Transplanting Unique Human Microbiomes to Improve Immunotherapy in Glioblastoma

移植独特的人类微生物组以改善胶质母细胞瘤的免疫治疗

• 批准号: 10216471
• 负责人: Kathleen M. Egan
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216471
• 关键词: 16S ribosomal RNA sequencing; Animal Model; Animals; Archives; Biological Response Modifier Therapy; Central Nervous System Neoplasms; Clinical Trials; Cryopreservation; Development; Effectiveness; Glioblastoma; Glioma; Gnotobiotic; Goals; Growth; Human; Human Microbiome; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunotherapy; Intervention; Link; Malignant Neoplasms; Metastatic Melanoma; Metastatic malignant neoplasm to brain; Methods; Microbe; Modeling; Modification; Mus; Neuraxis; Neuroepithelial; PD-1 inhibitors; Patients; Pre-Clinical Model; Primary Brain Neoplasms; Probiotics; Reporting; Resistance; Role; Sampling; Testing; Therapeutic; Transplantation; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; base; cancer cell; cell type; checkpoint therapy; fecal transplantation; gut microbes; gut microbiome; gut microbiota; improved; ineffective therapies; melanoma; metagenomic sequencing; microbial; microbial community; microbial signature; microbiome; microbiome analysis; microbiota; microbiota transplantation; mouse model; novel strategies; patient response; pre-clinical; preclinical study; predictive signature; preservation; public health relevance; response; therapy resistant; tumor; tumor microenvironment

PROJECT SUMMARY Immune checkpoint inhibitors (ICI) have been successful in treating some, but not all, patients with melanoma brain metastases (MBM). Disappointingly, the same immunotherapy has largely been ineffective for the treatment of patients with glioblastoma (GBM). However, recent studies in animal models and humans have suggested that the microbe composition of the gut can positively influence the effectiveness of ICI. Our central hypothesis is that the manipulation of the GBM patient’s microbiota can improve the poor responsiveness to ICI. In the current study, we propose to compare the gut microbe composition of GBM patients to those patients with MBM that have responded favorably to ICI (Aim 1). Using cryopreserved fecal samples from these patients, we will create animals with these human microbiomes to test whether the microbe composition will enhance ICI when the animals are challenged with GBM (Aim 2). The development and use of the humanized animal models in this proposal will establish the role of the human microbiome in the action of immunotherapy. Ultimately, the elucidation as to whether certain microbial communities can enhance the effectiveness of immunotherapy will lead to the development of new approaches that include modification or transplantation of these microbe communities in patients for increased therapeutic impact.

项目概要 免疫检查点抑制剂（ICI）已成功治疗一些（但不是全部）患有 令人失望的是，同样的免疫疗法对于黑色素瘤脑转移（MBM）基本上无效。 然而，最近对动物模型和人类的研究已经证实了这一点。 表明肠道微生物组成可以对 ICI 的有效性产生积极影响。 假设是，操纵 GBM 患者的微生物群可以改善对 ICI 的不良反应。 在当前的研究中，我们建议将 GBM 患者的肠道微生物组成与患有 GBM 患者的肠道微生物组成进行比较。 我们使用来自这些患者的冷冻粪便样本，对 ICI 反应良好（目标 1）。 将创造具有这些人类微生物组的动物来测试微生物成分是否会增强 ICI 当动物受到 GBM 挑战时（目标 2）人源化动物模型的开发和使用。 该提案将最终确定人类微生物组在免疫疗法中的作用。 阐明某些微生物群落是否可以增强免疫疗法的有效性将 导致新方法的开发，包括对这些微生物进行修饰或移植 患者社区以增加治疗效果。