Project 1: Treatment of GBM using an oncolytic HSV engineered to improve immunogenic tumor destruction

项目 1：使用经过改造的溶瘤 HSV 治疗 GBM，以改善免疫原性肿瘤破坏

基本信息

批准号：
10712280
负责人：
Joseph C Glorioso
金额：
$ 34.32万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-07 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10712280
关键词：
Adenosine Affect Aggressive behavior American Animals Antigen-Presenting Cells Antitumor Response Area Biological Assay CD8-Positive T-Lymphocytes Cell Death Cell Line Cell Separation Cells Characteristics Clinic Clinical Trials Clonal Expansion Collaborations Data Development Dissociation Engineering Evaluation Exhibits Genes Glioblastoma Glycoproteins Goals Growth HSV vector Heterogeneity Human Immune Immune checkpoint inhibitor Immunosuppression In Vitro Infiltration Inflammatory Interleukin-12 Ligands Macrophage Malignant Glioma Malignant neoplasm of brain Mediating Metabolic Modeling Modification Monitor Mus Mutation Myeloid Cells Myeloid-derived suppressor cells Nature Oncolytic Oncolytic viruses Outcome PD-1 inhibitors PTEN gene PVRL1 Pathway interactions Patients Performance Phenotype Population Production Proteins Receptor Cell Recruitment Activity Recurrence Resistance Safety Simplexvirus T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Time Transgenes Translating Treatment Efficacy Tumor Antigens Tumor Cell Line Tumor Immunity Variant Vertebral column Viral Viral Antigens Viral Genes Viral Load result Virus Virus Replication adaptive immune response adenosine deaminase anti-cancer arm cell killing clinical development combinatorial design effective therapy effector T cell efficacy evaluation efficacy study exhaust immunogenic improved in vitro activity in vivo in vivo evaluation insight mouse model mutant neoplastic cell novel oncolysis oncolytic herpes simplex virus oncolytic virotherapy patient derived xenograft model patient response pre-clinical prevent programmed cell death protein 1 recruit response single-cell RNA sequencing tumor tumor microenvironment vector

项目摘要

PROJECT SUMMARY – PROJECT 1 The effective treatment of glioblastoma (GBM) using oncolytic Herpes Simplex Virus (oHSV) will almost certainly require both broad intratumoral virus spread and tumor destruction and virus-induced anti-tumor immunity. The tumor microenvironment (TME) must be supportive of adaptive immune responses through the recruitment of active tumor antigen presenting cells and responsive CD8+ T cells. However, GBM tumors are notoriously “cold” tumors that are metabolically adept at preventing the development of a pro-inflammatory TME. This immune- suppressive GBM TME exhibits upregulated expression of (1) the checkpoint proteins TIGIT and PD-1, and their respective inhibitory ligands, and (2) the ectoenzymes CD39 and CD73 that increase local production of adenosine (ADO); both pathways confer immunosuppression and tumor aggression. Here we propose to improve the anti-tumor activity of rQNestin34.5v.1 an F strain oHSV-1. This virus has been engineered to allow tumor-specific expression of natural viral genes that thwart innate anti-viral cellular responses (e.g. ICP34.5). rQNestin34.5v.2, a modified version of rQNestin34.5v.1 with GFP removed, was shown to be safe in a patient trial with evidence of intratumoral viral antigen expression for extended time periods (NCT03152318). Three aims are designed to evaluate rQNestin34.5v.1 enhancement in patient derived xenograft (PDX) models and in syngeneic GBM mouse models. We propose in Aim 1, to test the hypothesis that syncytial mutant variants of rQNestin34.5v.1 will exhibit enhanced oncolytic activity, augmenting viral spread and persistence within the tumor. In Aim 2, we propose to test the hypothesis that the therapeutic efficacy of rQNestin34.5v.1 can be improved by arming the vector with a combination of IL-12, the checkpoint inhibitors (CPI) anti-PD-1 and anti- TIGIT (Aim 2A), or with the adenosine deaminase (ADA) gene (Aim 2B). The efficacy of ADA-armed oHSV will be tested in combination with oHSV expressing PTEN and anti-CD73 (oHSV-P10-CD73; Project 3) and depending on the outcome, both arming genes will be introduced into a single vector for treatment efficacy studies. Analysis of human clinical trial data has allowed Project 2 to define a TME profile characteristic of rQNestin34.5v2 responders, demonstrating a correlation between patient response and increased TCR diversity. In Aim 3, we will test the hypothesis that rQNestin34.5v.1 and armed derivatives will increase the accumulation of effector T cell populations and induce clonal expansion of T cells that recognize viral- and tumor-specific antigens. Aim 3 analyses will compare the armed vectors generated in Aim 2 to those generated by Projects 3 and 4 and will allow us to establish correlations across multiple oHSV variants with respect to clonal T cell expansion and animal survival. The proposed vector modifications may substantially improve rQNestin34.5v.1 performance and effectively increase the number of tumors responsive to oHSV treatment, thereby potentially providing a novel vector suitable for clinical development.

项目摘要 – 项目 1 使用溶瘤单纯疱疹病毒 (oHSV) 有效治疗胶质母细胞瘤 (GBM) 几乎肯定会需要广泛的瘤内病毒传播和肿瘤破坏以及病毒诱导的抗肿瘤免疫。肿瘤微环境（TME）必须通过招募活性肿瘤抗原呈递细胞和反应性 CD8+ T 细胞然而，GBM 肿瘤是出了名的“冷”。代谢上擅长预防促炎性 TME 发展的肿瘤。抑制性 GBM TME 表现出 (1) 检查点蛋白 TIGIT 和 PD-1 及其它们的表达上调各自的抑制配体，以及（2）胞外酶 CD39 和 CD73，可增加局部产生腺苷（ADO）；这两种途径都具有免疫抑制和肿瘤侵袭作用。提高 rQNestin34.5v.1 和 F 株 oHSV-1 的抗肿瘤活性。该病毒经过工程设计，允许。天然病毒基因的肿瘤特异性表达，阻碍先天抗病毒细胞反应（例如ICP34.5）。 rQNestin34.5v.2 是删除了 GFP 的 rQNestin34.5v.1 的修改版本，已被证明对患者是安全的具有肿瘤内病毒抗原长时间表达证据的试验（NCT03152318）。目的旨在评估 rQNestin34.5v.1 在患者来源的异种移植 (PDX) 模型和我们在目标 1 中提出了同基因 GBM 小鼠模型，以检验合胞体突变变体的假设。 rQNestin34.5v.1 将表现出增强的溶瘤活性，增强病毒在体内的传播和持久性在目标 2 中，我们建议检验 rQNestin34.5v.1 的治疗功效可以是的假设。通过用 IL-12、检查点抑制剂 (CPI)、抗 PD-1 和抗 - TIGIT（目标 2A），或带有腺苷脱氨酶（ADA）基因（目标 2B）的 ADA 武装 oHSV 的功效。与表达 PTEN 和抗 CD73 的 oHSV 结合进行测试（oHSV-P10-CD73；项目 3）并且根据结果，两个武装基因将被引入单个载体中以提高治疗效果人类临床试验数据的分析使项目 2 能够定义 TME 特征。 rQNestin34.5v2 应答者，证明患者应答与 TCR 多样性增加之间的相关性。在目标 3 中，我们将测试 rQNestin34.5v.1 和武装衍生物会增加积累的假设效应 T 细胞群并诱导识别病毒和肿瘤特异性的 T 细胞克隆扩增目标 3 分析将比较目标 2 中生成的武装载体与项目 3 生成的载体。和 4，将使我们能够建立多个 oHSV 变体与克隆 T 细胞的相关性所提出的载体修饰可能会显着改善 rQNestin34.5v.1。性能并有效增加对 oHSV 治疗有反应的肿瘤数量，从而可能提供适合临床开发的新型载体。