PREPHASE I GENE/IMMUNE THERAPY OF MALIGNANT BRAIN TUMOR

描述：（改编自申请人摘要）在美国，每年有超过4万人患恶性脑肿瘤。大约一半是原发的，其余的是转移性的。脑转移在许多系统性恶性肿瘤患者中很常见，包括肺癌、乳腺癌黑色素瘤、淋巴瘤和结肠癌。在35岁以下人群中，脑瘤是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上升。目前对恶性脑肿瘤患者的标准治疗包括手术、放射治疗和可能的化疗。不幸的是，尽管在过去的20年中进行了许多联合治疗试验，但患者的生存期仍然以月为单位。本应用中提出的实验旨在研究一种基于基因/免疫治疗的恶性脑肿瘤的新型非常规治疗策略。研究人员已经成功地将生长活性肿瘤疫苗免疫到动物的大脑中，从而产生了针对恶性脑肿瘤的疫苗。在该动物模型中，大脑内植入的恶性神经胶质细胞，经过基因修饰分泌干扰素- γ，引发肿瘤排斥反应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的小胶质细胞的激活以及CD4、CD8和自然杀伤细胞的浸润增强有关。本研究旨在：1)开展干扰素γ和白细胞介素12基因转移治疗动物恶性脑肿瘤的临床前实验；2)阐明脑内疫苗接种的基本原理。通过将疫苗直接输送到被认为具有免疫优势的大脑中来进行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，而且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.