ORLANDO, Fla.-Antibiotics delivered less than a month before immunotherapy treatment in patients with advanced kidney cancer may hamper the effectiveness of immune treatment and worsen disease, a recent study found (J Clin Oncol 2017;35(Suppl 6S; Abstract 462)).
In the retrospective analysis, patients with metastatic renal cell carcinoma who had received broad-spectrum antibiotics experienced a shorter median progression-free survival rate when treated with checkpoint inhibitor immunotherapy compared to those who had not received antibiotics in the period close to treatment. The findings provide further strong suggestion of a link between gut microbes and the immune system.
The study was led by Lisa Derosa, MD, an oncologist at the Gustave Roussy Cancer Institute at Paris-Sud University in Villejuif, France. Derosa presented the findings in a presscast and a poster session at the 2017 Genitourinary Cancers Symposium, cosponsored by ASCO, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
According to the authors, this study is the first to analyze the impact of antibiotics on immune checkpoint inhibitors and provides the first evidence of a relationship between the gut microbiome and patient response to immunotherapy.
Study Design
Derosa and colleagues followed 80 patients with metastatic renal cell carcinoma who were enrolled in prospective clinical trials of immune checkpoint inhibitors at the Gustave Roussy Cancer Institute. Immune checkpoint inhibitors block certain proteins made by immune system cells and some cancer cells. The proteins help keep immune responses in check and can prevent T cells from killing cancer cells.
The 80 patients were treated by single-agent PD-1 or PD-L1 inhibitors, combinations of PD-1 inhibitors and CTLA-4 inhibitor, or combinations of PD-L1 inhibitor and bevacizumab. In this group, 16 patients had been treated with broad-spectrum antibiotics up to 1 month before receiving the first dose of immunotherapy. The researchers performed statistical analyses using Kaplan-Meier method and Cox regression to adjust for risk factors.
Study Findings
The researchers found that, in patients who had received antibiotics, cancer worsened more quickly. This occurred regardless of factors such as age, gender, and tumor characteristics.
Most of the patients studied were men (65%), had clear cell histology (88%), and had undergone prior nephrectomy (80%). Disease risk was favorable in 21 percent of patients, intermediate in 57 percent, and poor in 22 percent.
The findings suggest that overall survival may be shorter with antibiotic use, but the authors recommend further study to reach a definitive conclusion. They plan to continue this study by enrolling additional patients. They will also continue studies of mice and seek to pinpoint the types of gut bacteria that affect response to immune checkpoint inhibitors and the types of antibiotics that have the greatest impact on outcomes.
Implications
This study raises some new points to consider as scientists work to understand the relationships among gut flora, antibiotic therapy, and immunity. "These early findings show that doctors prescribing cancer immunotherapy should pay closer attention to antibiotic use," Derosa said during the presscast.
"As cancer immunotherapy options grow and evolve, we're beginning to understand more about the relationship between gut bacteria and the immune response to cancer," noted Sumanta Pal, MD, moderator for the Genitourinary Cancers Symposium presscast. "It's remarkable that antibiotic use could have such a negative impact on the efficacy of immunotherapy. This study suggests that patient antibiotic use should be considered carefully so that the possible benefits of immunotherapy are not compromised."
The adverse consequences of antibiotics on gut flora have been attracting intense research and discussion for the past several years. "Antibiotics shape the ecology of the gut microbiome in profound ways, causing lasting changes to developing and mature microbiotas," Langdon, et al, wrote in 2016 (Genome Med 2016;8:39). "...In addition to the increased threat of resistance...overuse of broad-spectrum antibiotics must be quickly phased out in favor of more precise approaches and must be complemented by efficient methods to restore the microbiome after injury."
And as Zitvogel and coauthors voiced in 2015, "Modulating the gut microbiota may constitute a viable strategy for improving the clinical efficacy of anticancer chemo-, radio-, and immunotherapy (Sci Transl Med 2015;7(271):271ps1)."
"The data that were presented are just preliminary, so we have a lot of work to do," Derosa said of the study presented at the symposium. "I think the results are really important because of the kind of connections between microbiome, antibiotics, and immunotherapy."
Michelle Perron is a contributing writer.