Despite the unprecedented improvement in clinical outcomes with the advent of immune checkpoint blockade for cancer,1,2 robust biomarkers for therapeutic success as well as novel strategies to increase their efficacy are urgently needed. In addition to exploring novel immune checkpoints and other strategies to enhance responses, there is a growing interest in modulating the gut microbiome, given the mounting evidence of the role of gut microbes in shaping immune responses (and responses to immunotherapy).
Md Abdul Wadud Khan, PhD
Bertrand Routy, MD, PhD
However, along with these strategies, we must understand the impact of a number of factors that may impact gut microbes—including antibiotics—which can have a profound negative impact on the microbiome. Recent evidence shows that antibiotics may negatively affect responses to immune checkpoint blockade in patients with cancer, including the recently published report by Pinato et al3 in JAMA Oncology reviewed in this issue of The ASCO Post.
Preclinical Findings
Preclinical studies discovered the role of the gut microbiome in shaping responses to immunotherapy.4,5 First, in murine models, the absence of an intact gut microbiome (in germ-free or antibiotic-treated mice) abrogated the anticancer activity of immune checkpoint blockade–induced CD4-positive T cells. Then, fecal microbiota transplantation in germ-free mice from immune checkpoint blockade–treated patients’ feces restored checkpoint inhibitor activity.6 Moreover, several human cohort studies across a range of malignancies (melanoma, non–small cell lung cancer [NSCLC], and renal cell carcinoma) and geographic locations have demonstrated that differential responses to immune checkpoint blockade are observed based on the diversity and composition of the gut microbiota.6-8
Clinical Studies
Antibiotics can profoundly disrupt the ecologic diversity and composition of the gut microbiome.9 Given that the microbiome is now considered to play a key role in the immune-cancer setpoint, several trials have addressed the impact of antibiotic use before initiation of immune checkpoint blockade. Landmark findings published by Routy et al in Science in 2018 demonstrated that patients with NSCLC, renal cell carcinoma, and urothelial cancer treated with antibiotics prior to initiation of immune checkpoint blockade had worse clinical outcomes.6
Arielle Elkrief, MD
Jennifer A. Wargo, MD
Following this provocative observation, numerous additional studies were performed across a range of tumor types, corroborating these findings (Table 1 on page 84).3,6,10-23 These trials included a study by Derosa et al in 370 immune checkpoint blockade–treated patients with NSCLC and renal cell carcinoma; it demonstrated worse progression-free and overall survival in patients exposed to antibiotics.21 Another study by Mielgo-Rubio et al,11 also in an NSCLC population, confirmed this finding, also demonstrating that patients treated with intravenous chemotherapy had worse outcomes than those treated with oral formulations.
Several studies addressing the NSCLC population consistently demonstrated the negative impact of antibiotics on immune checkpoint blockade efficacy (Ouaknine et al,12 n = 72; Galli et al,13 n = 157; Do et al,14 n = 109; Huemer et al,15 n = 30). Two studies addressed the impact of antibiotics on the efficacy of immune checkpoint blockade in melanoma (Elkrief et al,18 n = 74; Tinsley et al,23 n = 201), and a negative association was again observed.
This pattern seems to be tumor-agnostic, since studies across many solid tumor types in patients receiving immune checkpoint blockade have corroborated the negative impact of antibiotics on clinical outcomes (see Table 1). However, there was still some scepticism regarding these findings, given potential confounders (patients who required antibiotic use had additional comorbidities, among other variables). Furthermore, the time frame at which antibiotics were most deleterious was not well understood.
Findings From Pinato et al Study
Many of these questions were addressed by Pinato et al,3 who performed a prospective multicenter cohort study in patients with melanoma, NSCLC, and other cancer types receiving immune checkpoint blockade therapy (n = 196 patients). In this study, treatment with antibiotics up to 30 days prior to treatment with immune checkpoint blockade was associated with worse overall survival in patients with melanoma (3.9 months vs 14 months) and NSCLC (2 months vs 26 months). Treatment with antibiotics prior to immune checkpoint blockade therapy was also associated with poorer responses to therapy overall. Interestingly, concurrent antibiotic therapy was not associated with poorer survival—suggesting gut microbes may be most important during the priming phase of response to immune checkpoint blockade.
No correlative analyses were performed on fecal samples from patients. Thus, the impact of antibiotics on the diversity and composition of gut microbes in this cohort is unknown. These provocative data merit further investigation in this regard.
Need for Antibiotic Stewardship
Together, the available data highlight the potential negative impact of administration of broad-spectrum antibiotics to patients with cancer just prior to treatment with immune checkpoint blockade—although important questions remain. It is still debated whether antibiotic use represents a true, independent therapeutic biomarker, or it is a surrogate for patients with a worse overall prognosis. The reports noted herein represent almost 2,000 patients in aggregate, and multivariate analysis performed across these studies supports the stance that antibiotics themselves are a negative prognostic factor in this patient population. Thus, these findings do call for a need for antibiotic stewardship and more selective use of antibiotics in the clinic, particularly in patients treated with immune checkpoint blockade in the 30-day time frame.24
It is still debated whether antibiotic use represents a true, independent therapeutic biomarker, or it is a surrogate for patients with a worse overall prognosis.— MD Abdul Wadud Khan, PhD, and colleagues
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It will be critical to engage with our colleagues in infectious disease to optimize more targeted antimicrobial approaches in patients with presumed infections, with careful follow-up and monitoring of therapeutic response. In addition, we will need to employ strategies to optimize reconstitution of the microbiome after potentially ablative antibiotic use—although ideal consortia remain unknown, and treatment with over-the-counter probiotics has been shown to delay the reconstitution of the gut microbiome.25
Nonetheless, the Pinato et al and other studies support a critical role for gut microbes in modulating immunity and response to immune checkpoint blockade. It is critical that we take this and factors impacting it into account when caring for our patients. ■
Dr. Khan is a postdoctoral researcher in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston. Dr. Routy is Assistant Professor of Hematology-Oncology at the University of Montreal Research Center, University of Montreal Healthcare Centre. Dr. Elkrief is a resident in the Division of Oncology, Department of Medicine, McGill University Healthcare Centre, Montreal. Dr. Wargo is Associate Professor and Principal Investigator, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center.
DISCLOSURE: Drs. Khan, Routy, Elkrief, and Wargo reported no conflicts of interest.
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