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.

项目摘要/摘要免疫检查点抑制剂（ICI）在各种癌症类型的长期生存中显着提高了包括黑色素瘤，非小细胞肺癌，三重阴性乳腺癌等。但是，ICI功效依靠多种癌症，宿主和环境变量，只有一小部分患者会做出反应这些抗体药物。因此，提高ICI响应能力的方法是一种高度理想的，未得到的临床需要。与人相关的微生物是宿主健康和疾病（包括癌症治疗）的关键调节剂。临床研究表明，特定的肠道细菌物种与改善ICI的患者结局相关这些活性微生物的治疗和定植可以直接引起临床前动物的抗肿瘤活性型号。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？我以前的工作表明，分泌的细菌肽聚糖水解酶足以足以在癌症的鼠模型中广泛改善了ICI治疗。而且，可以简单地概括此表型通过合成片段的共同给药，该片段模仿了肽聚糖水解酶的乘积。这些发现提出了令人兴奋的假设，即微生物代谢产物的产生可以直接改善ICI 功效。我建议的主要目的是检查细菌PG代谢产物的酶促动员癌症ICI治疗期间免疫调节的一般机制。 AIM 1将探索宿主酶作为新酶决定ICI功效的因素。 AIM 2将产生化学探针以发现ICI-Activing细菌酶。 AIM 3将研究PG动员作为一种增强新的ICI响应的广谱策略指示和针对新检查点目标。为了实现这些目标，我建立了一个广泛的和我与Linda Hsieh-Wilson博士在化学工具开发研究生研究的跨学科技能加州理工学院和我与霍华德博士一起在宿主微生物传播和癌症免疫学方面的博士后工作挂在Scripps Research。为了补充这些优势，我已经与领导者建立了合作癌症免疫疗法和宿主微生物相互作用的领域，以提供新的癌症模型系统培训并获得关键的人类衍生的孤立株，这将极大地帮助我建立一般性和 PG动员在ICI治疗期间的人类相关性。此外，我提出了全面的职业开发计划，以解决我有效管理实验室，传播的任何剩余差距我们的发现，并获得独立的资金。在K22期间获得这些技能将加剧在完成我的建议的过程中取得了进展，提供了我的第一个NCI R01所需的关键初步数据授予申请。我的科学和职业发展获得了K22奖，将帮助我实现自己的长期职业目标是成为宿主 - 微生物交集的成功独立调查员沟通和癌症免疫疗法。此外，这些努力可能会产生机械见解，并转化途径以了解和增强诊所中的差异ICI反应。