Therapy with fecal microbiota transplantation and immune checkpoint blockade for solid tumors

粪便微生物群移植和免疫检查点阻断治疗实体瘤

基本信息

批准号：
10393924
负责人：
GIORGIO TRINCHIERI
金额：
$ 23.68万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-16 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393924
关键词：
Address Age Antitumor Response Applications Grants Bioinformatics CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Clinical Clinical Trials Computer Analysis Correlative Study Diet Engraftment Exhibits Funding Funding Agency Gene Expression Profile Geographic Locations Human Human Papillomavirus Immune Immunologics Immunosuppression Innate Immune Response Intake Lymphocyte Malignant Neoplasms Monoclonal Antibodies Multiomic Data Mus Mutation Myelogenous Non-Small-Cell Lung Carcinoma Organism Outcome Pathway Analysis Patients Performance Pharmaceutical Preparations Phase II Clinical Trials Progression-Free Survivals Refractory Reporting Research Proposals Resistance Role Serious Adverse Event Serum Site Solid Neoplasm T-Cell Activation T-Lymphocyte T-cell inflamed Translational Research Translations United States National Institutes of Health Universities Virus anti-CTLA4 anti-PD-1/PD-L1 anti-PD1 antibodies cancer immunotherapy clinical center cohort fecal transplantation first-in-human gut microbiome gut microbiota immune checkpoint blockade immune-related adverse events improved melanoma metabolomics microbial microbiome microbiome composition microbiota neutrophil novel novel therapeutics phase 2 study predict clinical outcome predictive marker programmed cell death ligand 1 programmed cell death protein 1 refractory cancer resistance mechanism response response biomarker sex systemic inflammatory response tumor tumor microenvironment

项目摘要

ABSTRACT Immune checkpoint blockade (ICB) with blocking anti-CTLA-4 and/or anti-PD-1/PD-L1 monoclonal antibodies (mAbs) have induced durable clinical responses in patients with solid tumors, including melanoma, non-small cell lung cancer (NSCLC), and HPV+ cancers. However, the majority of cancer patients still fail to respond to ICB, supporting the need to identify predictive biomarkers of response, and develop novel therapies to overcome the mechanisms of resistance to ICB. Multiple studies have reported that a human beneficial gut microbiome is associated with response to anti-CTLA-4 or anti-PD-1 mAbs in cancer patients. Strikingly, there is limited concordance among species identified across different studies, which included small number of patients and used different analytical approaches. In addition, the administration of certain gut commensals or responder-derived fecal microbiota transplantation (FMT) promotes efficacy of anti-CTLA-4 and anti-PD1 mAbs in melanoma-bearing mice. Reintroduction of beneficial organisms and/or fecal microbiota transplantation (FMT) from responding mice restores sensitivity to ICB in tumor-bearing mice. Responder-derived FMT resensitized melanoma patients to anti-PD1 mAbs in two separate studies. In a first-in-human phase II study, we reported that R-FMT provided clinical benefit primary refractory melanoma patients, induced rapid and durable microbiota perturbation. Bioinformatic analysis demonstrated that the FMT-induced changes of the gut microbiome in treated patients governed the observed immunological and metabolomic changes in the periphery and at tumor sites. Our novel preliminary findings in melanoma support that baseline beneficial and detrimental enterotypes predict clinical outcome and immune-related adverse events (irAEs) in PD1-treated melanoma. They also support the hypotheses that FMT exhibiting a beneficial enterotype may :1) improve clinical outcome upon ICB, and 2) impede the occurrence of serious irAEs. Whether these findings in patients with advanced melanoma are relevant to large cohorts of cancer patients with melanoma, NSCLC or HPV+ cancer in distinct geographic locations has not been determined yet. These important questions are addressed in the present translational research proposal. This collaborative project in response to PAR 18-951 between the University of Pittsburgh and the NCI will take advantage of the NIH Clinical Center's unique access to a large cohort of patients with HPV+ cancers treated with cancer immunotherapy.

抽象的使用阻断性抗 CTLA-4 和/或抗 PD-1/PD-L1 单克隆抗体进行免疫检查点阻断 (ICB) （单克隆抗体）已在实体瘤（包括黑色素瘤、非小细胞瘤）患者中诱导了持久的临床反应。细胞肺癌 (NSCLC) 和 HPV+ 癌症。然而，大多数癌症患者仍然无法应对 ICB，支持识别反应的预测生物标志物并开发新疗法的需要克服 ICB 的耐药机制。多项研究表明，人类有益的肠道微生物组与癌症患者对抗 CTLA-4 或抗 PD-1 mAb 的反应相关。引人注目的是，有不同研究中确定的物种之间的一致性有限，其中包括少量患者并使用不同的分析方法。此外，施用某些肠道共生菌或应答者源性粪便微生物群移植 (FMT) 可提高抗 CTLA-4 和抗 PD1 mAb 的功效在携带黑色素瘤的小鼠中。重新引入有益生物和/或粪便微生物群移植来自应答小鼠的 FMT（FMT）可恢复荷瘤小鼠对 ICB 的敏感性。应答者衍生的 FMT 在两项独立的研究中，黑色素瘤患者对抗 PD1 单克隆抗体重新敏感。在一项首次人体 II 期研究中，我们报道了 R-FMT 为原发性难治性黑色素瘤患者提供了临床益处，诱导快速和持久的微生物群扰动。生物信息分析表明，FMT 诱导的肠道变化治疗患者的微生物组控制着观察到的免疫学和代谢组学变化周围和肿瘤部位。我们对黑色素瘤的新颖初步发现支持基线有益且有害肠型可预测 PD1 治疗的临床结果和免疫相关不良事件 (irAE) 黑色素瘤。他们还支持这样的假设：FMT 表现出有益的肠型可能：1) 改善 ICB 的临床结果，2) 阻止严重 irAE 的发生。这些发现是否在患者身上晚期黑色素瘤与大量患有黑色素瘤、NSCLC 或 HPV+ 的癌症患者相关不同地理位置的癌症尚未确定。这些重要问题得到解决在目前的转化研究提案中。该合作项目响应 PAR 18-951 匹兹堡大学和 NCI 将利用 NIH 临床中心的独特优势来获取一大群接受癌症免疫疗法治疗的 HPV+ 癌症患者。