Key Points

• Two phase 1 clinical studies suggest that fecal microbiota transplantation (FMT) may restore sensitivity to anti–programmed cell death protein 1 (anti–PD-1) inhibition among some patients whose metastatic melanoma has persisted or progressed during treatment with anti–PD-1 drugs.
• Further investigations are needed to better identify microbial, circulating, and intratumoral biomarkers in order to select the patients most likely to benefit from fecal microbiome–based therapy of melanoma.

“Several clinical, regulatory, and scientific questions need to be addressed for this approach to become an approved treatment.”—Christopher H. Woelk, PhD, and Alexandra Snyder, MD

According to 2 recent small phase 1 trials appearing in Science (2021;371:595-602. doi:10.1126/science.abf3363; 2021;371:602-609. doi:10.1126/science.abb5920), FMT may aid in reprogramming the human gut microbiome in patients with advanced melanoma. This may result in counteracting resistance to anti–PD-1 immunotherapy.

Several observational studies suggested an association between the gut microbiome of patients with metastatic melanoma and their responses to immune checkpoint inhibitor (CPI) therapies. Although it had also been shown that gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy in preclinical mouse models, FMT had not previously been studied in clinical trials of human patients whose melanoma had persisted or progressed after anti–PD-1 immunotherapy.

One of the studies included 7 FMT donors and 15 recipients from the Department of Medicine at the University of Pittsburgh Hillman Medical Center (UPMC) in Pittsburgh, Pennsylvania, and the National Institutes of Health Clinical Center in Bethesda, Maryland. The second trial included 2 FMT donors and 10 recipients from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel-HaShomer, Israel. All FMT donors were patients with metastatic melanoma who had responded to anti–PD-1 immunotherapy. Both of the Israeli donors had a complete response (CR), whereas the Pittsburgh donors included 4 with a CR and 3 with a partial response (PR); the researchers hypothesized that their gut microbiomes had been a factor in these favorable outcomes and, therefore, might be of benefit to recipients who had been resistant to similar treatments.

The FMT protocol in both studies included an initial native microbiota depletion regimen, which consisted of vancomycin and neomycin. Patients then underwent FMT via colonoscopy and oral stool capsules, which were followed by re-induction of nivolumab anti–PD-1 therapy (in the Israeli study), or FMT via colonoscopy only, which was followed by pembrolizumab (in the Pittsburgh study).

Study Results

The outcomes of the 15 FMT recipients in the Pittsburgh study included 3 recipients with a PR and 3 with stable disease. Similar results were found for the 10 FMT recipients in the Israeli study: 1 CR and 2 PRs. Both research teams concluded that their findings suggest that FMT is safe and that altering the mix of bacteria in the gut microbiome can enhance the efficacy of immunotherapy in a subset of patients.

According to University of Pittsburgh senior study author Hassane M. Zarour, MD, professor of medicine, immunology, and dermatology, coleader of the melanoma program at the Department of Medicine and UPMC Hillman Cancer Center, and James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at the University of Pittsburgh, this research provides “proof of principle in patients with melanoma that demonstrates that we can manipulate the microbiome to augment and improve immunotherapy effectiveness by reprogramming the tumor microenvironment and overcoming resistance to anti–PD-1 in advanced melanoma.”

Dr. Zarour and his team also found that some PD-1–refractory patients may not respond to FMT for reasons that may include an inability to respond to the tumor, regardless of the microbiota composition, because of the patient's immune-deficient status or possibly because of the lack of tumor immunogenicity. These researchers further wrote that there might also be an absence of bacterial taxa needed for anti–PD-1 therapy effectiveness in the FMT preparations, or there might be “failure of the FMT to successfully implant into the recipient and induce perturbations of host microbiota favoring anti–PD-1.”

In the Israeli study, the researchers observed clinical responses in 3 patients, including 2 PRs and 1 CR.

In addition to observing clinical antitumor responses, both teams conducted a wide variety of molecular tests supporting the hypothesis that FMT altered the gut microbiome of some patients, which influenced the composition of their gut-associated immune cells, and the composition of their tumor-infiltrating immune cells.

“Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment,” wrote lead investigator Erez Baruch, MD, PhD, who is currently a resident in internal medicine, physician–scientist pathway at UTHealth Houston, Texas.

Study Relevance

In a commentary accompanying both studies, Christopher H. Woelk, PhD, head of systems biology at Merck & Co's Exploratory Science Center in Cambridge, Massachusetts, and Alexandra Snyder, MD, head of the translational oncology and diagnostics leadership team and global clinical development at Merck & Co in Rahway, New Jersey, agreed that there is a possible therapeutic effect of FMT in CPI-treated patients according to these studies. “However, several clinical, regulatory, and scientific questions need to be addressed for this approach to become an approved treatment. Also, larger studies in a defined post-CPI population are needed to show FMT efficacy,” they wrote.

Dr. Baruch cautions, “At the moment, due to its complexity and associated risks if done improperly, microbiota modulation should remain in the highly monitored environment of clinical trials.”

Dr. Zarour from the University of Pittsburgh study agrees. He says that he is frequently asked if he thought that the results from this small group of patients would hold true with a larger group of patients. “I tell them we don't know, and finding funding for these trials is difficult. This is just a proof of principle, and we don't want to overstate the data since only 6 out of 15 patients had a favorable outcome. We believe further investigations are needed to better identify microbial, circulating, and intra-tumoral biomarkers in order to select patients most likely to benefit from microbiome-based therapy of melanoma.”

Dr. Baruch also points out how previous observational studies comparing gut microbiota of immunotherapy responders and nonresponders led to these 2 clinical trials. “This study was an example of how profiling the differences between responders and non-responders to a specific therapy can lead to the development of new therapies in only a few years.”

In their editorial, Dr. Woelk and Dr. Snyder also state, “Future work is needed to better understand which response profiles for sourcing donor FMT, engraftment procedures, and recipient phenotypes are required for successful CPI-FMT combination therapy.”

中文翻译：

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粪便微生物群移植可能有助于黑色素瘤免疫治疗抵抗

关键点

• 两项 1 期临床研究表明，粪便微生物群移植 (FMT) 可能会在一些转移性黑色素瘤在抗 PD-1 治疗期间持续存在或进展的患者中恢复对抗程序性细胞死亡蛋白 1（抗 PD-1）抑制的敏感性药物。
• 需要进一步研究以更好地识别微生物、循环和肿瘤内生物标志物，以选择最有可能从基于粪便微生物组的黑色素瘤治疗中受益的患者。

“要使这种方法成为一种获得批准的治疗方法，需要解决几个临床、监管和科学问题。”——Christopher H. Woelk 博士和 Alexandra Snyder 医学博士

根据最近发表在Science (2021;371:595-602.doi:10.1126/science.abf3363;2021;371:602-609.doi:10.1126/science.abb5920)上的 2 项小型 1 期试验，FMT 可能有助于重新编程晚期黑色素瘤患者的人体肠道微生物组。这可能会导致对抗 PD-1 免疫疗法的抵抗。

几项观察性研究表明，转移性黑色素瘤患者的肠道微生物组与其对免疫检查点抑制剂 (CPI) 疗法的反应之间存在关联。尽管在临床前小鼠模型中，肠道微生物群也可以影响肿瘤对抗 PD-1 免疫疗法的反应，但之前尚未在抗 PD-1 治疗后黑色素瘤持续或进展的人类患者的临床试验中研究 FMT。 1 免疫治疗。

其中一项研究包括来自宾夕法尼亚州匹兹堡匹兹堡大学希尔曼医学中心 (UPMC) 医学系和马里兰州贝塞斯达国立卫生研究院临床中心的 7 名 FMT 捐赠者和 15 名接受者。第二项试验包括来自以色列 Tel-HaShomer 的 Sheba 医疗中心的 Ella Lemelbaum 免疫肿瘤研究所的 2 名 FMT 捐赠者和 10 名接受者。所有 FMT 供体都是对抗 PD-1 免疫疗法有反应的转移性黑色素瘤患者。两名以色列捐赠者均获得完全缓解 (CR)，而匹兹堡捐赠者包括 4 名获得 CR 和 3 名获得部分缓解 (PR)；研究人员假设他们的肠道微生物组是这些有利结果的一个因素，因此，可能对对类似治疗有抵抗力的接受者有益。

两项研究中的 FMT 方案包括初始天然微生物群耗竭方案，其中包括万古霉素和新霉素。然后患者通过结肠镜检查和口服粪便胶囊接受 FMT，然后重新诱导 nivolumab 抗 PD-1 治疗（在以色列研究中），或仅通过结肠镜检查进行 FMT，然后是 pembrolizumab（在匹兹堡研究中） .

研究结果

匹兹堡研究中 15 名 FMT 接受者的结果包括 3 名 PR 和 3 名病情稳定。以色列研究中的 10 名 FMT 接受者也发现了类似的结果：1 名 CR 和 2 名 PR。两个研究小组都得出结论，他们的研究结果表明 FMT 是安全的，并且改变肠道微生物组中的细菌组合可以提高免疫疗法在一部分患者中的疗效。

匹兹堡大学高级研究作者 Hassane M. Zarour 医学博士、医学、免疫学和皮肤病学教授、医学系和 UPMC Hillman 癌症中心黑色素瘤项目的共同负责人，以及 James W. 和 Frances G. McGlothlin 主席表示在匹兹堡大学的黑色素瘤免疫治疗研究中，这项研究提供了“黑色素瘤患者的原理证明，表明我们可以通过重新编程肿瘤微环境和克服对抗 PD-1 的抗性来操纵微生物组来增强和提高免疫治疗效果。晚期黑色素瘤。”

Zarour 博士和他的团队还发现，一些 PD-1 难治性患者可能对 FMT 没有反应，原因可能包括无法对肿瘤做出反应，无论微生物群组成如何，因为患者的免疫缺陷状态或可能因为缺乏肿瘤免疫原性。这些研究人员进一步写道，FMT 制剂中也可能缺乏抗 PD-1 治疗有效性所需的细菌分类群，或者“FMT 未能成功植入受体并诱导宿主微生物群的扰动，有利于抗 PD-1。”

在以色列的研究中，研究人员观察了 3 名患者的临床反应，包括 2 名 PR 和 1 名 CR。

除了观察临床抗肿瘤反应外，两个团队还进行了广泛的分子测试，支持 FMT 改变了一些患者的肠道微生物组的假设，这影响了他们肠道相关免疫细胞的组成，以及他们的肿瘤浸润细胞的组成。免疫细胞。

“值得注意的是，FMT 治疗与肠道固有层和肿瘤微环境中免疫细胞浸润和基因表达谱的有利变化有关，”首席研究员 Erez Baruch 医学博士写道，他目前是内科住院医师，德克萨斯州休斯顿 UTHealth 的医师-科学家途径。

学习相关性

在伴随这两项研究的评论中，默克公司位于马萨诸塞州剑桥市的探索科学中心的系统生物学负责人 Christopher H. Woelk 博士和医学博士，医学博士，转化肿瘤学和诊断领导团队和全球临床开发负责人新泽西州拉威市的默克公司同意，根据这些研究，FMT 可能对接受 CPI 治疗的患者产生治疗效果。“然而，要使这种方法成为批准的治疗方法，还需要解决几个临床、监管和科学问题。此外，需要在特定的 CPI 后人群中进行更大规模的研究来证明 FMT 的功效，”他们写道。

Baruch 博士警告说：“目前，由于其复杂性和相关风险，如果操作不当，微生物群调节应保持在临床试验的高度监控环境中。”

匹兹堡大学研究的 Zarour 博士对此表示同意。他说，他经常被问到他是否认为这一小组患者的结果适用于更多的患者。“我告诉他们我们不知道，而且很难为这些试验找到资金。这只是一个原则证明，我们不想夸大数据，因为 15 名患者中只有 6 名获得了良好的结果。我们认为需要进一步研究以更好地识别微生物、循环和肿瘤内生物标志物，以便选择最有可能从基于微生物组的黑色素瘤治疗中受益的患者。”

Baruch 博士还指出，之前比较免疫治疗应答者和非应答者肠道微生物群的观察性研究是如何导致这 2 项临床试验的。“这项研究是一个例子，说明对特定疗法有反应者和无反应者之间的差异如何在短短几年内导致新疗法的开发。”

Woelk 博士和 Snyder 博士在他们的社论中还指出，“未来的工作需要更好地了解采购供体 FMT、植入程序和受体表型的哪些反应谱是成功的 CPI-FMT 联合治疗所必需的。”