Project 4: Modulating the natural killer cell response to oHSV1 in recurrent human GBM

项目 4：调节复发性人类 GBM 中自然杀伤细胞对 oHSV1 的反应

• 批准号: 10251085
• 负责人: MICHAEL A CALIGIURI
• 金额: $ 31.99万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251085
• 关键词: Affinity; Anti-Inflammatory Agents; Antibodies; Antigens; Antiviral Agents; Bacteria; Basic Science; Binding; Binding Proteins; Biological Assay; Brain Neoplasms; Cell Communication; Cell physiology; Cell-Mediated Cytolysis; Cells; Clinical Trials; Combined Modality Therapy; Complex; Correlative Study; Cytolysis; Development; Epidermal Growth Factor Receptor; FCGR3B gene; Fc Immunoglobulins; Fc Receptor; Foundations; Funding; Future; Genes; Glioblastoma; Glycoproteins; Goals; Herpes Simplex Infections; Host Defense; Human; Immune; Immune Evasion; Immune response; Immunity; Immunoglobulin G; In Vitro; Individual; Infection; Inflammatory Response; Injections; Innate Immune Response; Italy; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Mediating; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Oncolytic; Oncolytic viruses; Patients; Phase I Clinical Trials; Play; Primary Infection; Process; Prognosis; Property; Proteins; Published Comment; Publishing; Recurrence; Research; Role; Safety; Science; Signal Transduction; Simplexvirus; Site; Smad Proteins; Structural Models; Surface; Testing; Therapeutic; Tissues; Toxic effect; Transforming Growth Factor beta; Treatment Efficacy; Validation; Valproic Acid; Viral; Viral Genome; Viral Proteins; Virotherapy; Virus; Virus Diseases; Virus Replication; antibody-dependent cell cytotoxicity; cell killing; clinical efficacy; crosslink; cytotoxicity; design; efficacy clinical trial; epidermal growth factor receptor VIII; first-in-human; gene product; immunoregulation; improved; in vivo; monocyte; mutant; neoplastic cell; novel; oncolytic virotherapy; outcome prediction; passive antibodies; protein B; receptor; response; theories; tumor; tumor eradication; tumor microenvironment; vector

PROJECT SUMMARY – PROJECT 4 The ultimate goal of this proposal is to understand the role of innate immunity within the context of oncolytic herpes simplex viral (oHSV) therapy for glioblastoma (GBM), a highly fatal brain tumor. oHSV treatment of GBM relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Its safety in patients has been proven, yet evidence for significant efficacy remains to be established. Project 4 will focus on the host's natural killer (NK) cell response following oHSV administration. Due to their strong antiviral properties, NK cells represent a potential barrier to oHSV therapy. Alternatively, the anti-tumor NK cell response has the potential of augmenting the tumor clearing properties of oHSV therapy. Our previously published studies demonstrated that: 1) NK cells rapidly respond oHSV and eliminate the virus before it can effectively replicate and disseminate throughout the GBM; 2) transient immune modulation delaying the NK cell response to oHSV, even with a single injection of TGF-beta, significantly enhances oHSV replication, spread and anti-tumor efficacy following inoculation. As a result, we hypothesize that NK cells coordinate a robust inflammatory response following initial oHSV administration that limits oHSV replication, spread, and tumor lysis, thereby creating a barrier to effective oHSV therapy for GBM. A corollary to this hypothesis is that by understanding how NK cells recognize oHSV-infected GBM we can best modulate this process so as to optimize this highly selective therapy for GBM. We therefore recently developed a novel assay whereby we cloned each HSV1 gene into a vector that allowed us to determine its ability to either induce or inhibit NK cell activation. We discovered the mechanism by which NK cells recognize and destroy HSV-infected targets prior to the development of a primary immune response. We term this fundamental, novel discovery passive antibody dependent cellular cytotoxicity or passive ADCC, whereby the Fc fragment of IgG (IgGFc) forms a bridge between the NK cell Fc receptor for IgGFc, called CD16, and the GBM cell expressing HSV Us8, which encodes the Fc binding protein glycoprotein E (gE). The CD16-IgGFc-gE ternary complex activates NK cells to destroy oHSV-infected GBM without the requirement for the antigen-specific Fab portion of IgG. In this proposal, Project 4 will: (1) further investigate passive ADCC to best understand how to modulate the process so as to enhance the efficacy of oHSV therapy for GBM with Project 1; (2) determine the role of TGF-β signaling in regulating the NK cell interaction with oHSV-encoded viral proteins, specifically as relates to passive ADCC and to NOTCH signaling with Project 3; (3) To assess the NK cell immune response in patients with recurrent GBM who will be receiving our oHSV, rQNestin34.5 in Project 2. By elucidating how NK cells recognize and destroy oHSV- infected tumors in the context of other pro- and anti-inflammatory processes, we will best understand how to optimize this neuro-selective treatment for GBM as well as discern the key mechanistic signals leading to NK cell-mediated clearance of viral infection.

项目总结-项目4