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

• 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
• 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

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.

抗肿瘤免疫的引发依赖于常规树突状细胞（cDC 1）的特化亚群，CD 103 + DC具有将肿瘤抗原运输至淋巴结进行交叉呈递的独特能力。临界 cDC 1在癌症免疫监视中的作用使其成为免疫治疗的高度令人垂涎的靶标;然而， 它们的稀缺性，特异性参与DC的困难，以及抑制性肿瘤微环境（TME） 构成严重障碍。我们正在研究减毒重组脊髓灰质炎病毒（PV）的免疫治疗， PVSRIP 0，因为PV对DC的天然进化向性。在人类或黑猩猩中， 导致在外周（胃肠道）和淋巴组织中显著有效地靶向CD 11 c + DC。 PVSRIPO，用来自人鼻病毒2型的IRES工程化，在正常细胞中缺乏致细胞病变性，例如。 区议会相反，DC感染产生由特异性病毒dsRNA引起的“持续”I型干扰素（IFN）应答 参与PV模式识别受体（PRR）MDA 5的模式。PVSRIPO的机理研究 在离体人肿瘤切片中的治疗揭示：（i）主要结果是从肿瘤组织中持续释放I型IFN， 非恶性TME中的骨髓细胞亚群;（ii）PVSRIPO独特的先天印记提供了最佳的DC 用于CD 4 +T细胞TH 1极化和CD 8 +T细胞引发的活化刺激;（iii）PVSRIPO的“PRR-contextualized” IFN应答诱导多功能GzmB+、IFNg+、T-bet+抗肿瘤CD 8 +T细胞，其在免疫后控制肿瘤生长。 过继性转移我们报告了非常有希望的PVSRIPO在挑战中的1期临床试验结果 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 治疗募集cDC 1，导致这些细胞的局部感染，诱导迁移到淋巴结/脾， 并通过其所激发的内在先天炎症信号刺激肿瘤抗原交叉呈递。 我们提出了机制和翻译研究，以深入了解PVSRIPO靶向DC的方式， 不同骨髓亚群的亚致死性感染激活肿瘤抗原交叉呈递， 通过结内病毒施用增强DC接合。我们提出以下具体目标：（1） 揭示PVSRIPO感染后cDC 1募集、激活和淋巴结迁移的机制 TME。(2)确定介导PVSRIPO抗肿瘤作用的单核吞噬细胞区室;测试 T细胞内在IFN信号传导和趋化性的作用。(3)通过结周递送加强cDC 1接合 或在感染PVSRIPO反应性神经胶质瘤骨髓浸润后。 意义：这些研究探索了一个独特的机会，有效地参与CD 103 + DC在肿瘤抗原 交叉呈递和CD 8 +T细胞致敏，基于DC的天然向性和独特的先天性炎性 PVSRIPO的印记。这项研究的长期目标是提供恢复有效癌症的方法。 通过克服DC功能和CD 8 +T细胞引发的肿瘤相关缺陷，在患者中实现免疫监视。