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，但只有一部分患者对ICB有反应。在 此外，用ICB治疗的患者表现出免疫相关不良事件（irAE）的高发生率。因此，在本发明中， 迫切需要用于免疫治疗的有效而安全的组合方法。特别是最近 研究表明，肠道微生物组在癌症患者对ICB的反应率中起着至关重要的作用。的 目前恢复健康肠道微生物组的方法包括口服确定的益生菌或粪便 微生物群移植然而，将这些开发为药物产品将是非常具有挑战性的 这是由于规模扩大的制造和质量控制。为了应对这些挑战，我们正在开发一种新的 通过靶向结肠和调节肠道微生物组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糖凝胶制剂，可以调节肠道微生物组， 强烈的抗肿瘤T细胞反应。在初步的研究中，我们已经表明，我们的菊粉凝胶可以显着 增强抗PD-1 ICB疗法的抗肿瘤功效，而在多种鼠模型中无毒性。这里我们 将应用制药学，生物工程学和免疫学的多学科工具来了解 菊糖凝胶、结肠靶向、肠道微生物组和宿主免疫反应之间的结构与功能关系。 由于我们的菊糖凝胶完全基于FDA的一般认为安全（GRAS）名单，我们的方法可以提供一个 强大而安全和简便的策略，用于以安全和有效的方式增强宿主免疫应答。

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.