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

基本信息

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
项目类别：
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

项目摘要

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.

由于药物诱导的细胞应激，一些用于癌症的化学治疗药物引发了重生。病毒重新激活后，肿瘤表达的新抗原成为细胞毒性细胞的新靶标。这些新的抗原包括病毒裂解抗原，病原体相关的分子模式和替代肿瘤相关病毒重新激活后表达的分子。肿瘤中的病毒重新激活还会诱导肿瘤细胞死亡和将肿瘤相关的免疫原性抗原释放到肿瘤微环境或循环中。后者可能系统地增强抗肿瘤免疫反应。最后，肿瘤产生的外泌体循环，潜在的携带病毒基因组和抗原，可能是与肿瘤相关的免疫触发因素的另一种形式。因此，实际上，病毒重新激活可能有助于恢复患者的免疫细胞毒性，如果我们只能控制和限制病毒重新激活的水平和位置。我们的体外初步数据表明，这种情况是 BTZ和OTX015组合疗法可在KSHV阳性腹膜积液淋巴瘤（PEL）中实现。也就是说，用BTZ和OTX015诱导的KSHV重新激活KSHV阳性PEL的处理在阻断末端病毒颗粒形成的同时，裂解抗原的表达，导致PEL细胞死亡有限成熟病毒颗粒的脱落。此外，OTX015表现出强烈抑制炎性细胞因子 PEL生产。在这个补充项目中，候选人Shimoda博士将引入人源化的鼠标测试BTZ/OTX015治疗的假设的模型人源化的小鼠模型。具体目的是：目的1：在BTZ/OTX015治疗下的PEL人源化小鼠模型中评估免疫表型。我们将检验以下假设，即HLA-A0201限制性BC-3肿瘤在HLA-A0201中被BTZ/OTX015重新激活在增加肿瘤浸润的免疫细胞中，总体细胞毒性增强。免疫细胞表型和脾脏和肿瘤中细胞毒性CD107A+和IFNG+细胞的频率将通过流式细胞仪进行评估。我们的目的是确定该药物组合对抗肿瘤免疫反应具有总体有益作用。目标2：在肿瘤微环境中进行单细胞转录组分析 BTZ/OTX015治疗。我们将检验以下假设，即肿瘤微型诱导的转录变化可以通过单细胞RNA测序技术来鉴定HUPBL-NSG PEL小鼠中的药物环境。我们将评估药物对PEL肿瘤的作用以及肿瘤在单细胞水平下浸润免疫细胞。我们的目的是确定肿瘤和免疫细胞亚群中药物和细胞特异性独特的转录组变化。