GENETICALLY ENGINEERED ANTI ANGIOGENIC ANTI GLIOMA CTL'S

该项目的长期目标是在开发具有基因工程新的靶向和效应功能的免疫效应细胞的基础上，开发治疗恶性胶质瘤的新疗法。假设T细胞和潜在的其他效应细胞可以被设计成直接识别和杀死正在发育的肿瘤血管和肿瘤细胞本身。这将通过使用编码针对特定内皮细胞表面受体和胶质瘤相关肿瘤新抗原的嵌合T细胞受体(CTCR)的基因转移载体来实现。逆转录病毒基因转移也将用于尝试产生转基因T细胞，这种T细胞允许表达其他功能，包括共刺激、四环素反应性和释放具有强大抗血管生成活性的特定基因产物。由不同载体转导的T细胞的活性将在体外表征其靶细胞特异性和细胞溶解功能，并随后在包括脑内在内的几种不同的已有肿瘤模型中进行抗肿瘤活性的研究。除了评估转导细胞的治疗效果外，我们还将表征移植细胞的持久性和运输特性。我们还将比较过继转移转基因T细胞所实现的抗肿瘤活性，以及通过嵌合T细胞受体载体转导的造血干细胞植入致死照射受者所实现的抗肿瘤活性。该项目将为候选人提供基因转移技术、肿瘤免疫治疗和抗血管生成方面的研究基础，作为开发治疗人脑胶质瘤的翻译疗法的长期战略的一部分。

The long term goal of this project is to develop new therapies for the treatment of malignant glioma based on the development of immune effector cells with genetically engineered novel targeting and effector functions. It is hypothesized that T cells and potentially other effector cells can be engineered to directly recognize and kill the both the developing tumor vasculature and tumor cells themselves. This shall be accomplished through the use of gene transfer vectors that encode chimeric T cell receptors (cTCR) directed against specific endothelial cell surface receptors and glioma related tumor neoantigens. Retroviral gene transfer will also be used in an attempt to generate genetically-modified T cells which allow for the expression of additional functions including co-stimulation, tetracycline responsiveness, and release of specific gene products with potent anti-angiogenic activity. The activity of T cells transduced by the different vectors will be characterized in vitro for their target cell specificity and cytolytic function and, subsequently for anti-tumor activity in several different pre-existing tumor models including intracerebral models. In addition to assessing the therapeutic efficacy of the transduced cells, we will characterize the persistence and trafficking characteristics of the transplanted cells. We will also compare the anti-tumor activity achieved by adoptive transfer of genetically modified T cells to that achieved by the engraftment of lethally irradiated recipients by hematopoietic stem cells transduced by the chimeric T cell receptor vectors. This project shall provide the candidate with a research foundation in gene transfer technologies, tumor immunotherapy, and anti-angiogenesis as part of a long-term strategy to develop translational therapies for the treatment of cerebral glioma in man.