Type-1 Antigen Presenting Cells in CNS Tumors - Key to Efficient Anti-Tumor T-Cel

CNS 肿瘤中的 1 型抗原呈递细胞 - 高效抗肿瘤 T 细胞的关键

• 批准号: 8518922
• 负责人: Hideho Okada
• 金额: $ 2.28万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8518922
• 关键词: Acids; Adjuvant; Antigen-Presenting Cells; Antigens; Autoimmune encephalitis; Bone Marrow; CXCL10 gene; CXCL9 gene; Carboxymethylcellulose; Cells; Central Nervous System Neoplasms; Cervical lymph node group; Characteristics; Clinical Trials; Collaborations; Cross-Priming; Data; Dendritic Cells; Development; Engineering; Environment; Exhibits; Glioblastoma; Glioma; Histologic; Home environment; Homing; Human; Immunotherapeutic agent; Immunotherapy; Instruction; Interferon-alpha; Interferons; Interleukin-12; Lead; Ligands; Lysine; Malignant Neoplasms; Mediating; Melanoma Cell; Microglia; Modeling; Molecular; Mus; Neuraxis; Oncolytic; Operative Surgical Procedures; PTGS2 gene; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Poly I-C; Poly ICLC; Production; Research Personnel; Site; System; T cell response; T-Lymphocyte; Toxic effect; Treatment Efficacy; Up-Regulation; Vaccination; Vaccine Design; Vaccines; Vaccinia virus; base; celecoxib; chemokine; cytokine; improved; in vivo; inhibitor/antagonist; macrophage; novel; outcome forecast; pre-clinical; programs; success; tumor; vaccine efficacy; vaccine safety

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. RELEVANCE (See instructions):

尽管最近在手术、放射和化疗方法方面取得了进展，但 中枢神经系统(CMS)恶性肿瘤仍然令人沮丧。尽管疫苗的安全性-用于治疗的方法 中枢神经系统恶性肿瘤已被确立在早期临床试验阶段，疫苗策略的成功将 关键依赖于效应T细胞对中枢神经系统肿瘤的定位和发挥抗肿瘤作用的能力。基座 根据我们最近的研究，高效的中枢神经系统肿瘤归巢是具有1型表型(Tc1)的CTL的特征 与具有2型表型(Tc2)的相反，并且似乎是由1型趋化因子介导的， CXCL10。此外，体外培养的树突状细胞(DC)直接瘤内输送可分泌 干扰素-α通过上调1型趋化因子CXCL10/IP-10进一步增强Tc1归巢 在肿瘤环境中。而中枢神经系统肿瘤浸润性抗原提呈细胞(APC)，如小胶质细胞 和巨噬细胞，表现出2型(M2)表型，我们的数据表明 疫苗策略的有效性可以通过努力将2型偏离的微环境转化为 中枢神经系统(CNS)肿瘤。因此，我们将重点介绍将类型2转换为 临床前小鼠中枢神经系统肿瘤模型中的1型微环境，包括一种新的小鼠新生胶质瘤 表型和组织学上类似于人类多形性胶质母细胞瘤(GBM)的模型。我们的中央 假设T细胞为基础的抗中枢神经系统肿瘤治疗的疗效可以通过以下方式提高：(A)瘤内注射 给药一类表达1型细胞因子/趋化因子(Dc1)的DC，(B)给药 1型促进因子，包括赖氨酸稳定的佐剂多肌苷-多胞苷和 羧甲基纤维素(Poly-ICLC)，或(C)类型1的DD递送和给药的组合 促进因素。我们将评估以下具体目标(SA)。SA 1：确定肿瘤内是否 体外产生的Dc1可以增强系统1型CTL(Tc1)的治疗效果 治疗；SA 2：确定1型促进因子的传递是否会导致中枢神经系统M1表型 肿瘤浸润性ARC S。SA 3：确定重定向的中枢神经系统APC是否增强了治疗 Tc1治疗和/或外周DC-1疫苗接种的疗效。 相关性(请参阅说明)：