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.

尽管在过去二十年里进行了研究努力，胶质母细胞瘤（GBM）仍然是一种毁灭性的致命癌症 溶瘤病毒疗法的中位总生存期小于 15 个月，是治疗 GBM 的一种有前途的方法。 治疗，因为它不仅涉及直接裂解肿瘤细胞并保留正常细胞，而且还可以增强 然而，通过先天免疫反应早期清除溶瘤病毒， 肿瘤细胞中的病毒传播不良以及病毒进入和/或传播不足构成了限制 溶瘤病毒疗法的功效在此应用中，我们生成了溶瘤单纯疱疹病毒 1 (oHSV)。 携带“别吃我信号”，即被设计为表达抑制性配体 E-钙粘蛋白 自然杀伤 (NK) 细胞的受体 KLRG1 携带 E-钙粘蛋白的下一代 oHSV（称为 E-oHSV）。 重要的是，与我们和其他人使用的药物不同，它可以减少 NK 介导的有害 oHSV 清除。 之前用于通过先天免疫反应抑制溶瘤病毒清除的新型 E-oHSV 产生的免疫抑制作用不应该对全身甚至肿瘤（GBM）产生免疫抑制作用 也就是说，E-oHSV 仅减少结合或攻击 E-oHSV 感染的 NK 细胞的激活。 肿瘤微环境中的细胞，而剩余的 NK 细胞将保持其对抗 GBM 的效力 E-oHSV 细胞还显示出病毒产量的增强，这可能是通过增加病毒之间的细胞间融合来实现的。 然而，感染和未感染的 GBM 细胞不表达内源性 E-钙粘蛋白； 有趣的是，我们发现E-cadherin不仅在E-oHSV感染的细胞表面高表达，而且在 还负载有游离病毒颗粒，后者促进病毒进入和/或在实体瘤中传播。 溶瘤病毒的改进显着提高了携带患者来源 GBM 的小鼠的存活率 细胞并延长了原位、免疫活性 GBM 模型中的动物存活率。 我们建议机械地描述这种 E-oHSV 并加强我们的假设，即下一个- 表达E-钙粘蛋白的一代oHSV，E-oHSV，发挥多种作用来克服障碍 溶瘤病毒疗法对 GBM 治疗具有卓越的疗效，其目标有三个。 提出：目标 1 是探索 E-oHSV 的先天免疫反应被抑制的机制。 目标 2 是探索 E-oHSV 增强细胞间感染、病毒结合以及病毒传播的机制。 目的3是研究体内机制，并将其与NK抑制机制区分开来。 总的来说，我们的研究不仅涉及 E-oHSV 对 GBM 治疗的疗效和潜在毒性。 有关 NK 细胞和 OV 生物学的基本问题，还将开发 GBM 治疗的新疗法。 它还可能提供一个增强非 HSV 溶瘤病毒功效的平台。

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

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

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

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