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， 中枢神经系统（CMS）恶性肿瘤仍然令人沮丧。虽然疫苗的安全性， 中枢神经系统恶性肿瘤已在早期临床试验中确立，疫苗策略的成功将 关键取决于效应T细胞归巢CNS肿瘤并发挥抗肿瘤作用的能力。基于 在我们最近的研究中，有效的CNS肿瘤归巢是具有1型表型（Tc 1）的CTL的特征， 与具有2型表型（Tc 2）的那些相反，并且似乎由1型趋化因子介导， CXCL 10.此外，直接肿瘤内递送树突状细胞（DC）离体工程化以分泌肿瘤特异性抗原。 干扰素-α通过上调1型趋化因子CXCL 10/IP-10进一步增强Tc 1归巢 在肿瘤环境中。而CNS-肿瘤浸润性抗原呈递细胞（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转化2型偏离的微环境来实现。 中枢神经系统（CNS）肿瘤。因此，我们将重点关注将类型2转换为类型2的潜在方法。 临床前小鼠CNS肿瘤模型中的1型微环境，包括一种新的新生小鼠神经胶质瘤 表型和组织学上类似于人多形性胶质母细胞瘤（GBM）的模型。我们的中央 假设基于T细胞的抗CNS肿瘤疗法的功效可以通过以下方式改善：（a）肿瘤内 施用表达1型细胞因子/趋化因子（DC 1）的有效类别的DC，（B）施用 1型促进因子，包括由赖氨酸稳定的佐剂聚肌苷-聚胞苷酸， 羧甲基纤维素（聚-ICLC），或（c）DD-递送和1型胶原蛋白的施用的组合 促进因素。我们将评估以下具体目标（SA）。SA 1：确定肿瘤内 递送离体产生的DC 1可以增强系统性1型CTL（Tc 1）的治疗功效， 治疗; SA 2：确定1型促进因子的递送是否可导致CNS的M1表型 肿瘤浸润性ARC。SA 3：确定重定向的CNS-APC是否增强了治疗性免疫应答。 Tc 1治疗和/或基于外周DC 1的疫苗接种的有效性。 相关性（参见说明）：