Intestinal Microbiome Associated With Immune-Related Adverse Events for Patients Treated With Anti-PD-1 Inhibitors, a Real-World Study

Wenhui Liu,Jianquan Luo,Bao Sun,Haoneng Tang,Huiqing Chen,Zhiying Luo,Yiping Liu,Fang Ma

doi:10.3389/fimmu.2021.756872

Abstract

AimImmune checkpoint inhibitors (ICIs) have updated the treatment landscape for patients with advanced malignancies, while their clinical prospect was hindered by severe immune-related adverse events (irAEs). The aim of this study was to research the association between gut microbiome diversity and the occurrence of ICI-induced irAEs.Patients and MethodWe prospectively obtained the baseline fecal samples and clinical data from patients treated with anti-PD-1 inhibitors as monotherapy or in combination with chemotherapy or antiangiogenesis regardless of treatment lines. The 16S rRNA V3-V4 sequencing was used to test the gene amplicons of fecal samples. The development of irAEs was evaluated and monitored from the beginning of therapy based on CTCAE V5.01.ResultsA total of 150 patients were included in the study and followed up for at least 6 months. A total of 90 (60%) patients developed at least one type of adverse effect, among which mild irAEs (grades 1–2) occurred in 65 patients (72.22%) and severe irAEs (grades 3–5) in 25 patients (27.78%). Patients with severe irAEs showed a visible higher abundance of Streptococcus, Paecalibacterium, and Stenotrophomonas, and patients with mild irAEs had a higher abundance of Faecalibacterium and unidentified_Lachnospiraceae. With the aid of a classification model constructed with 5 microbial biomarkers, patients without irAEs were successfully distinguished from those with severe irAEs (AUC value was 0.66).ConclusionCertain intestinal bacteria can effectively distinguish patients without irAEs from patients with severe irAEs and provide evidence of gut microbiota as an informative source for developing predictive biomarkers to predict the occurrence of irAEs.

Highlights

In recent decades, immunosuppressive therapy has dramatically prompted a paradigm shift in therapy of cancer diseases [1, 2]
We collected the fecal samples from patients who acquired antiPD-1 inhibitor therapies between October 2018 and March 2021 in the Department of Oncology, Second Xiangya Hospital, Central South University (Changsha, China)
Ninety (60%) patients developed at least one type of adverse effect, among which 68 (72.22%) patients had mild irAEs and only 25 (27.78%) patients suffered from severe irAE

Summary

Introduction

Immunosuppressive therapy has dramatically prompted a paradigm shift in therapy of cancer diseases [1, 2]. Immune checkpoint inhibitors (ICIs), including antiprogrammed death 1 (anti-PD-1), antiprogrammed death 1 ligand (anti-PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, have been approved as first-line treatment strategy for a variety of advanced cancers, such as melanoma, gastric cancer, and hematological malignancies [3]. As only part of patients can benefit from ICI monotherapy, ICIs plus chemotherapy, or antiangiogenesis has been approved as successful first-line therapy for several malignant tumors regardless of the expression level of PD-L1 in tumor tissues [8,9,10]. The treatment benefits associated with ICIs come at the cost of immune-related toxicities (known as irAEs), which are distinctly different from chemotherapy-related toxicities, and been regarded as the off-target effects of an excessively activated immune system [11]. The increased efficacy of combination therapy is accompanied by a rising incidence of irAEs, especially severe or life-threatening irAEs [8, 12, 13]

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