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.
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