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: 10196995
• 负责人: HASSANE M ZAROUR
• 金额: $ 57.38万
• 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/10196995
• 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.

抽象的 有充分的证据表明，黑色素瘤患者（MPS）会产生针对肿瘤的免疫反应 相关抗原。但是，肿瘤抗原特异性细胞毒性T淋巴细胞（CTL）的高频 无法诱导肿瘤排斥。在肿瘤诱导的免疫抑制的众多机制中 有助于肿瘤对CTL反应的抗性，现在已经确定了抑制性受体这样的受体 PD1在抑制T细胞对肿瘤的反应中起关键作用。结果，阻断抗PD1的治疗 单克隆抗体已成为黑色素瘤最有效的疗法之一，可延长临床 30-40％高级议员的好处。有强有力的证据表明，现有的CD8+肿瘤浸润T细胞 与对PD1阻滞的临床抗肿瘤反应相关。但是，并非所有T细胞增添肿瘤都对 PD1封锁而不是所有黑色素瘤发炎。因此，支持反应或抗性的机制 pd1封锁仍然需要精确确定。两项研究表明肠道微生物组在 调节鼠类黑色素瘤模型中对CTLA4和PD1阻滞的临床反应。另外，两项研究 在NSCLC和肾脏癌（RC）和黑色素瘤患者（MPS）中，已表明 某些共生的存在与PD1阻滞后更好的临床结果相关。粪便菌群 来自黑色素瘤GF小鼠的PD1响应者（PD1R）的移植（FMT）可显着减少肿瘤 与PD1非反应器（PD1NR）的FMT相比，增长。我们观察到增加 与PD1NR相比 与最近出版的内容不同。我们的发现与最近的发现之间的差异 当人们认为更大的复杂性和个体间时，已发表的研究并不完全奇怪 人类肠道微生物群在许多宿主依赖变量上的变异性。因此至关重要 使用最先进的OMIC方法（宏基因组学）和 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 建议测试肠道微生物组是否调节免疫和对PD1阻滞的临床反应 上下文是一项从PD1RS获得的FMT的新型临床试验，结合了PD1NR中的PD1阻滞。这 项目将测试以下新假设：1）PD1RS在多样性方面表现出不同的肠道菌群谱。 与PD1NR相比，随着时间的流逝的丰度和动力学； 2）单个PD1R衍生的给药 fmt与PD1NR一起与PD1阻滞剂一起促进临床抗肿瘤反应。 3）发生 用FMT和PD1阻滞处理的MPS的临床反应与T细胞对黑色素瘤的反应有关。 该建议将利用调查人员在 黑色素瘤，人类癌症免疫学，肠道微生物组和元理论，生物统计学和系统生物学。