Antibiotics impair the response to immune checkpoint inhibitors. Credit: Mk2010 [CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)]

Antibiotics Can Impair the Response to Cancer Treatment

Patients that receive antibiotics before immunotherapy treatment have worse outcome.

A study in 2018 and another in 2019 found that prior antibiotic treatment makes cancer patients nonresponsive to immunotherapy. These studies may explain why some patients have such profound benefits from immune checkpoint inhibitor therapy and some do not.

Both studies included patients with advanced non-small cell lung cancer (NSCLC), renal cell carcinoma (kidney cancer), and urothelial carcinoma (a common cause of bladder cancer). The 2019 study also included patients with melanoma, and head and neck carcinoma.

In the 2018 study, Routy and colleagues evaluated 140 NSCLC patients, 67 renal cell carcinoma patients, and 42 urothelial carcinoma patients. The patients either received antibiotics within 2 months prior to starting immune checkpoint inhibitor therapy or within 1 month after the first immune checkpoint inhibitor treatment. Across these cancers, overall survival was reduced in patients who had received antibiotic treatment: overall survival averaged 11.5 months in patients who had received antibiotic treatment versus 20.6 months in those who had not.

The researchers determined that changes in the gut microbe community were responsible for the detrimental effects of antibiotics on the response to immune checkpoint inhibitor therapy. Analysis of fecal samples identified specific bacteria that were associated with a better response to immune checkpoint inhibitors. Indeed, mouse models of cancer showed that mice administered antibiotics also had impaired anti-tumor responses to immune checkpoint inhibitors. However, repopulating their gut microbes with the bacteria associated with responsive patients restored the anti-tumor effects of immune checkpoint inhibitors in these mice.

In the 2019 study, Pinato and colleagues evaluated the medical records of 196 cancer patients who were treated for solid tumors: 119 NSCLC patients, 38 melanoma patients, and the remainder had other types of solid tumors. All of the patients had advanced cancer and received immune checkpoint inhibitor therapy.

For this study, the researchers asked if prior antibiotic treatment or antibiotic treatment during immune checkpoint inhibitor therapy affected the response to therapy. Of the 196 patients, 29 took antibiotics up to 30 days before to receiving the immune checkpoint inhibitor treatment and 68 took antibiotics at the same time as receiving the immune checkpoint inhibitor treatment. For all types of cancer, the outcome was significantly worse specifically in those patients who had taken antibiotics prior to receiving immune checkpoint inhibitor therapy.

All types of cancer: Overall survival averaged 2 months for those receiving prior antibiotic treatment versus 26 months for those patients who did not.

Non-small cell lung cancer: Overall survival averaged 2.5 months for those receiving prior antibiotic treatment versus 26 months for those who did not.

Melanoma: Overall survival averaged 3.9 months for those receiving prior antibiotic treatment versus 14 months for those who did not.

Other tumors: Overall survival averaged 1.1 months for those receiving prior antibiotic treatment versus 11 months for those who did not.

Together these studies show that prior antibiotic treatment in cancer patients impairs the effectiveness of immune checkpoint inhibitor therapy. Along with other studies, these demonstrate that the interaction between microbes in the gut and the immune system is important for establishing an effective anti-tumor response to immune checkpoint inhibitors. From a practical perspective, in patients that have received antibiotics prior to immune checkpoint inhibitor therapy, it appears critical to wait for restoration of the gut microbe population before starting the cancer treatment. This process could be accelerated by providing a specifically formulated probiotic to rapidly restore this critical interaction between the gut microbes and the immune response.

Highlighted Articles

D. J. Pinato, et al., Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. 5, 1774–1778 (2019) DOI: 10.1001/jamaoncol.2019.2785

B. Routy, et al., Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). DOI: 10.1126/science.aan3706

Related Reading

V. Gopalakrishnan, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). DOI: 10.1126/science.aan4236

V. Matson, et al., The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018). DOI: 10.1126/science.aao3290