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局，尽管 诊断和治疗程序的进展。热衷于 利用免疫疗法治疗脑部疾病 肿瘤受到~免疫豁免~的概念的抑制 中枢神经系统(CNS)。然而，最近的数据表明， 中枢神经系统可能不是免疫特权部位， 尽管其独特的解剖学和生理学特征。中枢神经系统 有能力通过允许一种 限制免疫细胞进入并提供微环境 这有利于激活效应细胞。在动物身上 实验表明，在大脑中建立的肿瘤对 系统转移免疫T淋巴细胞，导致肿瘤 以免疫学特有的方式退化。原则和 动物研究中定义的方法学已外推至 开发一种治疗人类高级别胶质瘤的新方法。 患者将用辐射后的自体肿瘤细胞进行免疫 与GM-CSF一起作为佐剂来增强免疫反应。 7天后手术切除的淋巴引流将是 在体外用细菌超抗原激活，SEA随后 抗CD3抗体。大量这样的激活细胞将被注入 静脉注射给患者进行过继T细胞免疫治疗。 在这项以研究为导向的临床试验中，免疫学和 激活的T细胞的生理特性将在 细节。阿司匹林的毒性、免疫反应和肿瘤反应 接受治疗的患者将接受评估。希望这项研究将 为更好地了解宿主肿瘤提供信息 相互作用和改进程序，以产生 有效治疗的T细胞。其中的具体目标是 建议是：1)评估在体内的免疫反应性 接受过继免疫治疗的患者；2)澄清 抗原提呈机制及其佐剂活性 3)寻找GM-CSF体外反应性之间的相关性 淋巴T细胞及其抗肿瘤效果；以及4) 描述T细胞中重要的黏附/整合素分子 细胞激活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.