DC-BASED CYTOKINE GENE IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS

我们的主要目标是开发安全有效的基于DC的中枢神经系统细胞因子基因疗法（CGTs） (CNS)肿瘤的与项目2和项目3不同，项目2和项目3旨在评估CGT对全身免疫的影响， 无论是局部还是内脏noa-CNS肿瘤病变，项目1将特别注意辨别CGT的影响 中枢神经系统独特的免疫环境，特别是在脑肿瘤的背景下。基于我们之前 研究中，我们认为CGTs靶向增强IFN-7依赖性的1型T细胞应答， 在临床有益的肿瘤免疫的最佳诱导和维持中发挥关键作用， 在CNS中通过肿瘤内（i.t.）注射同基因树突状细胞（DC），所述树突状细胞已经被工程化以 产生某些细胞因子并且能够原位介导改善的交叉呈递功能。我们也 假设肿瘤部位内持续细胞因子产生是由一部分工程化DC引起的， 不离开注射部位，也在募集、激活和/或维持治疗上重要的 浸润的宿主效应T细胞（通过特异性疫苗接种引发）和DC。为了发展最 有效的治疗方法结合这一战略，这将是至关重要的，以获得一个fn-m的理解 图11显示了转染了精氨酸基因的DC（与非抗原呈递细胞[APC]，如成纤维细胞）对人表皮细胞的影响。 CNS肿瘤微环境的免疫生物学。我们假设中枢神经系统/肿瘤微环境抑制 通过各种分子机制，包括但不限于， 仅限于FasL/Fas和TGF-β 3依赖性途径。CGT可能克服这些抑制作用，并增加 内源性DC（通过反式作用）以及注射的DC介导DCl型功能的能力， 促进和/或维持脑中的1型抗肿瘤T细胞应答。在目前的提案中，我们将确定 优化1型效应T细胞募集和功能的有效单一或组合CGT方法 肿瘤微环境，我们假设它与肿瘤消退密切相关。我们相信这些 新的研究将为我们提供关于CNS免疫生物学的有价值的信息，以及如何基于DC的免疫生物学。 CGT可合理、安全、有效地应用于中枢神经系统肿瘤的治疗。

Our primary goal is to develop safe and effective DC-based cytokine gene therapies (CGTs) for central nervous system (CNS) tumors. In contrast to Projects 2 and 3, that are designed to evaluate CGT effects on systemic immunity and either localized or visceral noa-CNS tumor lesions, Project 1 will pay particular attention to discern the impact of CGT on the unique immunologic environment of the CNS, notably in the setting of brain tumors. Based on our previous studies, we believe that CGTs targeting the enhancement of IFN-7-dependent, Type-1 T cell responses that are believed to play critical roles in the optimal induction and maintenance of clinically beneficial tumor immunity, may be best accomplished in the CNS by intratumoral (i.t.) injection of syngeneic dendritic cells (DCs) that have been engineered to produce certain cytokines and which are capable of mediating improved crosspresenting functions in situ. We also hypothesize that sustained cytokine production within the tumor site, resulting from a subset of engineered DCs that do not leave the injection site, also plays a role in the recruitment, activation and/or maintenance of therapeuticallyimportant infiltrating host effector T cells (elicited by specific vaccination) and DCs. In order to develop the most effective therapeutic approaches incorporating this strategy, it will be critically important to gain a fn-m understanding of the impact of cytokine-gene transfected DCs (vs. non-antigen presenting cells [APCs], such as fibroblasts) on the immunobiology of the CNS tumor-microenvironment. We hypothesize that the CNS/tumor microenvironment inhibits the survival and function of both resident and injected DCs through various molecular mechanisms including, but not limited to, FasL/Fas- and TGF-J3-dependent pathways. CGT may overcome these inhibitory effects and augment the ability of endogenous DCs (via effects in trans) as well as injected DCs to mediate DCl-type functions required to promote and/or sustain Type-1 anti-tumor T cell responses in the brain. In the current proposal, we will determine effective single or combined CGT approaches that optimize Type-1 effeetor T cell recruitment and function into/within the tumor microenvironment, that we hypothesize will be critically linked to tumor regression. We believe that these novel studies will provide us with valuable information regarding CNS immunobiology in general, and how DC-based CGT may be rationally, safely, and effectively applied to treat tumors in the CNS.