Mechanistic factors limiting utility of adenovirus vectors for treatment of neopla

限制腺病毒载体治疗肿瘤的机制因素

基本信息

批准号：
10618174
负责人：
Dmitry Shayakhmetov
金额：
$ 61.36万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618174
关键词：
A549 Acceleration Address Adenovirus Vector Adenoviruses Affect Animal Model Animals Antigen-Antibody Complex Applications Grants Automobile Driving CD8-Positive T-Lymphocytes Capsid Cell Compartmentation Cell physiology Cells Clinical Trials Cytometry Data Development Dimensions Disease Dose Drug Targeting Environment Family Flow Cytometry Generations Genetic Diseases Growth Factor Human Human Cell Line Immune Immune response Immunity Immunologic Markers Immunosuppression In Vitro Infiltration Interleukin-1 Intravenous Isotope Labeling Kupffer Cells Lung Neoplasms Lymphoid Cell Malignant Neoplasms Malignant neoplasm of lung Mediating Mesocricetus auratus Metals Modality Modeling Molecular Mus Mutagenesis Mutation Myeloid Cell Activation Myeloid Cells Non-Small-Cell Lung Carcinoma Nude Mice Oncolytic Outcome PD-1 pathway Phenotype Play Population Predisposition Property Rodent Role Route Safety Signal Transduction Site System Therapeutic Time Translational Research Transplantation Treatment Efficacy Tumor Biology Tumor Promotion Tumor-Derived Variant Viral Viral Vector Virotherapy Virus Work Xenograft Model adaptive immunity anti-tumor immune response cancer cell cell killing cell stroma clinical translation clinically relevant combat cytokine cytotoxic cytotoxicity design drug candidate exhaustion genetic regulatory protein improved in vivo mouse model neoplastic neoplastic cell novel novel therapeutics patient derived xenograft model pharmacologic programmed cell death ligand 1 programmed cell death protein 1 response single-cell RNA sequencing species difference tissue repair translational medicine tumor tumor growth tumor progression tumorigenic vector

项目摘要

ABSTRACT Adenovirus-based vectors are a very attractive platform for development of novel drug candidates for treatment of numerous genetic diseases and cancer. Currently, the prevailing view of requisites for effective virus-based cancer therapeutics includes i) a potent cytotoxic capacity to trigger virus-mediated killing of as many tumor cells as possible in the shortest period of time, and ii) the capacity for stimulating adaptive anti-tumor immune response. While early efforts to develop potent oncolytic therapeutics were primarily focused on harnessing or even increasing virus-mediated tumor cell cytotoxicity, new data suggest that in vivo, therapeutic efficacy of viruses with low cytotoxic capacity is comparable or even better than that of viruses which are highly effective at killing cancer cells in vitro. The mechanistic factors underlying this mismatch between efficacy and potency in vivo remain poorly understood. While evaluating the therapeutic efficacy of systemically administered adenovirus-based vectors in a mouse model of disseminated lung cancer, we found that virus dose escalation leads to a reduction in median survival of tumor-bearing mice. In mice that developed a ‘non-responder’ phenotype, myeloid cells become highly activated in response to adenovirus administration. Based on these findings we propose the novel concept of a “reparative call”, whereby efficient tumor cell killing by the virus triggers activation of tumor-associated myeloid cells, which in turn secrete pro-tumorigenic growth factors, triggering accelerated tumor growth. This project is designed to comprehensively address mechanistic aspects of this concept by analyzing how cytotoxic potency may affect the efficacy of systemic virotherapy with Ad-based vectors. We will determine the mechanistic role of tumor-derived IL-33 in driving myeloid cell activation and will develop novel Ad vectors expressing soluble IL-33R to block IL-33-dependent tumor-cell activation. We will further analyze the therapeutic efficacy of soluble IL-33R-expressing Ad vectors in combination with clinically relevant drugs that target myeloid cells and the PD-1 pathway. The successful completion of this project will significantly advance our understanding of fundamental factors that are critical for effective clinical translation of Ad-based vector systems for therapy of neoplastic disease.

抽象的基于腺病毒的载体是开发新型药物治疗的非常有吸引力的平台许多遗传疾病和癌症。当前，有效基于病毒的必要条件的普遍观点癌症疗法包括i）潜在的细胞毒性能力触发病毒介导的杀死数量多个肿瘤细胞尽可能在最短的时间内，ii）刺激适应性抗肿瘤免疫的能力回复。尽管早期开发潜在的溶瘤疗法的努力主要集中于利用或即使增加了病毒介导的肿瘤细胞毒性，新数据也表明，体内的治疗有效性低细胞毒性能力的病毒比在高效的病毒相比是可比甚至更好的病毒在体外杀死癌细胞。在有效性与效力之间的这种不匹配的机械因素体内的理解仍然很差。同时评估系统管理的治疗效率在传播肺癌的小鼠模型中，基于腺病毒的载体，我们发现病毒剂量升级导致肿瘤小鼠中位存活率降低。在产生“无反应器”的老鼠中表型，髓样细胞因腺病毒给药而高度激活。基于这些调查结果我们提出了“修复呼叫”的新颖概念，从而使病毒有效地杀死了肿瘤细胞触发与肿瘤相关的髓样细胞的激活，这反过触发加速肿瘤生长。该项目旨在全面解决机理方面通过分析细胞毒性效力如何影响全身病毒疗法的效率，以基于AD的基于AD的效率向量。我们将确定肿瘤来源的IL-33在驱动髓样细胞激活中的机械作用，并将开发表达固体IL-33R的新型AD载体，以阻断IL-33依赖性肿瘤细胞活化。我们将进一步分析固体IL-33R表达AD载体的治疗效率与临床上的结合靶向髓样细胞和PD-1途径的相关药物。这个项目的成功完成将显着提高了我们对有效临床翻译至关重要的基本因素的理解基于AD的媒介系统用于治疗肿瘤疾病。