PREPHASE I GENE/IMMUNE THERAPY OF MALIGNANT BRAIN TUMOR

描述：（改编自申请人的摘要）在美国，每年有超过40，000人出现恶性脑肿瘤。大约一半是原发性的，其余的是转移性的。脑转移在患有许多系统性恶性肿瘤（包括肺癌、乳腺黑色素瘤、淋巴瘤和结肠癌）的患者中是常见的。脑肿瘤是35岁以下人群中癌症相关死亡的第二大常见原因，6至9岁儿童的发病率略有高峰。目前对恶性脑肿瘤患者的标准治疗包括手术、放疗和可能的化疗。不幸的是，尽管在过去的20年中进行了许多联合治疗试验，但患者的生存期仍以月为单位。本申请中提出的实验旨在研究一种基于基因/免疫治疗的治疗恶性脑肿瘤的新的非常规策略。研究人员已经成功地生产了针对动物恶性脑肿瘤的疫苗，方法是用具有生长能力的活肿瘤疫苗免疫脑。在该动物模型中，脑内植入的恶性神经胶质细胞，经遗传修饰以分泌干扰素-γ，引发肿瘤排斥和特异性保护性全身抗肿瘤免疫。这种生物学反应与整个大脑中小胶质细胞的活化以及CD 4、CD 8和自然杀伤细胞的浸润增强有关。拟议的研究旨在：1）通过干扰素γ和白细胞介素12的基因转移对动物中已建立的恶性脑肿瘤进行基因/免疫治疗的临床前实验，以及2）阐明脑中疫苗接种的基本原理。通过将疫苗直接递送到大脑（被认为是免疫特权的器官）中的抗肿瘤免疫的概念是新颖的。此外，这项研究很重要，不仅因为积极的结果将导致原发性或转移性脑肿瘤患者立即进行I期临床试验，还因为它将阐明针对中枢神经系统肿瘤的免疫治疗原理。

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.