Biomaterials for modulating the gut microbiome for immune activation

摘要 尽管免疫检查点阻滞剂(ICBS)取得了成功，但只有少数患者对ICBS有反应。在……里面 此外，接受ICBS治疗的患者表现出较高的免疫相关不良事件(IrAEs)发生率。因此， 迫切需要强大而安全的免疫治疗组合方法。尤其是最近 研究表明，肠道微生物群在癌症患者对ICBS的应答率中起着至关重要的作用。这个 目前恢复健康肠道微生物群的方法包括口服特定的益生菌或粪便 微生物区系移植。然而，将它们开发为医药产品将是非常具有挑战性的 由于规模扩大制造和质量控制。为了应对这些挑战，我们正在开发一种新的 可以通过靶向结肠和调节肠道微生物群来改善癌症免疫治疗的技术 在原地。我们正在开发一种口服菊粉凝胶配方，它可以调节肠道微生物群并促进 强烈的抗肿瘤T细胞反应。在初步研究中，我们已经表明，我们的菊粉凝胶可以显著 在多种小鼠模型中增强抗PD-1 ICB治疗的抗肿瘤效果。在这里，我们 将应用制药学、生物工程和免疫学的多学科工具来理解 菊粉凝胶、结肠靶向、肠道微生物群和宿主免疫反应之间的结构-功能关系。 由于我们的菊粉凝胶完全基于FDA的普遍认为是安全的(GRAS)名单，我们的方法可能会提供 以安全和有效的方式增强宿主免疫反应的强大而安全和简便的策略。

ABSTRACT Despite the success of immune checkpoint blockers (ICBs), only a subset of patients responds to ICBs. In addition, patients treated with ICBs exhibit high incidences of immune-related adverse events (irAEs). Thus, there is a critical need for powerful yet safe combination approaches for immunotherapy. In particular, recent studies have shown that the gut microbiome plays a crucial role in cancer patients' response rate to ICBs. The current approaches to restore healthy gut microbiome include oral ingestion of defined probiotics or fecal microbiota transplantation. However, it will be very challenging to develop these as a pharmaceutical product due to scale-up manufacturing and quality control. To address these challenges, we are developing a new technology that can improve cancer immunotherapy by targeting the colon and modulating the gut microbiome in situ. We are developing an oral inulin-gel formulation that can modulate the gut microbiome and promote strong anti-tumor T cell response. In preliminary studies, we have shown that our inulin-gel can significantly augment the anti-tumor efficacy of anti-PD-1 ICB therapy without toxicity in multiple murine models. Here, we will apply the multidisciplinary tools of pharmaceutics, bioengineering, and immunology to understand the structure-function relationship among inulin-gel, colon-targeting, gut microbiome, and host immune responses. As our inulin-gel is entirely based on FDA's generally regarded as safe (GRAS) list, our approach may offer a powerful yet safe and facile strategy for augmenting the host immune responses in a safe and effective manner.