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Innate Antiviral Signals for Cancer Immunotherapy

用于癌症免疫治疗的先天抗病毒信号

基本信息

批准号：
10604571
负责人：
Matthias Gromeier
金额：
$ 40.25万
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：
2018-06-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604571
关键词：
Acute Address Agonist Antigens Automobile Driving Biological Brain Brain Neoplasms CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Cellular Infiltrate Clinic Clinical Cross Presentation Dendritic Cells Dose Double-Stranded RNA Engineering Event Family Picornaviridae Functional disorder Funding Glioblastoma Glioma Goals Heterogeneity Human Human poliovirus Immune Immunity Immunobiology Immunologic Surveillance Immunologics Immunosuppression Immunotherapy Infection Infiltration Inflammation Inflammatory Inflammatory Response Institution Interferon Type I Interferons Internal Ribosome Entry Site Investigation Ligation Lytic Macrophage Malignant Glioma Malignant Neoplasms Mediating Mediator Microglia Modeling Mononuclear Mus Mutation Myelogenous Myeloid Cells Neoplasms Neurons Newly Diagnosed Non-Malignant Outcome Patients Pattern Pattern recognition receptor Phagocytes Phenotype Physiological Poliomyelitis Proliferating RNA Viruses Recombinants Recurrence Research Resistance Resolution Rhinovirus Role Shapes Signal Transduction Slice Syndrome System T cell infiltration T-Lymphocyte TNFRSF5 gene Testing Time Tissues Tumor Antigens Tumor Immunity Tumor Promotion Viral Virotherapy Virus Virus Replication Work attenuation brain parenchyma cancer cell cancer immunotherapy cell killing constitutive expression effector T cell experience immune cell infiltrate immune checkpoint blockade imprint improved insight neoplastic cell neuroinflammation neurotropic neurotropic virus novel therapeutics patient subsets polarized cell poliovirus receptor premature prevent programs radiological imaging receptor release factor 3 response sensor stem success targeted treatment trait tumor tumor microenvironment tumor progression

项目摘要

Glioblastomas (GBM) feature a profoundly immunosuppressive myeloid infiltrate that constitutes a formidable barrier to therapy. The infiltrate’s cellular composition, and the tissue context provided by specialized resident myeloid cells in the CNS (microglia), distinguish GBM from other malignancies. The principal mediators of immunosuppression in the tumor microenvironment (TME), glioma-associated macrophages/microglia (GAMM), are exceedingly difficult therapy targets. Their entrenched immune subversive traits, phenotypic heterogeneity and plasticity pose obstacles to targeted GAMM re-polarization. The goal of this project is to decipher the mechanisms of GBM immunotherapy with recombinant poliovirus, PVSRIPO, a neurotropic +strand RNA virus with a deep pro-inflammatory imprint. Poliovirus naturally targets the mononuclear phagocytic system— macrophages, microglia, dendritic cells (DC)—due to constitutive expression of its receptor CD155 in this compartment. Wild type poliovirus infection is lytic in DCs/macrophages. In contrast, PVSRIPO, engineered for attenuation by internal ribosomal entry site (IRES) exchange with human rhinovirus type 2, has a peculiar non- cytopathogenic host relationship defined by accentuated innate antiviral signaling. Infection of the glioma TME with PVSRIPO unleashes multilayered proinflammatory events, including lingering +strand RNA virus replication within GAMM, activation of diverse innate signaling cascades via multiple double-stranded RNA sensors, profuse type-I interferon dominant inflammation, polio-specific CD4+T cell immunologic recall in the tumor, and widespread microglia activation and proliferation in the normal brain. PVSRIPO has shown promise with single intratumor administration in recurrent GBM, yielding durable radiographic responses associated with long-term survival in a subset of patients. We uncovered that patients whose tumors had relatively lower mutational burden and who experienced a short time to 1st recurrence survived longer after PVSRIPO. These features were associated with enhanced TME inflammatory signatures, indicating that tumor-intrinsic conditions for GAMM engagement influence immunotherapy outcomes. Our central premise is that PVSRIPO generates glioma immune surveillance via proinflammatory activation of GAMM resulting in stimulation of local tumor antigen cross-presentation, T cell infiltration of brain parenchyma, and enhanced CD8+T cell effector functions. Realizing this potential in the clinic for all patients depends on resolving mechanisms that govern antitumor CD8+T cell immunity in the brain. To achieve this objective, we propose the following Specific Aims: (1) Determine the mechanisms of microglia/GAMM proinflammatory activation induced by recombinant poliovirus; (2) Elucidate the impact of microglia cross-presentation on PVSRIPO immunotherapy; (3) Determine if repeat dosing or CD40 ligation improve the antitumor efficacy of PVSRIPO.

胶质母细胞瘤（GBM）的特征是严重的免疫抑制性骨髓浸润，治疗的障碍渗透物的细胞成分，以及由专门的住院医生提供的组织背景 CNS中的髓样细胞（小神经胶质细胞）将GBM与其他恶性肿瘤区分开来。主要调解人肿瘤微环境中的免疫抑制（TME），神经胶质瘤相关巨噬细胞/小胶质细胞（GAMM），是非常困难的治疗目标。他们根深蒂固的免疫颠覆特性，表型异质性和可塑性对靶向GAMM再极化造成障碍。这个项目的目标是破译用重组脊髓灰质炎病毒PVSRIPO（一种亲神经性+链RNA病毒）免疫治疗GBM的机制有很深的致炎性印记脊髓灰质炎病毒天然地以单核吞噬细胞系统为目标- 巨噬细胞，小胶质细胞，树突状细胞（DC）-由于其受体CD 155的组成性表达，在这种情况下，车厢野生型脊髓灰质炎病毒感染在DC/巨噬细胞中是裂解性的。相比之下，PVSRIPO，通过与人鼻病毒2型的内部核糖体进入位点（IRES）交换的减毒，具有独特的非- 由增强的先天性抗病毒信号传导定义的致细胞病变宿主关系。用PVSRIPO感染胶质瘤TME释放多层促炎事件，包括在GAMM内的延迟+链RNA病毒复制，通过多种途径激活多种先天信号级联，双链RNA传感器，丰富的I型干扰素显性炎症，脊髓灰质炎特异性CD 4 +T细胞肿瘤中的免疫回忆，以及正常脑中广泛的小胶质细胞活化和增殖。 PVSRIPO在复发性GBM中显示出单次瘤内给药的前景，与一部分患者的长期生存相关的放射学反应。我们发现病人肿瘤突变负荷相对较低且首次复发时间较短的患者存活在PVSRIPO之后。这些特征与增强的TME炎症特征相关，表明 GAMM参与的肿瘤内在条件影响免疫治疗结果。我们的中心前提是PVSRIPO通过促炎作用产生胶质瘤免疫监视，激活GAMM，导致刺激局部肿瘤抗原交叉呈递、T细胞浸润的脑实质，并增强CD 8 +T细胞效应功能。在临床上实现这种潜力对于所有患者，这取决于控制抗肿瘤CD 8 +T细胞免疫的解决机制，个脑袋为了实现这一目标，我们提出了以下具体目标：（1）确定重组脊髓灰质炎病毒诱导的小胶质细胞/GAMM促炎激活;（2）阐明（3）确定是否重复给药或CD 40连接提高PVSRIPO的抗肿瘤效果。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PKR Binds Enterovirus IRESs, Displaces Host Translation Factors, and Impairs Viral Translation to Enable Innate Antiviral Signaling.

DOI：
10.1128/mbio.00854-22
发表时间：
2022-06-28
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Harnessing virus tropism for dendritic cells for vaccine design.

DOI：
10.1016/j.coviro.2020.07.012
发表时间：
2020-10
期刊：
Current opinion in virology
影响因子：
5.9
作者：
Mosaheb MM;Brown MC;Dobrikova EY;Dobrikov MI;Gromeier M
通讯作者：
Gromeier M

Early enterovirus translation deficits extend viral RNA replication and elicit sustained MDA5-directed innate signaling.

DOI：
10.1128/mbio.01915-23
发表时间：
2023-12-19
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

Aryl Hydrocarbon Receptor Signaling Controls CD155 Expression on Macrophages and Mediates Tumor Immunosuppression.

DOI：
10.4049/jimmunol.2000792
发表时间：
2021-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
McKay ZP;Brown MC;Gromeier M
通讯作者：
Gromeier M

Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.

脊髓灰质炎病毒疗法针对恶性神经胶质瘤骨髓浸润，弥漫性小胶质细胞激活吞噬中枢神经系统。

DOI：
10.1093/neuonc/noad052
发表时间：
2023
期刊：
Neuro-oncology
影响因子：
15.9
作者：
Yang,Yuanfan;Brown,MichaelC;Zhang,Gao;Stevenson,Kevin;Mohme,Malte;Kornahrens,Reb;Bigner,DarellD;Ashley,DavidM;López,GiselleY;Gromeier,Matthias
通讯作者：
Gromeier,Matthias