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

• 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
• 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

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.

项目总结/摘要 免疫检查点抑制剂（ICI）显著改善了各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，改善ICI反应性的方法是高度期望的、未满足的临床需求。 需要的与人类相关的微生物是宿主健康和疾病（包括癌症治疗）的关键调节剂。 临床研究表明，特定的肠道细菌种类与ICI患者结局的改善相关 这些活性微生物的治疗和定殖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根本性的问题：决定ICI的微生物机制是什么 功效？我以前的工作已经证明，分泌的细菌肽聚糖水解酶足以 广泛地改善了小鼠癌症模型中的ICI疗法。此外，这种表型可以简单地概括为 通过共同施用模拟肽聚糖水解酶产物的合成片段。这些 这些发现提出了一个令人兴奋的假设，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。目的1将探索宿主酶作为新的 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 内切酶目标3将研究PG动员作为一种广谱策略，以加强新的ICI反应。 并针对新的检查点目标。为了实现这些目标，我建立了一个广泛的， 从我毕业时与琳达Hsieh-Wilson博士在化学工具开发方面的工作中获得的跨学科技能， 加州理工学院和我的博士后工作在宿主微生物通讯和癌症免疫学与博士霍华德 在Scripps Research工作。为了补充这些优势，我与以下领域的领导人建立了合作关系： 癌症免疫治疗和宿主-微生物相互作用领域，以提供新癌症模型系统的培训 和获得关键的人源性分离物，这将大大有助于我建立普遍性的努力， ICI治疗期间PG动员的人体相关性。此外，我还提出了全面的职业生涯 发展计划，以解决我在有效管理实验室、传播 我们的研究结果，并获得独立的资金。在K22期间获得这些技能将推动 完成我的提案的进展，提供我的第一个NCI R 01所需的关键初步数据 补助金申请K22奖所带来的科学和职业发展将帮助我实现我的目标。 长期的职业目标是成为一个成功的独立研究者在宿主微生物的交叉点 沟通和癌症免疫治疗。此外，这些努力可能会产生机械的见解， 翻译途径，以了解和增强差异ICI反应在临床上。