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: 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
• 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

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.

抽象的 有充分的证据表明黑色素瘤患者（MP）会产生针对肿瘤的免疫反应 相关抗原。然而，高频率的肿瘤抗原特异性细胞毒性 T 淋巴细胞 (CTL) 通常 不能诱导肿瘤排斥。在肿瘤诱导的免疫抑制的众多机制中， 有助于肿瘤对 CTL 反应的抵抗，现在已经确定，抑制性受体如 PD1 在抑制 T 细胞对肿瘤的反应中发挥着关键作用。因此，阻断抗 PD1 治疗 单克隆抗体已成为黑色素瘤最有效的治疗方法之一，可提供长期的临床疗效 30-40% 的高级国会议员受益。有强有力的证据表明预先存在的 CD8+ 肿瘤浸润 T 细胞 与 PD1 阻断的临床抗肿瘤反应相关。然而，并非所有 T 细胞炎症肿瘤都对 PD1 阻断并非所有黑色素瘤都会发炎。因此，支持反应或抵抗的机制 PD1 阻断仍有待精确确定。两项研究表明肠道微生物组在 调节小鼠黑色素瘤模型中 CTLA4 和 PD1 阻断的临床反应。此外，两项研究 分别在 NSCLC 和肾癌 (RC) 以及黑色素瘤患者 (MP) 中显示， 某些共生体的存在与 PD1 阻断后更好的临床结果相关。粪便微生物群 来自携带黑色素瘤的 GF 小鼠的 PD1 反应者 (PD1R) 的移植 (FMT) 显着减少了肿瘤 与 FMT 相比，PD1 无反应者 (PD1NR) 的生长情况。我们观察到增加的 与 PD1NR 相比，PD1R 粪便中某些细菌共生体的丰度较高，尽管显着 与最近发布的不同。我们的发现与最近的发现之间存在显着差异 当人们考虑到更大的复杂性和个体间的差异时，发表的研究并不完全令人惊讶。 人类肠道微生物群的变异性取决于许多宿主依赖性变量。因此至关重要 使用最先进的组学方法（宏基因组学）将这些研究扩展到更多的议员中 系统生物学评估共生细菌与临床结果之间的直接因果关系。在这里，我们 提议测试肠道微生物组是否调节免疫和临床对 PD1 阻断的反应 背景是一项从 PD1R 获得的 FMT 与 PD1NR 中的 PD1 阻断相结合的新型临床试验。这 该项目将测试以下新假设：1) PD1R 在多样性方面表现出独特的肠道微生物群特征， 与 PD1NR 相比，随时间变化的丰度和动态； 2) 单一PD1R衍生的给药 针对 PD1NR 的 FMT 联合 PD1 阻断可促进临床抗肿瘤反应； 3）发生 FMT 和 PD1 阻断治疗的 MP 的临床反应与 T 细胞对黑色素瘤的反应相关。 该提案将利用研究人员完善的跨学科专业知识 黑色素瘤、人类癌症免疫学、肠道微生物组和元组学、生物统计学和系统生物学。