti-tumor T cell responses in the majority of patients has proven difficult. While standard tumor vaccination strategies stimulate tumor-specific cytotoxic T cell (CTL) responses in most patients, they provide very little benefit in terms of tumor progression and patient survival. We reasoned that the poor efficacy of current tumor vaccines may be due to the fact that they do not target the pathways by which endogenous CTL responses are generated. Using mouse models, we identified a novel cellular vaccine strategy that exploits an endogenous Ag presentation pathway. In this strategy, resident splenic DC are loaded with antigens (Ags) in situ by the intravenous injection of Ag-loaded monocytes. The administered monocytes migrate to the spleen, transfer Ag to DC for presentation to T cells, and stimulate robust T cell proliferation, CTL activity, and anti-tumor immune responses that are markedly superior to that seen with current vaccines. Our preclinical data suggests that this strategy may serve as a simple and efficacious immunotherapeutic platform for the treatment of human cancers. Here, we will, for the first time, test this novel cellular vaccine strategy in humans. After optimizing our protocol for the large-scale harvesting and Ag-loading of human monocytes, we will perform a Phase 1 safety and dose ranging study of monocyte vaccination in patients with GBM. In this study, increasing numbers of Ag-loaded human monocytes will be administered to cohorts of patients to determine if and when dose-limiting toxicity occurs and determine the dose of monocytes that stimulates the maximal Ag-specific T cell response. Once these safety and dosing parameters have been determined, we will perform an expanded Phase 1 study to confirm the safety of our optimal monocyte dose and determine its effects in terms of T cell response and potential clinical benefit. This project represents a first-in-man study to establish proof of principle for an entirely novel cellular vaccine strategy.