Effect of Antibiotics on Immunotherapy Outcomes ‘Urgently Requires’ Further Look

Antibiotic treatments administered within 30 days from the start of immune checkpoint inhibitor cancer therapy may lead to a reduction in patient response, according to a new study published in JAMA Oncology.

In particular, antibiotic therapy administered prior to immune checkpoint inhibitor therapy, not concurrently, was associated with worse response to treatment and overall survival (OS) outcomes, leading the investigators to conclude that further research on immunotherapy and the digestive microbiome is “urgently required.”

“Mechanistic studies are urgently required to investigate (antibiotic)-mediated gut dysbiosis not solely as a prognostic marker by as a therapeutically actionable driver of the anticancer immune response in the context of (immune checkpoint inhibitor) therapy,” they added.

To determine the association between broad-spectrum antibiotic therapy that was administered prior to or concurrently with immune checkpoint inhibitor therapy with treatment response and OS, the investigators conducted the prospective, multicenter, cohort study of 196 patients recruited from routine clinical practice between 2015 and 2018, at 2 tertiary academic referral centers. Tumor types being treated with immune checkpoint inhibitor therapy included non-small-cell lung cancers (NSCLC; n = 119), melanoma (n = 38), and other tumor types (n = 39).

The majority of patients were male (n = 137) at a median age of 68 years (range, 27-93).

The investigators found that prior therapy with antibiotics was associated with worse OS compared with those who did not receive it (2.0 vs 2.6 months; HR, 7.4; 95% CI, 4.3-12.8; P <.001), and a higher likelihood of primary disease that is refractory to immune checkpoint inhibitor therapy (81% vs 44%; P <.001). On the other hand, concurrent treatment with antibiotics was not associated with worse OS (HR, 0.9; 95% CI, 0.5-1.4; P = .76)

These findings were consistent across tumor types: OS was worse among patients with NSCLC (2.5 vs 26 months, P <.001), melanoma (3.9 vs 14 months, P <.001), and other tumor types (1.1 vs 11, P <.001) when treated with prior antibiotic therapy.

Moreover, multivariate analyses confirmed these findings, independent of tumor site, disease burden, and performance status.

To explain their findings, the investigators hypothesize that changes to the microbiome could be impacting later administration of drugs.

“Interestingly, our study suggests that the timing of (antibiotic) exposure is crucial in dictating its interaction with response to immunotherapy, leading us to postulate a potential ‘priming’ effect of (prior broad-spectrum antibiotic therapy) on patients’ anticancer immunity,” they wrote. “Broad-spectrum (antibiotic) use can cause prolonged disruption of the gut ecosystem and impair the effectiveness of the cytotoxic T-cell response against cancer, strengthening the biologic plausibility underling the adverse effect of (antibiotic) therapy on immunotherapy outcomes.”

The researchers acknowledged that the study was limited by its small sample size and its lack of direct comparison between antibiotic usage and the actual dynamic changes in the gut microflora.

Corresponding author David Pinato, MD, MRCP (UK), MRes, PhD, clinical senior lecturer and consulting medical oncologist at Imperial College London, told Cancer Network™ the findings could explain a major factor in the ineffectiveness of immunotherapies in certain patients.

“Currently the quest for biomarkers is ongoing but we need to know which molecular pathways are responsible for gut dysbiosis and lack of (checkpoint inhibition) response,” he said. “We are trying to understand the link between stool bacterial diversity and peripheral markers of immunity in these patients.”

Thus far, Pinato noted, it appears that these microbiome changes aren’t impairing the absorption of the therapies. “It is more that the microbiome differentially educates the immune system rather than impairing drug metabolism,” he explained.