Biomaterials for modulating the gut microbiome for immune activation

用于调节肠道微生物组以激活免疫的生物材料

• 批准号: 10614059
• 负责人: James J Moon
• 金额: $ 48.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614059
• 关键词: Address; Affect; Biocompatible Materials; Biomedical Engineering; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Cell Differentiation process; Cellular Metabolic Process; Chemosensitization; Colitis; Colon; Colorectal Cancer; Consumption; Data; Dietary Fiber; Disease; Drug Delivery Systems; Exhibits; Exposure to; Formulation; Gastrointestinal Diseases; Gastrointestinal tract structure; Gel; Goals; Human; Human Volunteers; Immune response; Immunity; Immunologic Stimulation; Immunology; Immunotherapy; In Situ; Incidence; Inflammatory Bowel Diseases; Inulin; Knowledge; Lead; Length; Mediating; Memory; Metabolic; Modeling; Mus; Nature; Oral; Oral Administration; Oral Ingestion; Patients; Pharmacologic Substance; Pharmacy (field); Play; Probiotics; Production; Property; Public Health; Quality Control; Research; Resistance; Role; Structure; Structure-Activity Relationship; Study Subject; T cell differentiation; T cell response; T-Lymphocyte; Therapeutic; Toxic effect; Translating; Volatile Fatty Acids; anti-PD-1; anti-PD1 therapy; cancer immunotherapy; cancer type; colon cancer patients; commensal microbes; drug development; efficacy evaluation; fecal transplantation; gut microbiome; gut microbiota; healthy volunteer; human subject; immune activation; immune checkpoint blockers; immune-related adverse events; improved; manufacturing scale-up; metabolomics; microbial; microbiome; mouse model; multidisciplinary; new technology; novel therapeutics; patient response; patient subsets; prebiotics; prevent; programmed cell death protein 1; stem; success; tool; tumor

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.

摘要