Despite recent advances made in surgical, radiological and chemotherapeutic approaches, the prognosis of central nervous system (CMS) malignancies remains dismal. Although the safety of vaccine-approaches for CNS malignancies has been established in early phase clinical trials, the success of a vaccine strategy will depend critically on the ability of effector T-cells to home to CNS tumors and exert anti-tumor effects. Based on our recent studies, efficient CNS tumor-homing is characteristic of CTLs with a type-1 phenotype (Tc1) as opposed to ones with the type-2 phenotype (Tc2), and appears to be mediated by a type-1 chemokine, CXCL10. In addition, direct intratumoral delivery of dendritic cells (DC) ex vivo engineered to secrete interferon (IFN)-alpha further enhances Tc1-homing via up-regulation of a type-1 chemokine CXCL10/IP-10 in the tumor environment. While CNS-tumor infiltrating antigen presenting cells (APCs), such as microglia and macrophage, exhibit type-2 (M2) phenotype, our data suggest that substantial improvements in the efficacy of vaccine strategies can be achieved by efforts to convert the type-2-deviated microenvironment of central nervous system (CNS) tumors. Hence, we will focus on potential means of converting a type-2 to a type-1 microenvironment in preclinical mouse CNS tumor models, including a novel de novo mouse glioma model that phenotypically and histologically resembles human glioblastoma multiforme (GBM). Our central hypothesis is that the efficacy of T-cell based anti-CNS tumor therapy can be improved by: (a) intratumoral administration of a potent class of DCs expressing type-1 cytokines/chemokines (DC1), (b) administration of type-1 promoting factors, including the adjuvant polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose (poly-ICLC), or (c) combination of both Dd-delivery and administration of type-1 promoting factors. We will evaluate the following Specific Aims (SA). SA 1: Determine whether intratumoral delivery of ex vivo generated DC1 can enhance the therapeutic efficacy of systemic type-1 CTL (Tc1) therapy;SA 2: Determine whether delivery of type-1 promoting factors can lead to M1 phenotype of CNS tumor-infiltrating ARC s. SA 3: Determine whether the re-directed CNS-APCs enhance the therapeutic efficacy of Tc1 therapy and/or peripheral DC 1-based vaccinations.

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National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Pittsburgh
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