Impact of Use of Antibiotics on Response to Immune Checkpoint Inhibitors and Tumor Microenvironment

Abstract

BACKGROUND: Antibiotic use can result in reduced efficacy of immune checkpoint blockade (ICB), presumably because of dysbiosis of the intestinal microbiome. We sought to determine the precise temporal relation between antibiotic therapy and its possible effects on ICB efficacy. We also investigated the histologic changes in the tumor microenvironment secondary to antibiotics use. METHODS AND OBJECTIVES: This was a single institution retrospective study that evaluated the impact of antibiotics on outcomes of patients with advanced or metastatic malignancy who were treated with ICB. Use of antibiotics among patients treated with ICB was assessed during a 12-week period before and after initiation of ICB. The primary outcome was response to ICB. Histologic changes in the tumor microenvironment following antibiotics use were also examined. RESULTS: Between January 1, 2011 and December 31, 2018, 414 patients were identified who received ICB, and 207 patients (50%) received antibiotics within 12 weeks (before/after) of initiation of ICB. In univariate analysis, antibiotic use following initiation of ICB was associated with a significantly reduced response (odds ratio [OR]: 0.33, 95% confidence interval [CI]: 0.2-0.52, P<0.001). There was no significant negative impact on response to immunotherapy when antibiotics were used before ICB initiation (OR: 0.87, 95% CI: 0.55-1.34, P=0.52). The maximal negative impact of antibiotics occurred in the first 6 weeks after initiating ICB, and was independently associated with significantly reduced likelihood of response to immunotherapy in multivariable analysis (OR: 0.48, 95% CI: 0.29-0.8, P=0.01). CONCLUSIONS: This study demonstrates that the use of antibiotics during ICB significantly negatively impacts the efficacy of immunotherapy. The maximal negative impact occurs if the antibiotics are used in the first 6 weeks after initiating ICB.