Biomaterials for modulating the gut microbiome for immune activation

摘要 尽管免疫检查点阻断剂 (ICB) 取得了成功，但只有一小部分患者对 ICB 产生反应。在 此外，接受 ICB 治疗的患者免疫相关不良事件 (irAE) 的发生率很高。因此， 迫切需要强大而安全的免疫治疗组合方法。特别是最近 研究表明，肠道微生物组在癌症患者对 ICB 的反应率中发挥着至关重要的作用。的 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 微生物群移植。然而，将它们开发为药品将非常具有挑战性 由于规模化生产和质量控制。为了应对这些挑战，我们正在开发一种新的 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 原地。我们正在开发一种口服菊粉凝胶制剂，可以调节肠道微生物组并促进 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着 在多种小鼠模型中增强抗 PD-1 ICB 疗法的抗肿瘤功效，且无毒性。在这里，我们 将应用药剂学、生物工程和免疫学的多学科工具来了解 菊粉凝胶、结肠靶向、肠道微生物组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 的普遍认为安全 (GRAS) 列表，因此我们的方法可能会提供 强大而安全且简便的策略，以安全有效的方式增强宿主免疫反应。

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.