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Multi-strain, live biotherapeutics as adjuncts to checkpoint inhibitor therapy

多菌株活生物治疗药物作为检查点抑制剂治疗的辅助药物

基本信息

批准号：
10406247
负责人：
Hyungsoo Kim
金额：
$ 21.27万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-17 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406247
关键词：
Ampicillin Antibiotics Antitumor Response Attenuated Bacteroides Bacteroides fragilis Bacteroides thetaiotaomicron Bifidobacterium Biological Response Modifier Therapy CD8B1 gene Cancer Patient Catabolism Cells Clostridium Communities Confusion Consumption Diet Etiology Family suidae Formulation Frequencies Gastric Mucin Germ-Free Gnotobiotic Histologic Human Immune checkpoint inhibitor Immune system Immunologic Markers Immunotherapy In Vitro Interferon Type II Inulin Investigation Laboratories Lead Malignant Neoplasms Mediating Mediator of activation protein Modeling Monitor Mucins Mus Non-Small-Cell Lung Carcinoma Patient-Focused Outcomes Patients Phenotype Phylogenetic Analysis Positioning Attribute Probiotics Reporting Ribosomal RNA Series Signal Transduction Testing Translational Research Treatment Efficacy Tumor Immunity Validation Work anti-CTLA4 anti-PD-1 anti-PD-1/PD-L1 anti-PD1 therapy anti-tumor immune response attenuation base candidate identification checkpoint therapy density fecal microbiota fecal transplantation feeding gut microbiota human model human subject improved improved outcome melanoma metabolome metabolomics microbial microbiota microbiota profiles mouse model neoplastic cell prebiotics response success targeted treatment tumor tumor growth

项目摘要

PROJECT SUMMARY A series of recent studies have highlighted the importance of the composition of the gut microbiota as a factor determining the efficacy of checkpoint inhibitor therapy to treat a variety of cancers. These studies have identified a number of phylogenetically unrelated taxa that lack consistency across reports, generating confusion and skepticism in the field. We evaluated the effect of prebiotics (inulin and mucin) and found that these treatments induce alterations in gut microbiota composition and lead to tumor growth attenuation in some but not all of the tumor models tested. Comparison of microbiota profiles of mice associated with effective tumor control to those that failed to do so, suggests that bacterial species encoding anti-tumor phenotypes are enriched in a number of distinct phylogenetic clades. Similarly, we observed that anti-tumor taxa are positively correlated with distinct TILs profiles suggesting that an optimized bacterial cocktail capable of stimulating multiple anti-tumor immune responses may allow more robust tumor growth control. We will test whether inulin feeding restores tumor control of gnotobiotic mice colonized with fecal microbiota from patients that were non-responsive to checkpoint inhibitor therapy. We are strongly positioned to engage in translational efforts to target the isolation and validation of relevant phylogenetic groups to identify taxa promoting improved responsiveness to checkpoint inhibitors as an important step toward developing optimized probiotic formulations for use in human patients. We will explore mechanistic aspects of inulin's ability to confer anti-tumor immunity we will conduct metabolomics analyses using gnotobiotic mice colonized with defined, low-complexity communities and in vitro cultures to identify inulin- dependent metabolites that may signal the gut immune system to induce anti-tumor immunity.

项目概要最近的一系列研究强调了肠道微生物群的组成作为一个因素的重要性确定检查点抑制剂疗法治疗多种癌症的功效。这些研究已确定许多系统发育无关的分类单元在报告中缺乏一致性，产生混乱和领域内的怀疑态度。我们评估了益生元（菊粉和粘蛋白）的效果，发现这些治疗方法诱导肠道微生物群组成的改变，并导致某些但不是全部的肿瘤生长减弱测试的肿瘤模型。与有效肿瘤控制相关的小鼠微生物群谱的比较但未能做到这一点，表明编码抗肿瘤表型的细菌种类富含多种不同的系统发育分支。同样，我们观察到抗肿瘤类群与不同的 TIL 谱表明优化的细菌混合物能够刺激多种抗肿瘤免疫反应可能允许更强有力的肿瘤生长控制。我们将测试菊粉喂养是否可以恢复肿瘤控制的无菌小鼠被来自对检查点抑制剂无反应的患者的粪便微生物群定植治疗。我们有能力参与转化工作，以分离和验证相关的系统发育群体来识别促进检查点抑制剂反应性改善的分类群这是开发用于人类患者的优化益生菌制剂的重要一步。我们将探索菊粉赋予抗肿瘤免疫力的能力的机制方面，我们将使用以下方法进行代谢组学分析用明确的、低复杂性群落和体外培养物定殖的限生小鼠，以鉴定菊糖可能向肠道免疫系统发出信号以诱导抗肿瘤免疫的依赖性代谢物。