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治疗新候选药物的非常有吸引力的平台目前，流行的观点认为需要以病毒为基础来治疗多种遗传病。癌症疗法包括 i) 强大的细胞毒性能力，可触发病毒介导的杀死尽可能多的肿瘤细胞尽可能在最短的时间内，以及ii)刺激适应性抗肿瘤免疫的能力虽然开发有效的溶瘤疗法的早期努力主要集中在利用或新数据表明，甚至增加病毒介导的肿瘤细胞的细胞毒性，在体内，治疗效果低细胞毒能力的病毒与高效的病毒相当甚至更好体外杀死癌细胞的机制因素。在评估全身给药的治疗效果时，对体内的了解仍知之甚少。在播散性肺癌小鼠模型中使用基于腺病毒的载体，我们发现病毒剂量递增导致荷瘤小鼠的中位生存期降低。根据这些表型，骨髓细胞响应腺病毒给药而变得高度激活。研究结果我们提出了“修复呼叫”的新概念，即病毒有效杀死肿瘤细胞触发肿瘤相关骨髓细胞的激活，进而分泌促肿瘤生长因子，该项目旨在全面解决机制方面的问题。通过分析细胞毒性效力如何影响基于 Ad 的全身病毒疗法的疗效，理解了这一概念我们将确定肿瘤来源的 IL-33 在驱动骨髓细胞激活中的机制作用，并将我们将开发表达可溶性 IL-33R 的新型 Ad 载体来阻断 IL-33 依赖性肿瘤细胞激活。结合临床进一步分析表达可溶性IL-33R的Ad载体的治疗效果靶向骨髓细胞和PD-1通路的相关药物将顺利完成。显着增进我们对有效临床转化至关重要的基本因素的理解用于治疗肿瘤疾病的基于广告的载体系统。