Project 2: A Novel Cellular Tumor Vaccine Strategy for Glioblastoma

项目概要-项目2 胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，具有极差的预后， 总生存期<21个月。GBM的标准疗法在很大程度上是无效的。GBM的免疫疗法 似乎具有最大的成功潜力，但受限于GBM肿瘤 免疫原性。因此，GBM的有效治疗可能需要主动免疫疗法，例如 针对GBM抗原的疫苗接种。不幸的是，刺激有效的抗肿瘤T细胞反应， 大多数病人都很难接受。虽然标准的肿瘤疫苗接种策略刺激肿瘤特异性 尽管大多数患者存在细胞毒性T细胞（CTL）应答，但它们在肿瘤进展方面提供的益处非常少 患者生存率。我们推断，目前的肿瘤疫苗效果不佳可能是由于以下事实， 它们不靶向产生内源性CTL应答的途径。使用小鼠模型， 我们鉴定了一种利用内源性Ag呈递途径的新型细胞疫苗策略。在这 策略，通过静脉内注射负载Ag的DC，使驻留的脾DC原位负载抗原（Ag）。 单核细胞所施用的单核细胞迁移到脾脏，将Ag转移到DC以呈递给T细胞， 并刺激强烈的T细胞增殖、CTL活性和抗肿瘤免疫应答， 上级于现有疫苗。我们的临床前数据表明，这种策略可以作为一种 用于治疗人类癌症的简单有效的免疫抑制平台。在这里，我们将，为 第一次在人类身上测试这种新的细胞疫苗策略。在优化了我们的大规模协议后， 收获人单核细胞和Ag负载，我们将进行1期安全性和剂量范围研究， GBM患者的单核细胞疫苗接种。在这项研究中，越来越多的载银人单核细胞， 将给予患者队列，以确定是否以及何时发生剂量限制性毒性，并确定 刺激最大Ag特异性T细胞应答的单核细胞剂量。一旦这些安全性和剂量 参数已经确定，我们将进行一项扩展的1期研究，以确认我们的安全性， 最佳单核细胞剂量，并确定其在T细胞应答和潜在临床益处方面的作用。这 该项目是首次在人体内进行的研究，旨在为一种全新的细胞疫苗建立原理证明 战略

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.