Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin

通过表达 E-钙粘蛋白的下一代 oHSV 克服病毒治疗的障碍

• 批准号: 10544483
• 负责人: Jianhua Yu
• 金额: $ 37.49万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544483
• 关键词: Address; Animals; Binding; Biology; Cell Adhesion Molecules; Cell fusion; Cell physiology; Cells; Complex; Creativeness; Cytolysis; Data; Diagnosis; Dose; E-Cadherin; Eating; Engineering; FDA approved; Fc Immunoglobulins; Glioblastoma; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Herpesvirus 1; Immune; Immune response; Immunity; Immunocompetent; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Immunosuppression; Infection; Innate Immune Response; Killer Cells; Laboratories; Ligands; Malignant Neoplasms; Manuscripts; Mediating; Minor; Modeling; Mus; N-Cadherin; NK Cell Activation; Names; Natural Killer Cells; Neoplasm Metastasis; Normal Cell; Oncolytic viruses; Operative Surgical Procedures; Paper; Patients; Penetration; Pharmaceutical Preparations; Play; Production; Publications; Publishing; Radiation therapy; Reporting; Reproduction; Research; Role; Signal Transduction; Site; Solid Neoplasm; Surface; Testing; Toxic effect; Viral; Virotherapy; Virus; anti-tumor immune response; blood-brain barrier crossing; cancer therapy; chemotherapy; chimeric antigen receptor; cytotoxicity; immune clearance; improved; in vivo; interest; neoplastic cell; next generation; novel; novel strategies; novel therapeutics; oncolytic herpes simplex virus; oncolytic virotherapy; particle; receptor; receptor binding; trafficking; tumor; tumor eradication; tumor microenvironment

Despite research efforts over the past two decades, glioblastoma (GBM) is still a devastating, deadly cancer with a median overall survival of less than 15 months. Oncolytic virotherapy is a promising approach for GBM treatment because it not only involves direct lysis of tumor cells and spares normal cells but also boosts immune responses to tumor cells. However, early clearance of oncolytic viruses by innate immune responses, poor virus propagation in tumor cells, and insufficient viral entry and/or spread present barriers that limit the efficacy of oncolytic virotherapy. In this application, we generated oncolytic herpes simplex virus 1 (oHSV) carrying a “don't eat me signal”, i.e., being engineered to express a ligand, E-cadherin, of the inhibitory receptor of natural killer (NK) cells, KLRG1. This next-generation oHSV carrying E-cadherin (named E-oHSV) reduces the deleterious NK-mediated clearance of oHSV. Importantly, unlike the drugs that we and others previously used to suppress oncolytic virus clearance by innate immune responses, the novel E-oHSV that we generated should not have an immunosuppressive effect systemically or even in the tumor (GBM) microenvironment. That is, E-oHSV only reduces activation of NK cells that bind to or attack E-oHSV-infected cells in the tumor microenvironment, while the remaining NK cells will maintain their potency against GBM cells. E-oHSV also showed enhanced viral production likely by increasing cell-to-cell fusion between virus- infected and uninfected cells. GBM cells do not have endogenous E-cadherin expression; however, interestingly, we found that E-cadherin is not only highly expressed on the surface of E-oHSV-infected cells but also loaded on free viral particles, the latter of which facilitates viral entry and/or spread in solid tumors. These improvements on oncolytic viruses led to significantly enhanced survival of mice bearing patient-derived GBM cells and also prolonged animal survival in an orthotopic, immunocompetent GBM model. In this application, we propose to mechanistically characterize this E-oHSV and to strengthen our hypothesis that a next- generation oHSV expressing E-cadherin, E-oHSV, plays multiple roles to overcome the barriers of oncolytic virotherapy and thus has a superior efficacy for GBM treatment. Three aims have been proposed: Aim 1 is to explore the mechanisms by which innate immune responses to E-oHSV are inhibited. Aim 2 is to explore the mechanisms by which E-oHSV enhances cell-to-cell infection, viral binding, and thus viral spread and distinguish them from the NK inhibition mechanism. Aim 3 is to investigate in vivo mechanisms, efficacy, and potential toxicity of E-oHSV for GBM treatment. Collectively, our study will not only address fundamental questions on NK cell and OV biology, but will also develop novel therapeutics for GBM treatment. It may also provide a platform to enhance efficacy of non-HSV oncolytic viruses.

尽管在过去的二十年里进行了研究，但胶质母细胞瘤（GBM）仍然是一种毁灭性的致命癌症 中位生存期不到15个月溶瘤病毒治疗是治疗GBM的一种有前途的方法 治疗，因为它不仅涉及直接溶解肿瘤细胞和保留正常细胞， 对肿瘤细胞的免疫反应。然而，先天免疫应答对溶瘤病毒的早期清除， 病毒在肿瘤细胞中的不良增殖以及病毒进入和/或扩散不足存在限制肿瘤细胞增殖的障碍。 溶瘤病毒疗法的功效。在本申请中，我们产生了溶瘤单纯疱疹病毒1（oHSV） 传递着“别吃我”的信号被改造以表达抑制性的配体，E-钙粘蛋白， 自然杀伤（NK）细胞受体KLRG 1。这种携带E-cadherin的下一代oHSV（命名为E-oHSV） 减少NK介导的有害oHSV清除。重要的是，与我们和其他人使用的药物不同， 先前用于抑制通过先天免疫应答的溶瘤病毒清除，我们 产生的免疫抑制剂不应具有全身性或甚至在肿瘤（GBM）中的免疫抑制作用 微环境也就是说，E-oHSV仅减少结合或攻击E-oHSV感染的NK细胞的活化。 肿瘤微环境中的NK细胞，而剩余的NK细胞将保持其对GBM的效力 细胞E-oHSV也显示出病毒产量的增加，这可能是通过增加病毒与宿主细胞之间的细胞间融合来实现的。 感染和未感染的细胞。GBM细胞不具有内源性E-钙粘蛋白表达;然而， 有趣的是，我们发现E-cadherin不仅在E-oHSV感染的细胞表面高度表达， 也装载在游离病毒颗粒上，后者促进病毒进入和/或在实体瘤中扩散。这些 溶瘤病毒的改进导致携带患者源性GBM的小鼠的存活率显著提高 细胞，并且还延长了原位免疫活性GBM模型中的动物存活。在本申请中， 我们建议从机制上描述这种E-oHSV，并加强我们的假设，即下一个- 表达E-cadherin的oHSV一代，E-oHSV，在克服免疫缺陷的障碍中起着多种作用。 溶瘤病毒疗法，因此对GBM治疗具有上级功效。三个目标是 目的1：探讨E-oHSV天然免疫应答被抑制的机制。 目的2是探索E-oHSV增强细胞间感染、病毒结合，从而增强病毒感染的机制。 传播并从NK抑制机制中区分它们。目的3是研究体内机制， E-oHSV用于GBM治疗的有效性和潜在毒性。总的来说，我们的研究不仅要解决 我们将研究NK细胞和OV生物学的基本问题，而且还将开发用于GBM治疗的新疗法。 它还可以提供一个平台，以增强非HSV溶瘤病毒的功效。

项目成果

Regulation of Human Natural Killer Cell IFN-γ Production by MicroRNA-146a via Targeting the NF-κB Signaling Pathway.

MicroRNA-146a 通过靶向 NF-κB 信号通路调节人自然杀伤细胞 IFN-γ 的产生

• DOI: 10.3389/fimmu.2018.00293
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Wang H;Zhang Y;Wu X;Wang Y;Cui H;Li X;Zhang J;Tun N;Peng Y;Yu J
• 通讯作者: Yu J

IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB.

• DOI: 10.4049/jimmunol.1601554
• 发表时间: 2017-10-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Victor AR;Nalin AP;Dong W;McClory S;Wei M;Mao C;Kladney RD;Youssef Y;Chan WK;Briercheck EL;Hughes T;Scoville SD;Pitarresi JR;Chen C;Manz S;Wu LC;Zhang J;Ostrowski MC;Freud AG;Leone GW;Caligiuri MA;Yu J
• 通讯作者: Yu J

Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells.

黑树莓通过增强结肠上皮和自然杀伤细胞中 Smad4 的表达来抑制结直肠癌。

• DOI: 10.3389/fimmu.2020.570683
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Huang YW;Lin CW;Pan P;Shan T;Echeveste CE;Mo YY;Wang HT;Aldakkak M;Tsai S;Oshima K;Yearsley M;Xiao J;Cao H;Sun C;Du M;Bai W;Yu J;Wang LS
• 通讯作者: Wang LS

Effects of Dietary Interventions on Gut Microbiota in Humans and the Possible Impacts of Foods on Patients' Responses to Cancer Immunotherapy.

• DOI: 10.2991/efood.k.200824.002
• 发表时间: 2020-08
• 期刊: eFood
• 作者: Wang LS;Mo YY;Huang YW;Echeveste CE;Wang HT;Chen J;Oshima K;Yearsley M;Simal-Gandaraf J;Battino M;Xiao J;Chen J;Sun C;Yu J;Bai W
• 通讯作者: Bai W

Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors.

• DOI: 10.1002/ijc.31366
• 发表时间: 2018-08-15
• 期刊: International journal of cancer
• 影响因子: 6.4
• 作者: Pan P;Oshima K;Huang YW;Agle KA;Drobyski WR;Chen X;Zhang J;Yearsley MM;Yu J;Wang LS
• 通讯作者: Wang LS