Therapy with fecal microbiota transplantation and immune checkpoint blockade for solid tumors

摘要 使用阻断性抗CTLA-4和/或抗PD-1/PD-L1单克隆抗体进行免疫检查点阻断（ICB） （mAb）在实体瘤患者中诱导了持久的临床反应，包括黑色素瘤、非小细胞肺癌、 细胞肺癌（NSCLC）和HPV+癌症。然而，大多数癌症患者仍然无法对 ICB，支持需要确定反应的预测性生物标志物，并开发新的治疗方法， 克服对ICB的抗性机制。多项研究表明，人类有益的肠道 微生物组与癌症患者对抗CTLA-4或抗PD-1 mAb的应答相关。引人注目的是， 不同研究中确定的物种之间的一致性有限，其中包括少数 患者和使用不同的分析方法。此外，某些肠道刺激剂或 应答者来源的粪便微生物群移植（FMT）促进抗CTLA-4和抗PD 1 mAb的功效 在黑色素瘤小鼠中。重新引入有益生物和/或粪便微生物群移植 (FMT)恢复了荷瘤小鼠对ICB的敏感性。应答者衍生FMT 在两项独立的研究中，对黑色素瘤患者对抗PD 1 mAb重新敏感。在一项首次人体II期研究中， 我们报道了R-FMT对原发性难治性黑色素瘤患者提供了临床益处， 持久的微生物群扰动。生物信息学分析表明，FMT诱导的肠道变化 治疗患者中的微生物组控制了观察到的免疫和代谢组学变化， 外周和肿瘤部位。我们在黑色素瘤中的新的初步发现支持了基线有益和 有害肠型可预测PD 1治疗患者的临床结局和免疫相关不良事件（irAE） 黑素瘤他们还支持这样的假设，即FMT表现出有益的肠型可能：1）改善 ICB后的临床结局，和2）阻止严重irAE的发生。是否这些发现在病人 晚期黑色素瘤患者与黑色素瘤、NSCLC或HPV+癌症患者的大型队列相关 不同地理位置的癌症尚未确定。这些重要的问题得到解决 在目前的翻译研究计划中。该合作项目是为了响应PAR 18-951， 匹兹堡大学和NCI将利用NIH临床中心独特的访问权限， 接受癌症免疫疗法治疗的HPV+癌症患者的大型队列。

ABSTRACT Immune checkpoint blockade (ICB) with blocking anti-CTLA-4 and/or anti-PD-1/PD-L1 monoclonal antibodies (mAbs) have induced durable clinical responses in patients with solid tumors, including melanoma, non-small cell lung cancer (NSCLC), and HPV+ cancers. However, the majority of cancer patients still fail to respond to ICB, supporting the need to identify predictive biomarkers of response, and develop novel therapies to overcome the mechanisms of resistance to ICB. Multiple studies have reported that a human beneficial gut microbiome is associated with response to anti-CTLA-4 or anti-PD-1 mAbs in cancer patients. Strikingly, there is limited concordance among species identified across different studies, which included small number of patients and used different analytical approaches. In addition, the administration of certain gut commensals or responder-derived fecal microbiota transplantation (FMT) promotes efficacy of anti-CTLA-4 and anti-PD1 mAbs in melanoma-bearing mice. Reintroduction of beneficial organisms and/or fecal microbiota transplantation (FMT) from responding mice restores sensitivity to ICB in tumor-bearing mice. Responder-derived FMT resensitized melanoma patients to anti-PD1 mAbs in two separate studies. In a first-in-human phase II study, we reported that R-FMT provided clinical benefit primary refractory melanoma patients, induced rapid and durable microbiota perturbation. Bioinformatic analysis demonstrated that the FMT-induced changes of the gut microbiome in treated patients governed the observed immunological and metabolomic changes in the periphery and at tumor sites. Our novel preliminary findings in melanoma support that baseline beneficial and detrimental enterotypes predict clinical outcome and immune-related adverse events (irAEs) in PD1-treated melanoma. They also support the hypotheses that FMT exhibiting a beneficial enterotype may :1) improve clinical outcome upon ICB, and 2) impede the occurrence of serious irAEs. Whether these findings in patients with advanced melanoma are relevant to large cohorts of cancer patients with melanoma, NSCLC or HPV+ cancer in distinct geographic locations has not been determined yet. These important questions are addressed in the present translational research proposal. This collaborative project in response to PAR 18-951 between the University of Pittsburgh and the NCI will take advantage of the NIH Clinical Center's unique access to a large cohort of patients with HPV+ cancers treated with cancer immunotherapy.