ACTIVE IMMUNOTHERAPY FOR GLIOBLASTOMA

描述(改编自申请人的摘要)：本报告的目的 项目是推进基于细胞和基因的免疫治疗的前景 恶性胶质瘤从初步动物研究到I/II期临床 审判。我们已经证明，胶质瘤肿瘤抗原的呈递通过 抗病毒自体树突状细胞皮下接种 自体主要组织相容性复合体I型相关肿瘤 在小鼠胶质瘤模型中，多肽诱导了强大的抗肿瘤免疫反应。 我们之前曾证明，用经过改造的肿瘤细胞接种可以 分泌型粒细胞/巨噬细胞集落刺激因子(GM-CSF)诱导的 细胞毒性T细胞介导的免疫应答在小鼠脑胶质瘤和脑胶质瘤中的作用 转移模型。我们已经将这些临床前研究应用于临床。 多形性胶质母细胞瘤和间变性星形细胞瘤患者的治疗方案。 我们正在完成一项基于树突状细胞的初步I期试验 治疗策略。初步结果表明，这种形式的 树突状细胞疫苗可以诱导细胞毒性T细胞反应，靶向 颅内肿瘤细胞。本文提出了三个研究假设：1) 诱导外周抗原提呈将产生肿瘤特异性 T细胞。2)细胞毒T细胞向颅内胶质瘤迁移并杀伤 细胞。3)外周接种会引起临床反应，并扩大 胶质母细胞瘤和间变性星形细胞瘤患者的存活率。基于我们的 假设，我们将进行两个阶段的外周疫苗接种研究 治疗胶质瘤，首次使用另一种形式的树突状细胞 肿瘤致敏的树突状细胞递增剂量免疫治疗 裂解物衍生的多肽。同时，我们将启动一项第一阶段协议 使用由同种异体胶质瘤细胞和成纤维细胞混合组成的疫苗 被设计成能分泌GM-CSF。在这些研究中，我们提出了以下建议 具体目标：1)监测患者的细胞免疫反应；2) 评估这些免疫策略的安全性和有效性。A阶段 第二阶段试验将在培训补助金的第三年根据第一阶段开始 学习。

DESCRIPTION (Adapted from the Applicant's Abstract): The purpose of this project is to advance promising cell based and gene based immunotherapy of malignant gliomas from preliminary animal studies to phase I/II clinical trials. We have shown that glioma tumor antigen presentation through subcutaneous vaccination with autologous dendritic cells primed against autologous major histocompatibility complex type I (MHC-I)-associated tumor peptides induces a potent anti-tumor immune response in a murine glioma model. We previously demonstrated that vaccination with tumor cells engineered to secrete granulocyte/macrophage-colony stimulating factor (GM-CSF) elicits a cytotoxic T-cell mediated immune response in murine intracranial glioma and metastasis models. We have implemented these preclinical studies into clinical protocols for patients with glioblastoma multiforme and anaplastic astrocytoma. We are completing a preliminary phase I trial based on a dendritic cell therapeutic strategy. Preliminary results demonstrate that this form of dendritic cell vaccination can induce a cytotoxic T-cell response which targets intracranial tumor cells. Three hypotheses are proposed for investigation: 1) Induction of peripheral antigen presentation will generate tumor specific T-cells. 2) Cytotoxic T-cells will migrate to and kill intracranial glioma cells. 3) Peripheral vaccination will induce clinical responses and extend survival in patients with glioblastoma and anaplastic astrocytoma. Based on our hypotheses, we will carry out two phase I studies of peripheral vaccination against glioma, the first using an alternative form of dendritic cell immunotherapy with an escalated dose of dendritic cells primed with tumor lysate derived peptides. Concurrently, we will initiate a phase I protocol using a vaccine consisting of allogeneic glioma cells mixed with fibroblasts engineered to secrete GM-CSF. In these studies, we propose the following specific aims: 1) to monitor patients for cellular immune responses and 2) to evaluate the safety and the efficacy of these immunologic strategies. A phase II trial will be initiated in year 3 of the training grant based on the phase I studies.