Resolving Spatiotemporal Dynamics of Recombinant Poliovirus Immunotherapy

解决重组脊髓灰质炎病毒免疫疗法的时空动力学问题

基本信息

批准号：
10676548
负责人：
Matthias Gromeier
金额：
$ 37.77万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-28 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676548
关键词：
Adoptive Transfer Antigen-Presenting Cells Antigens Attenuated Autopsy Brain Brunhilde Virus CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Patient Cell physiology Cells Cervical lymph node group Chemotaxis Clinical Clinical Trials Cross Presentation Cytoplasm Dendritic Cells Dendritic cell activation Disease Double-Stranded RNA Engineering Focal Infection Glioblastoma Glioma Human Human poliovirus ITGAM gene ITGAX gene Immune Immunity Immunologic Stimulation Immunologic Surveillance Immunology Immunotherapy In Vitro Infection Infiltration Inflammatory Injections Interferon Type I Interferons Internal Ribosome Entry Site Investigation Lymphatic System Lymphoid Tissue Macaca Macrophage Malignant Neoplasms Mediating Modeling Mononuclear Mus Myelogenous Myeloid Cells Natural Killer Cells Necrosis Nodal Non-Malignant Normal Cell Oral Outcome Pan Genus Pathogenicity Patients Pattern Pattern recognition receptor Peripheral Phagocytes Proteins RNA Viruses Reaction Receptor Signaling Recombinants Recurrence Reporting Repression Research Resistance Resolution Rhinovirus Role Schedule Signal Transduction Site Slice Spleen Stimulus T cell response T-Lymphocyte TAP1 gene Testing Tropism Tumor Antigens Tumor Immunity Tumor-associated macrophages Vaccines Viral Virulence Virus Widespread Disease antitumor effect cancer immunotherapy cell motility cytotoxic gastrointestinal glymphatic system immune checkpoint blockade imprint in vivo insight lymph nodes lymphoid structures melanoma migration pathogen patient subsets radiological imaging recruit response safety study sensor spatiotemporal trafficking translational study tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

Priming of antitumor immunity relies on a specialized subset of conventional Dendritic Cells (cDC1s), CD103+ DCs, that have unique capabilities of trafficking tumor antigens to lymph nodes for cross-presentation. The critical role of cDC1s in cancer immune surveillance make them highly coveted targets for immunotherapy; however, their scarcity, the difficulty of specifically engaging DCs, and the suppressive tumor microenvironment (TME) pose severe obstacles. We are investigating immunotherapy with attenuated, recombinant poliovirus (PV), PVSRIPO, because of the naturally evolved tropism of PV for DCs. In humans or chimpanzees, oral PV infection leads to remarkably effective targeting of CD11c+DCs in peripheral (gastrointestinal) and lymphoid tissues. PVSRIPO, engineered with an IRES from human rhinovirus type 2, lacks cytopathogenicity in normal cells, eg. DCs. Rather, DC infection yields ‘sustained’ type-I interferon (IFN) responses elicited by specific viral dsRNA patterns that engage the PV pattern recognition receptor (PRR) MDA5. Mechanistic investigations of PVSRIPO treatment in ex vivo human tumor slices revealed that: (i) the main outcome is sustained type-I IFN release from myeloid cell subsets in the non-malignant TME; (ii) PVSRIPO’s unique innate imprint provides optimal DC activation stimuli for CD4+T cell TH1-polarization and CD8+T cell priming; (iii) PVSRIPO’s ‘PRR-contextualized’ IFN response induces polyfunctional GzmB+, IFNg+, T-bet+ antitumor CD8+T cells that control tumor growth after adoptive transfer. We reported very promising Ph1 clinical trial results with PVSRIPO in challenging indications: recurrent glioblastoma and recurrent, nonresectable melanoma. Our premise is that PVSRIPO therapy recruits cDC1s, leads to local infection of these cells, induces migration to lymph nodes/spleen, and stimulates tumor antigen cross-presentation via the intrinsic innate inflammatory signature it elicits. We propose mechanistic and translational studies to gain insight into targeting of DCs by PVSRIPO, the way sublethal infection of distinct myeloid subsets activates tumor antigen cross-presentation, and rational means of enhancing DC engagement by intranodal virus administration. We propose the following Specific Aims: (1) Unravel mechanisms of cDC1 recruitment, activation, and lymph node migration upon PVSRIPO infection of the TME. (2) Determine the mononuclear phagocyte compartment(s) that mediate PVSRIPO antitumor effects; test the roles of T cell-intrinsic IFN signaling and chemotaxis. (3) Reinforce cDC1 engagement by perinodal delivery or upon infection of the PVSRIPO-reactive glioma myeloid infiltrate. Significance: these studies explore a unique opportunity for effectively engaging CD103+DCs in tumor antigen cross-presentation and CD8+T cell priming, based on the natural tropism for DCs and unique innate inflammatory imprint of PVSRIPO. The long-term objective of this research is to provide means for re-instating effective cancer immune surveillance in patients by overcoming tumor-associated deficits in DC function and CD8+T cell priming.

抗肿瘤免疫的启动取决于常规树突状细胞（CDC1）的专门子集CD103+ DC具有运输肿瘤抗原到淋巴结的独特能力以进行交叉呈递。关键 CDC1在癌症免疫监视中的作用使它们成为免疫疗法的高度令人垂涎的靶标。然而，他们的稀缺性，专门吸引DC的困难以及抑制性肿瘤微环境（TME）构成严重的障碍。我们正在研究减弱，重组脊髓灰质炎病毒（PV）的免疫疗法， PVSripo，由于DC的PV自然发展。在人类或黑猩猩中，口腔PV感染导致周围（胃肠道）和淋巴组织中CD11C+DC的有效靶向。 PVSRIPO由人类鼻病毒2型的IRES设计，在正常细胞中缺乏细胞致病性，例如。 DCS。相反，直流感染产生了特定病毒DSRNA引起的“持续” I型干扰素（IFN）反应参与PV模式识别受体（PRR）MDA5的模式。 PVSripo的机械研究在体内人类肿瘤切片中的治疗表明：（i）主要结果是持续的I型IFN释放非恶性TME中的髓样细胞子集；（ii）PVSRIPO独特的先天印记提供了最佳的DC CD4+T细胞Th1-果胶和CD8+T细胞启动的激活刺激；（iii）PVSripo的“ PRR封闭式” IFN响应诱导多功能GZMB+，IFNG+，T-bet+抗肿瘤CD8+T细胞，可控制肿瘤生长后收养转移。我们报道了PVSripo在挑战中非常有希望的PH1临床试验结果适应症：复发性胶质母细胞瘤和复发性，不可切除的黑色素瘤。我们的前提是PVSripo 疗法报告CDC1导致这些细胞的局部感染，可诱导迁移到淋巴结/脾脏，并通过IT引起的固有先天炎症特征刺激肿瘤抗原交叉呈递。我们提出机械和翻译研究，以深入了解PVSripo（方式）对DC的靶向。不同的髓样子群的一余感会激活肿瘤抗原交叉表达，而有理平均通过鼻内病毒加强DC参与。我们提出以下特定目标：（1） PVSRIPO感染后，CDC1募集，激活和淋巴结迁移的解体机制 TME。（2）确定介导PVSripo抗肿瘤作用的单核吞噬室；测试 T细胞中的IFN信号传导和趋化性的作用。（3）通过围产期递送加强CDC1参与或感染PVSRIPO反应性神经胶质瘤髓样浸润。意义：这些研究探索了有效与CD103+DC在肿瘤抗原中的独特机会基于DC和独特的先天炎症的自然热情，交叉呈递和CD8+T细胞启动 PVSripo的烙印。这项研究的长期目标是提供重新介绍有效癌症的手段通过克服DC功能和CD8+T细胞启动中肿瘤相关的防御能力，患者的免疫监测。