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Study interactions between lung microbiota and immune cells in NSCLC

研究 NSCLC 中肺微生物群与免疫细胞之间的相互作用

基本信息

批准号：
10926447
负责人：
Chen Zhao
金额：
$ 60.62万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10926447
关键词：
Animal Experiments Antibiotic Therapy Antibiotics Bacteria CCR Cells Clinical Protocols Clinical Research Clinical Trials Collaborations Data Development Enrollment Funding Genetically Engineered Mouse Gnotobiotic Goals Human Immune Institutional Review Boards Journals Lung Manuscripts Methods Modeling Mus Non-Small-Cell Lung Carcinoma Oncogenic Pathology Pathway interactions Patients Pennsylvania Phase Plants Process Retrospective Studies Review Committee Sampling Spatial Distribution Therapeutic Tumor Burden Universities aerosolized anti-PD1 antibodies cancer immunotherapy design follow-up germ free condition lung cancer cell lung microbiota metatranscriptomics microbiome neoplastic cell novel novel therapeutic intervention patient prognosis pembrolizumab pre-clinical preservation safety and feasibility safety testing tertiary lymphoid organ tumor tumor microenvironment

项目摘要

Using the novel spatial meta-transcriptomic method we developed, we discovered intratumor bacteria of NSCLC were enriched with tumor cells compared to immune cells and associated with multiple oncogenic pathways in tumor cells. Bacteria burden increased from tumor-adjacent normal lung and tertiary lymphoid structures to tumor cells to the airways. The findings of our study emphasized the importance of direct interaction between tumor cells and bacteria, supporting the therapeutic potential of reducing bacteria burden in the tumor microenvironment. Our manuscript titled "spatial meta-transcriptomics reveal associations of intratumor bacteria burden with lung cancer cells showing a distinct oncogenic signature" has been accepted by the Journal for ImmunoTherapy of Cancer and is currently in press. To follow up on our observations, we collaborated with Dr. Jin at the University of Pennsylvania and successfully reduced the intratumor bacterial burden in genetically engineered mouse (GEM) models of NSCLC by giving aerosolized antibiotics. It further reduced tumor burden when we combined it with an anti-PD-1 antibody. This is the first non-chemotherapy-based treatment showing efficacy in the GEM model of NSCLC. Based on our preclinical data, we designed a Phase I clinical study testing the safety and feasibility of combining aerosolized antibiotics and pembrolizumab in patients with advanced NSCLC. We have successfully obtained funding and support for this trial. The clinical protocol has been reviewed by TGMB and CCR Scientific Review Committee. We are in the process of submitting it to IRB and expect to start enrollment later this year. This will be the first clinical study to modulate the intratumor microbiome in patients with NSCLC. Compared to prior retrospective studies, our clinical trial results will lay the ground for a deep understanding of the function of the intratumor microbiome in patients and the development of novel therapeutic approaches. To enable further mechanistic studies of patients' intratumor microbiome, we have started creating a GEM model harboring patients' intratumor microbiome via intra-tracheal inoculation. Our animal experiment proposal was approved by CCR Gnotobiotic Facility Review Committee, and we are currently in the process of establishing the GEM model under germ-free conditions. This model will help us bridge the gap in the intratumor microbiome between mice and humans. Besides investigating the interactions among patients' intratumor microbiome, immune cells, and tumor cells, we plan to optimize our aerosolized antibiotics treatments via this model.

使用我们开发的新的空间元转录组学方法，我们发现NSCLC的肿瘤内细菌与免疫细胞相比富含肿瘤细胞，并且与肿瘤细胞中的多种致癌途径相关。细菌负荷从肿瘤邻近的正常肺和三级淋巴结构到肿瘤细胞到气道增加。我们的研究结果强调了肿瘤细胞和细菌之间直接相互作用的重要性，支持了减少肿瘤微环境中细菌负荷的治疗潜力。我们的手稿题为“空间元转录组学揭示肿瘤内细菌负荷与肺癌细胞的关联，显示出独特的致癌特征”已被癌症免疫治疗杂志接受，目前正在出版中。为了跟进我们的观察结果，我们与宾夕法尼亚大学的Jin博士合作，通过给予雾化抗生素，成功降低了NSCLC基因工程小鼠（GEM）模型中的肿瘤内细菌负荷。当我们将其与抗PD-1抗体组合时，它进一步降低了肿瘤负荷。这是首个在NSCLC GEM模型中显示疗效的非化疗基础治疗。基于我们的临床前数据，我们设计了一项I期临床研究，测试雾化抗生素和帕博利珠单抗联合治疗晚期NSCLC患者的安全性和可行性。我们已经成功地为这项试验获得了资金和支持。临床方案已由TGMB和CCR科学审查委员会审查。我们正在将其提交给IRB，预计今年晚些时候开始招募。这将是第一项调节NSCLC患者肿瘤内微生物组的临床研究。与之前的回顾性研究相比，我们的临床试验结果将为深入了解患者肿瘤内微生物组的功能和开发新的治疗方法奠定基础。为了能够对患者的肿瘤内微生物组进行进一步的机制研究，我们已经开始通过气管内接种创建包含患者的肿瘤内微生物组的GEM模型。我们的动物实验方案已获得CCR Gnotobiotic Facility Review Committee的批准，目前正在建立无菌条件下的GEM模型。这种模型将帮助我们弥合小鼠和人类之间肿瘤内微生物组的差距。除了研究患者肿瘤内微生物组、免疫细胞和肿瘤细胞之间的相互作用外，我们还计划通过该模型优化雾化抗生素治疗。