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

摘要 封闭抗CTLA-4和/或抗PD-1/PD-L1单抗的免疫检查点阻断(ICB) (单抗)在实体瘤患者中诱导持久的临床反应，包括非小黑色素瘤 细胞肺癌(NSCLC)和人乳头瘤病毒癌。然而，大多数癌症患者仍然对 ICB，支持识别预测反应的生物标记物的需要，并开发新的治疗方法 克服对ICB的抗性机制。多项研究报告称，对人类有益的肠道 微生物群与癌症患者对抗CTLA-4或抗PD-1单抗的应答有关。令人惊讶的是，在那里 在不同研究中发现的物种之间的一致性有限，其中包括少量的 并使用了不同的分析方法。此外，某些肠道共生症的管理或 应答者来源的粪便微生物区系移植(FMT)促进抗CTLA-4和抗PD1单抗的疗效 在携带黑色素瘤的小鼠身上。有益生物的重新引入和/或粪便微生物区系移植 有反应的小鼠(FMT)可恢复荷瘤小鼠对ICB的敏感性。响应者派生的FMT 在两项单独的研究中，黑色素瘤患者对抗PD1单抗重新敏感。在一项首次人类第二阶段研究中， 我们报告说，R-FMT为原发性难治性黑色素瘤患者提供了临床上的好处，诱导迅速和 持久的微生物区系扰动。生物信息学分析表明，FMT诱导的肠道变化 接受治疗的患者中的微生物组控制着观察到的免疫学和代谢学变化 在肿瘤周围和肿瘤部位。我们对黑色素瘤的新的初步发现支持基线有益和 不良肠型可预测PD1治疗后的临床结局和免疫相关不良事件 黑色素瘤。他们还支持这样的假设，即表现出有益的肠型的FMT可能会：1)改善 ICB的临床转归，以及2)阻碍严重irAEs的发生。这些发现是否在患者身上 晚期黑色素瘤与大量黑色素瘤、NSCLC或HPV癌症患者相关 不同地理位置的癌症尚未确定。这些重要的问题都得到了解决 在目前的翻译研究提案中。该合作项目响应PAR 18-951之间的 匹兹堡大学和NCI将利用NIH临床中心独特的访问方式 接受癌症免疫治疗的大量HPV癌症患者。

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.