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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

基本信息

批准号：
10006177
负责人：
JOHN H. SAMPSON
金额：
$ 69.14万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10006177
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

项目摘要

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.

项目总结-项目一