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

• 批准号: 10441408
• 负责人: HASSANE M ZAROUR
• 金额: $ 50.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441408
• 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; pembrolizumab; programmed cell death ligand 1; programmed cell death protein 1; receptor; reconstitution; response; sex; tumor; tumor growth; tumor immunology

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

项目成果

Facts and Hopes for Gut Microbiota Interventions in Cancer Immunotherapy.

癌症免疫疗法中肠道菌群干预措施的事实和希望。

• DOI: 10.1158/1078-0432.ccr-21-1129
• 发表时间: 2022-10-14
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research

IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma.

• DOI: 10.1158/1078-0432.ccr-20-0575
• 发表时间: 2020-10-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Chauvin JM;Ka M;Pagliano O;Menna C;Ding Q;DeBlasio R;Sanders C;Hou J;Li XY;Ferrone S;Davar D;Kirkwood JM;Johnston RJ;Korman AJ;Smyth MJ;Zarour HM
• 通讯作者: Zarour HM

Targeting novel inhibitory receptors in cancer immunotherapy.

• DOI: 10.1016/j.smim.2020.101436
• 发表时间: 2020-06
• 期刊: Seminars in immunology
• 影响因子: 7.8
• 作者: Ding QQ;Chauvin JM;Zarour HM
• 通讯作者: Zarour HM

Screening costs associated with donor selection for fecal microbiota transplantation for treatment of PD-1 refractory melanoma patients.

• DOI: 10.1097/cmr.0000000000000871
• 发表时间: 2023-04-01
• 期刊: MELANOMA RESEARCH
• 影响因子: 2.2
• 作者: Fortman, Dylan;Avellan, Maria G. Pazan;Hurd, Drew;Schwartz, Marc;Dubner, Howard;Hewitt, Corey;Berton, Samantha;Ernst, Scarlett;Rose, Amy;Wang, Hong;Zarour, Hassane;Davar, Diwakar
• 通讯作者: Davar, Diwakar