Lung cancer

Do antibiotics reduce the anti-cancer efficacy of checkpoint inhibitors?

There is now ‘compelling’ evidence that antibiotics may reduce the effectiveness of immune checkpoint inhibitors in cancer patients, a hotly-disputed review has concluded.

Treatment with broad spectrum antibiotics during the month before starting immunotherapy is particular likely to reduce efficacy due to dysbiosis, according to an article published  by an international group of oncologists led by researchers from the Montreal University.

Writing in Annals of Oncology, they said there was a strong biological rationale for the gut microbiome to have an important role in modifying immune responses to cancer cells, as well as the microbiota being able to exert pro-inflammatory and immunosuppressive functions.

In their review they found that all but one of 12 clinical studies involving 1800 patients showed a negative impact of prior treatment with broad spectrum antibiotics on therapeutic outcomes of PD-1 or PD-L1 immunotherapy in cancers including NSCLC, melanoma and renal cell carcinoma.

While the studies were retrospective, they confirmed consistent findings from pre-clinical studies showing that disruption of the gut microbiome was associated with reduced efficacy of immune checkpoint inhibitors.

“These findings coupled to the pre-clinical data  … provide compelling evidence that the gut microbiome determines the immune-cancer set point and that [broad-spectrum antibiotic] administration may have important implications in the care of cancer patients receiving immune-modulatory treatments,” the review authors said.

But an Australian oncologist has rejected their conclusion, saying the link between antibiotics and immunotherapy should be  regarded as a myth until evidence went beyond an association to show causation.

Speaking at Australasian Lung Cancer Trials Group’s (ALTG) Annual Scientific Meeting (ASM) in Sydney, Professor Ken O’Byrne of Greenslopes Hospital, Brisbane, said the studies included in the review showed that patients taking antibiotics tended to have poor performance status.

Therefore the worse outcomes seen in patients who took antibiotics prior to immunotherapy could simply be a reflection of them being sicker, he said.

“This is not good science, it’s taking a jump that misleads. At the moment we have no robust data that shows that taking antibiotics has any effect on immunotherapy, only observations. So we have to be very careful and look very critically at this data,” he said.

“This kind of myth is very concerning to me because if I have a patient who needs antibiotics, they should get them,” he told the meeting.

In the Canadian review, the authors acknowledged  there were still many unanswered questions on whether postponing immunotherapy after antibiotics could be justified.

A longer duration of antibiotic treatment appeared to have a more pronounced negative effect on immune checkpoint inhibitor efficacy, but further data was needed to confirm this, they said. Likewise there was uncertainty about gut microbiome recovery time after stopping antibiotic treatment and whether a one, two or three month cut-off period was needed before starting immunotherapy.

“Beyond the firm recommendation to use [antibiotics] judiciously, more robust, prospective data are required to elaborate guidelines for the optimal management of patients who do require antibiotics shortly before or while on immune checkpoint inhibitors,” they wrote.

Meanwhile, clinical trials were also underway to evaluate interventions designed to reverse antibiotic-induced dysbiosis, for instance by faecal microbiota transplantation (FMT) and probiotics, they noted.

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