PREPHASE I GENE/IMMUNE THERAPY OF MALIGNANT BRAIN TUMOR

描述：(摘自申请者的摘要)美国每年有超过4万人患上恶性脑瘤。大约一半是原发的，其余是转移性的。脑转移常见于患有肺癌、乳腺黑色素瘤、淋巴瘤和结肠癌等多种全身恶性肿瘤的患者。在35岁以下的人群中，脑瘤是癌症相关死亡的第二大常见原因，在6岁至9岁的儿童中发病率略有上升。目前对恶性脑瘤患者的护理标准包括手术、放射治疗，可能还有化疗。不幸的是，尽管在过去的20年里进行了许多联合模式治疗试验，但患者的存活率仍然只有几个月的数字。本申请中提出的实验旨在研究一种基于基因/免疫疗法的治疗恶性脑瘤的新的非常规策略。研究人员已经成功地将一种具有生长能力的活肿瘤疫苗免疫到大脑中，从而成功地在动物身上接种了针对恶性脑瘤的疫苗。在这个动物模型中，大脑内植入的恶性胶质细胞，经过基因改造，可以分泌干扰素-伽马，引发肿瘤排斥反应和特定的保护性系统抗肿瘤免疫。这种生物学反应与脑内小胶质细胞的激活以及CD4、CD8和自然杀伤细胞的渗透增强有关。这项研究的目的是：1)通过干扰素-γ和白介素12的基因转移对已建立的动物恶性脑瘤进行基因/免疫治疗的临床前实验；2)阐明脑内接种的基本原理。通过将疫苗直接注射到大脑--一个被认为具有免疫特权的器官--进行抗肿瘤免疫的概念是新的。此外，这项研究很重要，不仅因为阳性结果将导致对原发或转移性脑瘤患者立即进行I期临床试验，而且还因为它将阐明针对中枢神经系统肿瘤的免疫疗法的原理。

DESCRIPTION: (Adapted from applicant's abstract) Malignant brain tumors arise in more than 40,000 people in the United States each year. About half are primary and the remainder are metastatic. Brain metastasis is frequent in patients suffering from many systemic malignancies including lung, breast melanoma, lymphoma, and colon cancers. Brain tumors are the second most common cause of cancer-related death in people up to the age of 35, with a slight peak of incidence in occurrence among children between the ages of 6 and 9. Current standard of care of patients with malignant brain tumor includes surgery, radiation therapy, and possibly chemotherapy. Unfortunately, despite numerous combined modality treatment trials over the part 2 decades, patient survival is still numbered in months. The experiments proposed in this application are designed to study a novel unconventional strategy for the treatment of malignant brain tumors based on gene/immune therapy. The investigators have produced successful vaccination against malignant brain tumors in animals by immunization into the brain with a live growth-competent tumor vaccine. In this animal model, intra-cerebrally-implanted malignant glial cells, genetically- modified to secrete interferon-gamma, elicit tumor rejection and specific protective systemic anti-tumor immunity. This biologic response is associated with activation of microglia throughout the brain and enhanced infiltration by CD4, CD8, and natural killer cells. The proposed research is intended to: 1) conduct pre- clinical experimentation of gene/immune therapy of established malignant brain tumors in animals by gene transfer of interferon gamma and interleukin 12, and 2) elucidate the basic principles of vaccination in the brain. The concept of anti-tumor immunization by delivering a vaccine directly into the brain, an organ thought to be immunologically-privileged, is novel. Furthermore, this research is important not only because positive results will lead to immediate phase I clinical trials in patients with either primary or metastatic brain tumors, but also because it will shed light on the principle of immunotherapy against central-nervous-system tumors.