Biomaterials for modulating the gut microbiome for immune activation

摘要

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.