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: 10246884
• 负责人: JOHN H. SAMPSON
• 金额: $ 63.14万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246884
• 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 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.

项目摘要--项目1 我们最近在《自然》杂志上报道，胶质母细胞瘤(GBM)患者随机接受针对 使用破伤风/白喉(TD)疫苗站点的巨细胞病毒(CMV)主要被膜蛋白pp65 预适应方案在统计学上显著增加了无进展生存期(PFS)和总体 生存(OS)：一项小型但随机、盲法、对照试验。以这种方式治疗的患者中有一半是 尽管只有10%的患者通常能活过5年，但近5年后仍然活着。我们的目标是CMV 因为许多不同的群体，包括我们自己，已经表明CMV抗原(AGs)，比如 免疫优势的pp65在基底膜中发现，但在正常脑周围不存在；这表明CMV pp65可能是 被颠覆为高度免疫原性且通常表达均一的抗肿瘤免疫治疗靶点。 在我们的初步研究中，结合对小鼠的深入机制研究，我们证明了 用TD Recall AGS对接种部位进行预处理可增加DC向引流淋巴结的迁移 (DLNS)，预测PFS和OS。对小鼠的机制研究表明，这些化合物的抗肿瘤效果 疫苗依赖于肿瘤中存在的疫苗抗原，强调pp65是 GBM。疗效还取决于TD回忆反应和全身高水平的趋化因子(C-C Motif)配体3(CCL3)，这是在小鼠和患者中唯一升高的免疫介质。我们相信这些 在我们提议的第二阶段试验中，有更多的患者参与，数据证实了这一点。这也将使我们能够 以证实在人类患者身上的一些机械性发现。 然而，系统性免疫抑制在一定程度上是由高水平的调节性T细胞(Tregs)介导的。 患有GBM的患者仍然可能限制疫苗效果。最近，我们和其他人证明了一种临床- 针对CD27的等级抗体在转基因小鼠和人类中特异性地耗尽Tregs。我们还有 证明，与以CD25为靶点来耗尽Treg的临床方法不同，抗CD27抗体 同时增加疫苗诱导的免疫反应。此外，它还专门协调CD4+和 CD8+T细胞反应增强疫苗诱导的免疫原性并提高小鼠的存活率 已确诊的原位神经胶质瘤。总体而言，我们假设TD预适应将增加DC迁移， 系统性CCL3和OS，在CMV疫苗应答进一步增强的同时，Tregs将减少 当一种新的抗CD27单抗加入到该方案中时。