SYSTEMIC T CELL IMMUNOTHERAPY OF MALIGNANT GLIOMAS

恶性脑肿瘤如多形性胶质母细胞瘤和 间变性星形细胞瘤通常有致命的结果， 诊断和治疗程序的进步。 热情 利用免疫疗法治疗脑 肿瘤被免疫豁免的概念所抑制。 中枢神经系统（CNS）。 然而，最近的数据显示， 中枢神经系统可能不是免疫特权部位， 尽管其具有独特的解剖学和生理学特征。 中枢神经系统 有能力调节免疫反应， 限制免疫细胞进入并提供微环境 这有助于激活效应细胞。 在动物 在实验中，在大脑中建立的肿瘤对 全身转移免疫T淋巴细胞，导致肿瘤 以免疫学特异性的方式消退。 原则和 动物研究中定义的方法已经外推到 为患有高级别神经胶质瘤的人类开发新的治疗方法。 患者将接受放射性自体肿瘤细胞免疫 沿着GM-CSF作为佐剂以增强免疫应答。 引流淋巴结切除手术7天后将 在体外用细菌超抗原SEA活化，然后用 抗CD 3抗体。 大量的这种激活的细胞将被注入 静脉注射给患者进行过继性T细胞免疫治疗。 在这项研究驱动的临床试验中，免疫和 活化的T细胞的生理特性将在 详细的毒性、免疫反应性和肿瘤反应 将对接受治疗的患者进行评估。 希望这项研究将 为更好地了解宿主肿瘤提供信息 互动和改进程序， 治疗有效的T细胞。 具体目标是 建议是：1）评估体内免疫反应性 接受过继免疫治疗的患者; 2）阐明 抗原呈递机制和佐剂活性 GM-CSF; 3）寻求GM-CSF的体外反应性之间的相关性， 淋巴结T细胞及其抗肿瘤功效;以及4） 表征在T细胞中重要的粘附/整合素分子 细胞活化以及归巢到肿瘤部位。

Malignant brain tumors such as glioblastoma multiforme and anaplastic astrocytoma usually have a fatal outcome in spite of advances in diagnostic and treatment procedures. Enthusiasm to utilize immunotherapeutic approached for treatment of brain tumors was dampened by the concept of ~immune privilege~ of the central nervous system (CNS). However, recent data suggest that the CNS may not be an immunologically privileged site, albeit its distinct anatomical and physiological features. The CNS has the capacity to regulate immune responses by allowing a restricted entry of immune cells and providing a microenvironment that is conducive to the activation of effector cells. In animal experiments, tumors established in the brain are reactive to the systemically transferred immun T lymphocytes, resulting in tumor regression in an immunologically specific manner. Principles and methodology defined in animal studies have been extrapolated to develop a novel treatment for humans with high-grade gliomas. Patients will be immunized with irradiated autologous tumor cells along with GM-CSF as an adjuvant to boost the immune response. Draining lymph nodes resected surgically 7 days later will be activated in vitro with a bacterial superantigen, SEA followed by anti-CD3. A large number of such activated cells will be infused intravenously to the patient for adoptive T-cell immunotherapy. In this research-driven clinical trial, immunological and physiological properties of the activated T cells will be analyzed in detail. Toxicity, immunological reactivities and tumor responses of treated patients will be evaluated. It is hoped that this study will provide information for a better understanding of host-tumor interactions and for improving procedures for the generation of potent therapeutically effective T cells. The specific aims in this proposal are: 1) to assess the in vivo immunological reactivity of patients undergoing adoptive immunotherapy; 2) to elucidate mechanisms of antigen presentation and the adjuvant activity of GM-CSF; 3) to seek correlations between in vitro reactivities of lymph node T cells and their antitumor efficacy; and 4) to characterize adhesion/integrin molecules that are important in T cell activation as well as homing to the tumor site.