Project 1: Targeting cytomegalovirus antigens in glioblastoma with regulatory T cell depletion

项目 1：通过消除调节性 T 细胞来靶向胶质母细胞瘤中的巨细胞病毒抗原

• 批准号: 10477338
• 负责人: Annick Desjardins
• 金额: $ 56.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477338
• 关键词: Acquired Immunodeficiency Syndrome; Alpha Interleukin 2 Receptor; Antibodies; Antigens; Biological Assay; Biological Response Modifiers; Blinded; Brain; Brain Neoplasms; CCL3 gene; CD8-Positive T-Lymphocytes; Cancer Vaccines; Clinical; Cytomegalovirus; Cytomegalovirus Vaccines; Data; Dendritic Cell Vaccine; Dendritic Cells; Diphtheria; Diphtheria Toxoid; Dose; Excision; Genetic Markers; Glioblastoma; Glioma; Goals; Human; IL2RA gene; Immune response; Immunosuppression; Infection; Integumentary system; Interleukin 2 Receptor; Investigational Therapies; Laboratories; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Memory; Messenger RNA; Methods; Monoclonal Antibodies; Mus; Nature; Newly Diagnosed; Nucleic Acids; Operative Surgical Procedures; Patients; Physiologic pulse; Pilot Projects; Prevention; Progression-Free Survivals; Prophylactic treatment; Proteins; Publishing; Radiation Dose Unit; Radiation therapy; Randomized; Regimen; Regulatory T-Lymphocyte; Reporting; Role; Series; Serum; Site; T cell response; T-Cell Depletion; T-Lymphocyte; Tetanus; Transgenic Mice; Treatment Protocols; Tumor Antigens; Vaccinated; Vaccination; Vaccines; Viral; Viral Antigens; Virus Latency; cell motility; chemotherapy; cohort; combat; dendritic cell vaccination; draining lymph node; gamma-Chemokines; immunogenic; immunogenicity; improved; innovation; latent infection; lymph nodes; migration; mouse model; neoplasm immunotherapy; novel; phase II trial; phase III trial; preconditioning; predictive marker; response; tumor; vaccine efficacy; vaccine immunogenicity; vaccine response

PROJECT SUMMARY – Project 1 We recently reported in Nature that patients with glioblastoma (GBM) randomized to receive a vaccine against Cytomegalovirus (CMV) major integument protein pp65 using a tetanus/diphtheria (Td) vaccine site preconditioning regimen had a statistically significant increase in progression-free survival (PFS) and overall survival (OS) in a small but randomized, blinded, and controlled trial. Half of the patients treated this way were still alive nearly 5 years later despite only 10% of patients typically surviving past 5 years. We targeted CMV because many different groups, including our own, had shown that CMV antigens (Ags), like the immunodominant pp65, are found in GBM, but not surrounding normal brain; this suggests CMV pp65 could be subverted as a highly immunogenic and often homogeneously expressed target for anti-tumor immunotherapy. In our preliminary study, combined with in-depth mechanistic studies in mice, we demonstrated that preconditioning the vaccination site with Td recall Ags increased DC migration to the draining lymph nodes (DLNs), which predicted PFS and OS. Mechanistic studies in mice revealed that the antitumor efficacy of these vaccines was dependent on the vaccinating Ag being present in the tumor, underscoring pp65 as a target in GBM. Efficacy was also dependent on a Td recall response and high systemic levels of the chemokine (C-C motif) ligand 3 (CCL3), which was the only immune mediator elevated in mice and patients. We believe these data warrant confirmation in our proposed Phase 2 trial with a larger series of patients. This will also allow us to confirm some of the mechanistic findings in human patients. However, systemic immunosuppression mediated in part by elevated levels of regulatory T cells (TRegs) in patients with GBM still likely limits vaccine efficacy. Recently, we and others have demonstrated that a clinical- grade antibody targeting CD27 specifically depletes TRegs in transgenic mice and humans. We have also demonstrated that, unlike clinical approaches targeting CD25 to deplete TRegs, that the anti-CD27 antibody simultaneously increases vaccine-induced immune responses. Moreover, it specifically coordinates CD4+ and CD8+ T cell responses leading to enhanced vaccine-induced immunogenicity and increased survival in mice with established orthotopic glioma. Overall, we hypothesize that Td preconditioning will increase DC migration, systemic CCL3, and OS, and that TRegs will be reduced while CMV vaccine responses are further enhanced when a novel anti-CD27 mAb is added to this regimen.

项目概要-项目1 我们最近在《自然》杂志上报道，胶质母细胞瘤（GBM）患者随机接受了一种疫苗， 使用破伤风/白喉（Td）疫苗位点的巨细胞病毒（CMV）主要外皮蛋白pp 65 预处理方案在无进展生存期（PFS）和总体无进展生存期（PFS）方面具有统计学显著性增加。 生存期（OS）在一项小型但随机、设盲和对照试验中。接受这种治疗的患者中， 尽管只有10%的患者通常存活超过5年，但仍存活近5年。我们针对CMV 因为许多不同的研究小组，包括我们自己的研究小组，已经表明CMV抗原（Ags），如 免疫显性pp 65在GBM中发现，但在正常脑周围没有发现;这表明CMV pp 65可能是 作为抗肿瘤免疫治疗的高度免疫原性和通常均质表达的靶标被颠覆。 在我们的初步研究中，结合对小鼠的深入机制研究，我们证明， 用Td回忆抗原预处理接种部位增加DC向引流淋巴结的迁移 在小鼠中的机制研究表明，这些药物的抗肿瘤功效与其对PFS和OS的预测有关。 疫苗依赖于肿瘤中存在的疫苗抗原，强调pp 65是肿瘤中的靶点。 GBM。疗效也依赖于Td回忆反应和趋化因子（C-C）的高全身水平 基序）配体3（CCL 3），其是小鼠和患者中升高的唯一免疫介质。我们相信这些 数据需要在我们提出的2期试验中得到证实，该试验涉及更大的患者系列。这也将使我们 来证实一些在人类患者身上的机械发现。 然而，全身性免疫抑制部分由调节性T细胞（TReg）水平升高介导， 患有GBM的患者仍然可能限制疫苗的效力。最近，我们和其他人已经证明了一个临床- 在转基因小鼠和人类中，靶向CD 27的分级抗体特异性地耗尽TReg。我们还 证明，与靶向CD 25以消耗TReg的临床方法不同，抗CD 27抗体 同时增加疫苗诱导的免疫反应。此外，它特异性地协调CD 4+和 CD 8 + T细胞应答导致疫苗诱导的免疫原性增强和小鼠存活率增加 原位神经胶质瘤总的来说，我们假设Td预处理会增加DC迁移， 系统性CCL 3和OS以及TReg将减少，而CMV疫苗应答进一步增强 当一种新的抗-CD 27 mAb加入到这个方案中时。