Dissecting the Gut Microbiota for Immune Checkpoint Blockade (ICB) - Resisting Microbes and Exploring the Generalizability of Microbiota-ICB Studies

解剖肠道微生物群以进行免疫检查点封锁 (ICB) - 抵抗微生物并探索微生物群-ICB 研究的普遍性

• 批准号: 10359703
• 负责人: Joan Shang
• 金额: $ 4.66万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359703
• 关键词: Animals; Applications Grants; Attenuated; Automobile Driving; Bacteria; Cancer Model; Cancer Patient; Clinical; Clinical Research; Clinical Trials; Colorectal Cancer; Communities; Consensus; Data; Disease; Exhibits; Failure; Flow Cytometry; Future; Germ-Free; Gnotobiotic; Goals; Grant; Health; Hematologic Neoplasms; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologics; Immunotherapy; Individual; Intervention; Investigation; Knowledge; Laboratory Finding; Light; Link; MC38; Malignant Neoplasms; Measures; Methods; Microbe; Minority; Modeling; Mus; Myeloid Cells; Natural Immunity; Outcome; Patients; Phase; Play; Population; Reporting; Research; Research Personnel; Role; Solid; Standardization; T-Lymphocyte; Therapeutic; Treatment Efficacy; Work; Xenograft procedure; adaptive immunity; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD-L1 therapy; base; cancer care; cancer therapy; cancer type; draining lymph node; dysbiosis; experimental study; fecal transplantation; fighting; gut microbiota; human microbiota; immune checkpoint blockade; improved; insight; interest; melanoma; microbial; microbial community; microbiome; microbiome research; microbiota; mouse model; novel; patient response; responders and non-responders; response; stool sample; targeted treatment; treatment response; trend; tumor; tumor growth; tumor xenograft

PROJECT SUMMARY Immune checkpoint blockade (ICB) has yielded durable tumor regression and stabilized disease in 10-30% of patients for a range of solid and hematological malignancies. While its promising results have revolutionized cancer care, much work is needed to expand ICBs' benefit to a greater number of cancer patients. Various studies have highlighted the microbiota's impact on the innate and adaptive immunity and its potential role as a modifiable target to improve ICB response rates. Dysbiosis and decreased gut microbial diversity have been linked to poorer outcomes in patients receiving ICB. In two ongoing clinical trials, preliminary results of fecal microbiota transplantation of an ICB-responsive patient's microbiota into an ICB-non-responsive patient exhibit restored clinical response. Additionally, enrichment of specific bacteria has been identified in both mice and human that respond to checkpoint blockade. This unexpected link between the microbiome and cancer holds a promising opportunity to enhance cancer treatment by modifying the patient's microbiota. While there are a growing number of studies on microbiota-ICB interactions, mechanisms through which the microbiota modulates immune responses to cancer and cancer treatment remains unknown. To better understand the microbiota's contribution to immune activity and ICB treatment, I have established a gnotobiotic model of anti- PD-L1 treated melanoma. I have demonstrated and standardized methods to evaluate how a defined microbial community can inhibit B16 melanoma response to anti-PD-L1, and I have begun fractionating non-responder communities to identify and characterize effector species driving response failure. This grant aims to understand the robustness of ICB-microbiota interactions across different cancer types and tumor models, identify and characterize the first bacteria to drive non-response to anti-PD-L1 and explore potential mechanisms of non-response. Aim 1 – Based on preliminary data, I have selected two mice SPF microbiotas and two defined human microbiotas that exhibit contrasting tumor growth response rates to anti- PD-L1 when colonized into germfree, B16 melanoma-bearing mice. I aim to understand the robustness and generalizability of microbiome-immunotherapy findings across tumor types and ICBs by exploring tumor growth differences following checkpoint blockade therapy (anti-PD-L1, anti-PD-1, and anti-CTLA-4). Aim 2 – Based on previous lab findings that at baseline, germ free mice respond to anti-PDL1, we anticipate that there exists one or more effector species in each non-responder community that drives non-response to anti-PD-L1. To strategically elucidate the causative bacterial strains, I will fractionate each NR microbiota into orthogonal sub-communities, colonize germ-free mice, evaluate tumor growth trends, and analyze myeloid and T-cell populations in tumors and draining lymph nodes. By studying these gnotobiotic animals with different clinical responses to ICB, we hope to uncover the effector species that attenuate checkpoint blockade response, elucidate mechanisms, and identify novel avenues to modify the microbiota to improve cancer outcomes.

项目摘要 免疫检查点阻断（ICB）在10-30%的患者中产生了持久的肿瘤消退和稳定的疾病。 患者的一系列实体和血液恶性肿瘤。虽然其有前途的结果已经彻底改变了 尽管ICB在癌症治疗方面发挥了重要作用，但仍需要开展大量工作，以扩大ICB对更多癌症患者的益处。各种 研究强调了微生物群对先天性和适应性免疫的影响，以及其作为一种免疫系统的潜在作用。 可修改的目标，以提高国际协调机构的答复率。生态失调和肠道微生物多样性下降已经成为 与接受ICB的患者的不良结局相关。在两个正在进行的临床试验中，粪便的初步结果 将ICB响应患者的微生物群移植到ICB非响应患者中的方法 恢复临床反应。此外，在小鼠和小鼠中已经鉴定出特定细菌的富集， 对检查站封锁作出反应人。微生物组和癌症之间的这种意想不到的联系， 这是通过改变患者的微生物群来增强癌症治疗的有希望的机会。虽然有 越来越多的关于微生物-ICB相互作用的研究，通过这些机制，微生物 调节对癌症的免疫应答，并且癌症治疗仍然未知。更好地了解 微生物群对免疫活性和ICB治疗的贡献，我已经建立了一个抗- PD-L1治疗黑色素瘤。我已经证明和标准化的方法，以评估如何确定的微生物 社区可以抑制B16黑色素瘤对抗PD-L1的反应，我已经开始对无反应者进行分级 社区，以确定和表征驱动响应失败的效应物种。该补助金旨在 了解ICB-微生物群相互作用在不同癌症类型和肿瘤中的稳健性 模型，识别和表征第一个驱动抗PD-L1无应答的细菌，并探索 潜在的无反应机制。目的1 -根据初步数据，我选择了两只SPF小鼠， 微生物群和两种确定的人类微生物群，对抗- PD-L1在无菌、B16黑色素瘤荷瘤小鼠中定殖时。我的目标是了解鲁棒性， 通过探索肿瘤，微生物群免疫治疗结果在肿瘤类型和ICB中的普遍性 检查点阻断治疗（抗PD-L1、抗PD-1和抗CTLA-4）后的生长差异。目标2 - 基于先前的实验室发现，在基线时，无菌小鼠对抗PDL 1有反应，我们预计， 在每一个无反应群落中存在一个或多个效应物种， 抗PD-L1抗体为了从战略上阐明致病菌株，我将对每个NR微生物群进行分类， 分成正交亚群落，在无菌小鼠中定殖，评估肿瘤生长趋势，并分析骨髓 以及肿瘤和引流淋巴结中的T细胞群。通过研究这些生物， ICB的不同临床反应，我们希望揭示减弱检查点阻断的效应物种类， 反应，阐明机制，并确定新的途径来修改微生物群，以改善癌症 结果。