Transplanting Unique Human Microbiomes to Improve Immunotherapy in Glioblastoma

项目总结 免疫检查点抑制剂(ICI)已经成功地治疗了一些，但不是所有的患者 黑色素瘤脑转移(MBM)。令人失望的是，同样的免疫疗法很大程度上对 胶质母细胞瘤(GBM)的治疗然而，最近在动物模型和人类中的研究已经 提示肠道微生物组成对ICI的疗效有积极影响。我们的中央 假说是，操纵GBM患者的微生物区系可以改善对ICI的不良反应。 在目前的研究中，我们建议比较GBM患者和那些患有BM的患者的肠道微生物组成。 对ICI反应良好的MBM(目标1)。使用这些患者的冷冻粪便样本，我们 将创造出具有这些人类微生物群的动物，以测试微生物组成是否会增强ICI 当动物接受GBM挑战时(目标2)。人性化动物模型的开发与应用 在这项提案中将确立人类微生物群在免疫治疗中的作用。归根结底， 澄清某些微生物群落是否可以增强免疫治疗的有效性将 导致新方法的发展，包括对这些微生物的修饰或移植 社区对患者的治疗效果增加。

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.