权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Fecal Microbiota Transplant and PD-1 blockade in Melanoma

黑色素瘤中的粪便微生物群移植和 PD-1 阻断

基本信息

批准号：
10018469
负责人：
HASSANE M ZAROUR
金额：
$ 49.85万
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：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018469
关键词：
16S ribosomal RNA sequencing Age Antitumor Response B-Lymphocytes Bacteria Bacteroides Bifidobacterium Binding Bioinformatics Biometry CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 blockade CXCR6 gene Cell Maturation Cell physiology Cells Cessation of life Clinical Clinical Trials Correlative Study Cytotoxic T-Lymphocytes Dendritic Cells Diet Etiology Evaluation Exhibits Experimental Neoplasms Failure Feces Frequencies Funding Agency Germ-Free Human Immune Immune response Immunologics Immunosuppression In Vitro Innate Immune Response Intestines Investigation Ligands Liver Metagenomics Metastatic Neoplasm to the Liver Modeling Monoclonal Antibodies Mus Non-Small-Cell Lung Carcinoma Outcome PD-1 blockade PD-1/PD-L1 Patients Pharmaceutical Preparations Play Publishing RNA Regulatory T-Lymphocyte Renal carcinoma Reporting Research Personnel Resistance Role Systems Biology T cell response T-Lymphocyte T-cell inflamed Testing Time Tumor Antigens Tumor-Infiltrating Lymphocytes United States National Institutes of Health adaptive immune response anti-CTLA4 anti-PD-1 anti-PD1 antibodies anti-PD1 therapy antitumor effect base cancer immunotherapy cohort commensal bacteria dysbiosis effector T cell exhaust experimental study fecal transplantation gut microbiome gut microbiota immune checkpoint blockade inter-individual variation melanoma microbiota profiles mouse model novel programmed cell death ligand 1 programmed cell death protein 1 receptor reconstitution response sex tumor tumor growth tumor immunology

项目摘要

Abstract There is ample evidence that melanoma patients (MPs) develop immune responses directed against tumor- associated antigens. However, high frequencies of tumor antigen-specific cytotoxic T-lymphocytes (CTL) often fail to induce tumor rejection. Among the numerous mechanisms of tumor-induced immunosuppression that contribute to the resistance of tumors to CTL responses, it is now well established that inhibitory receptors like PD1 play a critical role in dampening T cell responses to tumors. As a result, therapy with blocking anti-PD1 monoclonal antibodies has become one of the most potent therapies of melanoma, providing prolonged clinical benefits to 30-40% advanced MPs. There is strong evidence that pre-existing CD8+ tumor-infiltrating T cells correlate with clinical antitumor response to PD1 blockade. However, not all T cell-inflamed tumors respond to PD1 blockade and not all melanomas are inflamed. Hence, the mechanisms supporting response or resistance to PD1 blockade remain to be precisely determined. Two studies have shown the role of the gut microbiome in regulating clinical responses to CTLA4 and PD1 blockade in murine melanoma model. In addition, two studies in NSCLCs and renal cancers (RC), and melanoma patients (MPs), respectively, have shown that the presence of certain commensals correlated with better clinical outcome upon PD1 blockade. Fecal microbiota transplant (FMT) from PD1 responders (PD1Rs) in melanoma-bearing GF mice reduced significantly tumor growth as compared to FMT from PD1 non-responders (PD1NRs). We have observed the increased abundance of certain bacterial commensals in stools of PD1Rs as compared to PD1NRs, albeit significantly different from the ones recently published. The striking differences between our findings and the recent published study are not totally surprising when one considers the greater complexity and inter-individual variability of the human gut microbiota upon many host-dependent variables. It is therefore critically important to expand these studies in a larger number of MPs using state-of-the-art omic approach (metagenomics) and Systems Biology to evaluate the direct causality between commensal bacteria and clinical outcome. Here, we propose to test whether the gut microbiome modulates immune and clinical responses to PD1 blockade in the context a novel clinical trial with FMT obtained from PD1Rs combined with PD1 blockade in PD1NRs. This project will test the novel hypotheses that: 1) PD1Rs exhibit distinct gut microbiota profiles in terms of diversity, abundance and dynamics over time compared with PD1NRs; 2) the administration of single PD1R-derived FMT to a PD1NRs together with PD1 blockade promotes clinical antitumor response; and 3) the occurrence of clinical responses in MPs treated with FMT and PD1 blockade correlates with T cell responses to melanoma. This proposal will take advantage of the well-established and cross-disciplinary expertise of the investigators in melanoma, human cancer immunology, gut microbiome and metaomics, biostatistics, and systems biology.

摘要