Augmenting cancer checkpoint immunotherapies via microbially-derived metabolites

通过微生物衍生的代谢物增强癌症检查点免疫疗法

基本信息

批准号：
10506732
负责人：
Matthew Everett Griffin
金额：
$ 19.8万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10506732
关键词：
Acetylmuramyl-Alanyl-Isoglutamine Address Affinity Animal Model Antibodies Antigens Applications Grants Bacteria Biochemical Biological Models CD47 gene Cancer Model Cancer Patient Caring Cell Wall Cells Chemicals Chemosensitization Clinic Clinical Clinical Research Collaborations Communication Complement Data Development Plans Disease Drug Targeting Eligibility Determination Endopeptidases Enterococcus Environment Enzymes Foundations Funding Genetic Glycopeptides Glycoside Hydrolases Goals Health Human Hydrolase Hydrolysis Immune Immune checkpoint inhibitor Immune response Immunity Immunologics Immunotherapy Intrinsic factor K22 Award KPC model Knock-out Laboratories Malignant Neoplasms Mediating Methods Microbe Modeling Molecular Muramidase Myelogenous N-Acetylmuramoyl-L-alanine Amidase Non-Small-Cell Lung Carcinoma Orthologous Gene Outcome PTPRC gene Patient-Focused Outcomes Patients Pattern Peptidoglycan Phagocytosis Pharmaceutical Preparations Phenotype Polysaccharides Population Postdoctoral Fellow Probiotics Production Proteins Reporter Research Research Personnel Residual state Role Science Signal Transduction T-Cell Activation Tissues Training Work antimicrobial antimicrobial peptide cancer immunotherapy cancer therapy cancer type career career development checkpoint therapy chemoproteomics experimental study gastrointestinal epithelium gut microbiota host-microbe interactions immune checkpoint blockade immunoregulation improved in vivo Model insight melanoma member microbial microbial colonization microbial host microorganism mouse model next generation oral supplementation pancreatic ductal adenocarcinoma model patient response patient subsets pre-clinical precision oncology rapid test response skill acquisition skills small molecule synergism targeted treatment therapy outcome tool tool development transgene expression triple-negative invasive breast carcinoma tumor tumor immunology

项目摘要

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) have significantly improved long-term survival across diverse cancer types including melanoma, non-small cell lung cancer, triple negative breast cancer, and others. However, ICI efficacy relies on multiple cancer, host, and environmental variables, and only a small fraction of patients will respond to these antibody drugs. Methods to improve ICI responsiveness are therefore a highly desirable, unmet clinical need. Human-associated microbes are critical regulators of host health and disease including cancer treatment. Clinical studies have shown that specific gut bacterial species correlate with improved patient outcomes of ICI therapy, and colonization by these active microbes can directly elicit antitumor activity in preclinical animal models. These observations raise a fundamental question: what are the microbial mechanisms that dictate ICI efficacy? My previous work has demonstrated that a secreted bacterial peptidoglycan hydrolase is sufficient to broadly improve ICI therapy in murine models of cancer. Moreover, this phenotype could be recapitulated simply by coadministration of a synthetic fragment that mimics the product of the peptidoglycan hydrolase. These findings raise the exciting hypothesis that the production of microbial metabolites can directly improve ICI efficacy. The main objective of my proposal is to examine enzymatic mobilization of bacterial PG metabolites as a general mechanism of immune modulation during cancer ICI therapy. Aim 1 will explore host enzymes as new factors that determine ICI efficacy. Aim 2 will produce chemical probes to discover ICI-activating bacterial enzymes. Aim 3 will examine PG mobilization as a broad-spectrum strategy to potentiate ICI response in new indications and against new checkpoint targets. To accomplish these goals, I have built a broad and interdisciplinary skill set from my graduate work in chemical tool development with Dr. Linda Hsieh-Wilson at Caltech and my postdoctoral work in host-microbial communication and cancer immunology with Dr. Howard Hang at Scripps Research. To complement these strengths, I have established collaborations with leaders in the fields of cancer immunotherapy and host-microbial interactions to provide training in new cancer model systems and access to critical human-derived isolates, which will greatly aid in my efforts to establish the generality and human relevance of PG mobilization during ICI treatment. In addition, I have proposed a comprehensive career development plan to address any residual gaps in my abilities to effectively manage a laboratory, disseminate our findings, and obtain independent funding. The acquisition of these skills during the K22 period will fuel progress towards the completion of my proposal, providing key preliminary data needed for my first NCI R01 grant application. My scientific and career development enabled by the K22 award will help me to achieve my long-term career goal to become a successful independent investigator at the intersection of host-microbial communication and cancer immunotherapy. Moreover, these efforts may yield mechanistic insights and translational avenues to understand and augment differential ICI responses in the clinic.

项目概要/摘要免疫检查点抑制剂 (ICIs) 显着改善了多种癌症类型的长期生存率包括黑色素瘤、非小细胞肺癌、三阴性乳腺癌等。然而，ICI 疗效依赖于多种癌症、宿主和环境变量，只有一小部分患者会对这些抗体药物。因此，提高 ICI 反应性的方法是非常理想的、尚未满足的临床方法。需要。与人类相关的微生物是宿主健康和疾病（包括癌症治疗）的关键调节因子。临床研究表明，特定的肠道细菌种类与 ICI 患者预后的改善相关这些活性微生物的治疗和定植可以直接在临床前动物中引发抗肿瘤活性模型。这些观察结果提出了一个基本问题：决定 ICI 的微生物机制是什么？功效？我之前的工作已经证明，分泌的细菌肽聚糖水解酶足以广泛改善小鼠癌症模型中的 ICI 治疗。此外，这种表型可以简单地概括通过共同施用模拟肽聚糖水解酶产物的合成片段。这些研究结果提出了一个令人兴奋的假设：微生物代谢产物的产生可以直接改善 ICI 功效。我的建议的主要目的是检查细菌 PG 代谢物的酶促动员癌症 ICI 治疗期间免疫调节的一般机制。目标 1 将探索新的宿主酶决定 ICI 疗效的因素目标 2 将生产化学探针来发现 ICI 激活细菌酶。目标 3 将研究 PG 动员作为一种广谱策略，以增强新的 ICI 反应迹象并针对新的检查点目标。为了实现这些目标，我建立了一个广泛且我与 Linda Hsieh-Wilson 博士一起从事化学工具开发的研究生工作中获得了跨学科技能加州理工学院和我与霍华德博士一起从事宿主微生物通讯和癌症免疫学方面的博士后工作挂在斯克里普斯研究中心。为了补充这些优势，我与以下领域的领导者建立了合作关系：癌症免疫治疗和宿主-微生物相互作用领域，提供新癌症模型系统的培训以及获得关键的人类来源的分离株，这将极大地帮助我努力建立普遍性和 ICI 治疗期间 PG 动员的人类相关性。另外，我还提出了一个全面的职业生涯制定计划，以解决我有效管理实验室、传播能力方面的任何剩余差距我们的研究结果，并获得独立的资助。在K22期间获得这些技能将有助于完成我的提案的进展，为我的第一个 NCI R01 提供了所需的关键初步数据拨款申请。 K22 奖促进了我的科学和职业发展，将帮助我实现我的目标长期职业目标是成为宿主-微生物交叉点上成功的独立研究者沟通和癌症免疫治疗。此外，这些努力可能会产生机械见解和理解和增强临床中差异 ICI 反应的转化途径。