Nano-Therapeutic Approaches for Oncogenic Herpesvirus-Mediated Malignancies

疱疹病毒介导的致癌性恶性肿瘤的纳米治疗方法

• 批准号: 9902205
• 负责人: Yoshihiro Izumiya
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-06 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902205
• 关键词: Allogenic; Antigens; Antineoplastic Agents; Automobile Driving; B-Cell Lymphomas; Blood Circulation; CD8-Positive T-Lymphocytes; Cell Death; Cells; Cellular Stress; Chromium; Combined Modality Therapy; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Disease; Drug Combinations; Drug Delivery Systems; Environment; Evolution; Flow Cytometry; Frequencies; Genetic Transcription; Genomics; Goals; Herpesviridae; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immune system; Immunologic Cytotoxicity; Immunologic Surveillance; In Vitro; Inflammatory; Kaposi Sarcoma; Link; Location; Lymphocyte; Lymphoma; Lymphoproliferative Disorders; Lytic; Lytic Phase; Lytic Virus; Malignant Neoplasms; Mediating; Methods; Molecular; Mononuclear; Mus; Natural Killer Cells; Oncogenic; Parents; Patients; Pattern; Peritoneal Fluid; Pharmaceutical Preparations; Phenotype; Process; Production; Research; Spleen; Stress; Suspensions; Symptoms; T-Lymphocyte; Technology; Testing; Transplantation; Tumor-infiltrating immune cells; Viral; Viral Antigens; Viral Genome; Virus; anti-tumor immune response; cancer therapy; cytokine; cytotoxic; cytotoxicity; data mining; dosage; drug efficacy; exosome; experimental study; humanized mouse; immunogenic; improved; intraperitoneal; mouse model; nanomedicine; nanoparticle; nanotherapeutic; neoantigens; neoplastic cell; parent project; particle; pathogen; peripheral blood; response; single cell sequencing; single-cell RNA sequencing; synthetic peptide; transcriptome; tumor; tumor microenvironment

Some chemotherapeutic drugs for cancers trigger reactivation because of cellular stress induced by the drugs. Upon viral reactivation, neo-antigens expressed by tumors become new targets for cytotoxic cells. These neo- antigens include virus lytic antigens, pathogen-associated molecular patterns and surrogate tumor-associated molecules expressed upon viral reactivation. Viral reactivation in tumors also induces tumor cell death and releases tumor-associated immunogenic antigens into the tumor micro-environment or circulation. The latter may boost anti-tumor immune response systemically. Finally, exosomes produced by tumors into circulation, which potentially carry virus genomes and antigens, can be another form of tumor associated immune triggers. Thus, viral reactivation may, in fact, help revive a patients' immune cytotoxicity if we can only control and limit the level and location of viral reactivation. Our in vitro preliminary data suggests that this scenario is achievable in KSHV-positive peritoneal effusion lymphoma (PEL) by the BTZ and OTX015 combination therapy. That is, the treatment of KSHV-positive PELs with BTZ and OTX015 induced reactivation of KSHV and expression of lytic antigens while blocking terminal viral particle formation, resulting in PEL cell death with limited shedding of mature viral particles. In addition, OTX015 showed strong suppression of inflammatory cytokine production by PEL. In this supplement project, the candidate, Dr. Shimoda will introduce a humanized mouse model to test the hypothesis that BTZ/OTX015 therapy creates immunogenic tumor micro-environment in a humanized mouse model of PEL. Specific Aims are: Aim 1: To evaluate immune phenotype in a humanized mouse model of PEL under BTZ/OTX015 therapy. We will test the hypothesis that KSHV reactivation by BTZ/OTX015 in HLA-A0201-restricted BC-3 tumors results in increased tumor-infiltrating immune cells with overall enhanced cytotoxicity. Immune cell phenotype and the frequency of cytotoxic CD107a+ and IFNg+ cells in spleen and tumors will be evaluated by flow cytometry. Our goal is to establish that the drug combination has overall beneficial effect on anti-tumor immune response. Aim 2: To conduct single cell transcriptome analysis of the tumor micro-environment during BTZ/OTX015 therapy. We will test the hypothesis that transcriptional changes induced in a tumor micro- environment by drugs in huPBL-NSG PEL mice can be identified by single cell RNA sequencing technology. We will evaluate the drug effects on PEL tumors as well as tumor infiltrating immune cells at single cell level. Our goal is to identify the drug and cell-specific unique transcriptome changes in tumor and immune cell subsets.

一些用于癌症的化疗药物由于药物诱导的细胞应激而触发再活化。 在病毒再活化后，肿瘤表达的新抗原成为细胞毒性细胞的新靶标。这些新- 抗原包括病毒裂解抗原、病原体相关分子模式和替代肿瘤相关抗原。 在病毒再活化时表达的分子。肿瘤中的病毒再活化也诱导肿瘤细胞死亡， 将肿瘤相关免疫原性抗原释放到肿瘤微环境或循环中。后者可能 增强全身抗肿瘤免疫反应。最后，肿瘤产生的外泌体进入循环， 可能携带病毒基因组和抗原，可能是另一种形式的肿瘤相关免疫触发因素。因此，在本发明中， 事实上，如果我们能够控制和限制病毒的激活， 病毒再激活的程度和位置我们的体外初步数据表明，这种情况是 通过BTZ和OTX 015联合治疗，在KSHV阳性腹膜渗出性淋巴瘤（PEL）中可实现。 也就是说，用BTZ和OTX 015处理KSHV阳性PEL诱导了KSHV的再活化， 表达裂解抗原，同时阻断末端病毒颗粒形成，导致PEL细胞死亡， 成熟病毒颗粒脱落。此外，OTX 015显示出对炎性细胞因子的强抑制作用。 由PEL生产。在这个补充项目中，候选人下田博士将介绍一种人源化小鼠 模型来检验BTZ/OTX 015疗法在肿瘤中产生免疫原性肿瘤微环境的假设。 PEL的人源化小鼠模型。具体目标是： 目的1：评估BTZ/OTX 015治疗下的人源化PEL小鼠模型中的免疫表型。 我们将检验BTZ/OTX 015在HLA-A0201限制性BC-3肿瘤中KSHV再激活的假设， 在增加的肿瘤浸润免疫细胞中具有总体增强的细胞毒性。免疫细胞表型和 将通过流式细胞术评价脾和肿瘤中细胞毒性CD 107 a+和IFNg+细胞的频率。我们 目的是确定药物组合对抗肿瘤免疫应答具有总体有益作用。 目的2：进行肿瘤微环境的单细胞转录组分析， BTZ/OTX 015疗法。我们将检验在肿瘤微环境中诱导的转录变化的假设， 通过单细胞RNA测序技术可以鉴定药物在huPBL-NSG PEL小鼠中对环境的影响。我们 将在单细胞水平上评价药物对PEL肿瘤以及肿瘤浸润免疫细胞的作用。我们 目的是鉴定肿瘤和免疫细胞亚群中药物和细胞特异性的独特转录组变化。