Transplanting Unique Human Microbiomes to Improve Immunotherapy in Glioblastoma

项目摘要 免疫检查点抑制剂（ICI）已经成功地治疗了一些，但不是全部， 黑色素瘤脑转移瘤（MBM）。令人不安的是，同样的免疫疗法在很大程度上对 胶质母细胞瘤（GBM）患者的治疗。然而，最近在动物模型和人类中的研究 表明肠道的微生物组成可以积极影响ICI的有效性。我们的中央 一个假设是，GBM患者的微生物群的操纵可以改善对ICI的不良反应性。 在目前的研究中，我们建议将GBM患者的肠道微生物组成与GBM患者的肠道微生物组成进行比较。 MBM对ICI反应良好（目标1）。使用这些患者的冷冻保存的粪便样本，我们 将创造具有这些人类微生物组的动物，以测试微生物组合物是否会增强ICI 当用GBM攻击动物时（目的2）。人源化动物模型的开发与应用 在这项提案中，将确定人类微生物组在免疫疗法中的作用。最终 阐明某些微生物群落是否可以增强免疫疗法的有效性， 导致包括修饰或移植这些微生物的新方法的发展 患者社区，以增加治疗效果。

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.