Cancer patients on immunotherapy fare worse if they have recently taken antibiotics, with their response and overall survival rate “crashing.”
The findings come from a study of almost 200 cancer patients in the UK taking a type of immunotherapy called checkpoint inhibitors, part of the standard treatment pathway for cancer patients on the NHS.
Researchers found that patients who received broad spectrum antibiotics in the month leading up to starting the treatment had significantly worse responses to immunotherapy.
Compared with patients who received antibiotics alongside the immunotherapy or not at all, antibiotic treatment before immunotherapy was associated with lower overall survival rates and patients’ cancers were more likely to progress.
The researchers suggest this may be because antibiotics disrupt the balance of bacteria and microbes in the gut, called the microbiome, which in turn impact the immune system.
The prospective study, led by researchers at Imperial College London and published today in the journal JAMA Oncology, highlights the importance of the timing of antibiotic treatment and the need for further studies to understand the mechanisms at play.
The researchers say that the findings have the potential to influence clinical practice, including a higher threshold for giving antibiotics to cancer patients starting immunotherapy.
Dr. David Pinato, from Imperial’s Department of Surgery & Cancer and corresponding author of the study, said: “Cancer immunotherapy can be successful in around 20 percent of patients, but it’s very difficult to predict who is going to respond.
This work adds further evidence that antibiotics have an impact. We have shown that with prior antibiotic exposure, patients’ response to immunotherapy and survival crashes.”
Immune response
In the study, the team looked at 196 patients receiving immunotherapy as part of their routine care on the NHS, and who were treated at Imperial College Healthcare and Chelsea and Westminster Hospital NHS Trusts.
Patients’ primary disease included non-small cell lung cancer, melanoma, head and neck cancer, carcinomas and other types of cancer.
All patients were treated with immune checkpoint inhibitors, a therapy which disrupts the ability of cancer cells to ‘hide’ themselves, enabling the body’s immune cells to target and destroy tumours.
The researchers looked at whether patients had received broad spectrum antibiotics up to 30 days prior to beginning their immunotherapy treatment, or whether they received antibiotics during their therapy – with respiratory infections being the most common cause for being prescribed antibiotics.
A total of 26 patients received prior antibiotics and 68 received them during their immunotherapy, and median overall survival after therapy was 14.6 months.
However, analysis revealed that patients with prior antibiotic use had a median overall survival of just two months, compared to 26 months for those with no antibiotic use prior to treatment.
A similar effect was seen across all cancer types.
Patients with prior antibiotic use were likely to be less responsive to immunotherapy, with their primary disease almost twice as likely to progress.
The study also showed the effect was independent of the class of antibiotic used—which for this group of patients included beta-lactams, quinolones, macrolides, sulphonamides, tetracyclines, aminoglycosides and nitroimidazole.
Critical timing
According to the researchers, more work is urgently needed to understand the mechanism behind the reduced response and drop off in overall survival.
But they believe that broad spectrum antibiotics before immunotherapy disrupt the balance of microbes in the gut – collectively called the microbiome – reducing the diversity of bugs present and potentially impacting on the body’s immune response.
“We know that giving patients antibiotics affects their microbiome and increasingly, the evidence shows it influences treatment outcomes,” Dr. Pinato added.
“It is important that patients who need antibiotics to treat bacterial infections receive the drugs they need,” he explained. “But these findings urge for more care in the decision-making process for some patients.
It raises questions of whether we need a higher threshold for antibiotic prescribing in cancer patients due to receive immunotherapy.”
The team highlight some limitations to the findings, including the small number of patients, and a lack of direct observations of changes to the gut microbiome.
They also add that it is not possible to account fully for the impact any other health conditions the patients may have had (comorbidities) could have had on their survival. However, they explain they remain confident of the link and the need for further studies to expand on these findings.
The researchers now aim to carry out further studies to see what impact, if any, prior antibiotic use is having on the microbiome of patients with a follow-up observational clinical trial funded by the NIHR Imperial Biomedical Research Centre.
They add that future studies could investigate whether rebalancing or augmenting the microbiome could improve patient outcomes.
Gastrointestinal (GI) tumors, including colorectal cancer (CRC), gastric cancer, pancreatic cancer, hepatocellular carcinoma (HCC), and cholangiocarcinoma, account for a large proportion of all cancers[1,2].
Due to the limited effectiveness of traditional chemotherapy, especially for pancreatic cancer and HCC, great efforts have been made in immunotherapy, which has become a potential treatment option for GI tumors in the last decade.
In addition, current management strategies and treatments for GI tumors have also been enriched by immune checkpoint inhibitors (ICIs), such as advanced treatment for microsatellite instable CRC and second-line treatment for HCC.
However, only a fraction of patients benefited from ICIs and there are some factors affecting their efficacy, such as tumor genomics, PD1 ligand 1 (PD-L1) levels, and gut microbiota[3].
The correlations between the gut microbiota community and clinical response to ICIs have been confirmed by an increasing number of investigations. Early studies found that the effects of CTLA-4 blockade were associated with T cell responses specific for distinct Bacteroides species and tumors in antibiotic-treated or germ-free mice did not respond to CTLA-4 blockade[4].
Cancer immunotherapy may be modulated by manipulating the microbiota[5]. Similarly, the anticancer immunity in mouse models induced by anti-PD-L1 is reported to rely on Bifidobacterium, which might improve the effectiveness of anticancer immunity through augmenting dendritic cell functions and subsequently enhancing CD8+ T cell priming and accumulation in the tumor microenvironment.
Furthermore, oral administration of Bifidobacterium can generate a similar effect to anti-PD-L1 treatment on tumor elimination, indicating the potentially important role of Bifidobacterium in strengthening immune functions[5].
Subsequently, an increasing number of studies have revealed a correlation between the response to anti-PD-1 and the abundance of diversified bacteria, including Ruminococcaceae bacteria, Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium[6–8].
Since extensively and overused antibiotics can lead to an abnormal intestinal microbiota composition, the effect of antibiotics on immunotherapy has also been explored in several studies.
For example, some studies have indicated that antibiotics can weaken the effectiveness of immunotherapy, while others argued that antibiotics have no influence on immunotherapy.
In this review, we summarize the relationship between antibiotics, microbiota, and GI tumors, the current status of immunotherapy in GI tumors, and the influence of antibiotics on immunotherapy in a comprehensive manner.
ANTIBIOTICS, MICROBIOTA, AND GI TUMORS
The link between antibiotics and cancers has been around for a long time. Several decades ago, the hypothesis that the use of antibiotics may increase the risk of cancer was first proposed[9]. Studies have shown the association between increased use of antibiotics and increased incidence and mortality of breast cancer[10,11].
Antibiotics are also known to influence the development and progression of GI tumors, most notably for colorectal cancer. Cao et al[12] reported a study of 1195 newly diagnosed colorectal adenomas in patients who underwent at least one colonoscopy and reported information on antibiotic use.
They found that antibiotic use at ages 20–39 and 40–59 was significantly associated with an increased risk of colorectal adenoma after age 60. Two other case-control studies supported this conclusion: one study found a positive association between the use of anti-anaerobic antibiotics and colorectal cancer, but no association was found for anti-aerobic agents[13]; another study found that a high (≥ 8) number of prescriptions of antibiotics was associated with an increased risk of colorectal cancer (CRC), and when antibiotics were used for ≥ 70 d compared to no use of antibiotics, the risk of CRC significantly increased, and both anti-aerobic agents and anti-anaerobic antibiotics were associated with an increased risk of CRC[14]. Indeed, penicillin can lead to an increased risk of esophageal, gastric, and pancreatic cancers[15], and antibiotic exposure can promote the development of tumors in the liver[16].
However, the effect of the microbiota on cancers further complicates the relationship between antibiotics, bacteria, and cancers.
The microbiota is reported to be involved in the initiation, progression, and dissemination of cancer both at epithelial barriers and in sterile tissues, and gut microbiota can modulate the response to cancer therapy and susceptibility to toxic side effects[17].
There are papers showing some microbes associated with GI tumors (Table (Table1),1), and common examples of microbes involved in cancer include Helicobacter pylori, which is associated with gastric cancer, Clonorchis sinensis and Opisthorchis viverrini, which are associated with bile duct cancer, and enterotoxigenic Bacteroides fragilis, which is associated with colon cancer[18,19].
In mice receiving broad-spectrum antibiotics, reductions in microbiota, inflammation, and colonic polyposis, which is a precancerous lesion of colon cancer, were observed[20]. Immune and inflammatory pathways could be regulated by chronic inflammatory conditions, while chronic inflammatory conditions could be affected by microbiota and antibiotics[20,21].
These observations suggested that a further investigation into the influence of antibiotics on the treatment for GI tumors is necessary.
ANTIBIOTICS AND IMMUNOTHERAPY
PD-L1 expression in the tumor tissue has been considered to be a biomarker for pembrolizumab in NSCLC[37]; however, some PD-L1-positive patients do not benefit from pembrolizumab, while some PD-L1-negative patients could benefit from nivolumab or other ICIs. How to select the appropriate population for ICIs is still a question.
A recent study found that tumor mutation burden or tumor infiltrating lymphocytes might be relevant biomarkers for patients treated with ICIs[38,39], and accumulating evidence supports the hypothesis that the gut microbiota has a great influence on immunotherapy, including ICIs[19].
Therefore, tumor mutation burden, tumor infiltrating lymphocytes, and the gut microbiota are considered potential immunotherapy biomarkers. The gut microbiota plays a crucial role in balancing inflammation, infection, and commensal antigens, which can modulate the host immune system both locally and systemically[40].
As interest in the influence of microbiota on immunotherapy has escalated, microbiota and cancer, specific gut microbes, and administration of antibiotics have also attracted extensive attention.
Early studies focusing on the relationship between immunotherapy and antibiotics were all conducted in murine models. For example, cyclophosphamide (CTX) is a well-known chemotherapy that can stimulate antitumor immune responses, including inducing the death of immunogenic cancer cells, destroying immunosuppressive T cells, and promoting Th1 and Th17 cells to control tumor growth.
However, mice treated with antibiotics to kill gram-positive bacteria have been found to have a reduction in the number of pathogenic Th17 cells and a worse treatment response[41]. When pathogenic Th17 cells were transferred to antibiotic-treated mice, the antitumor efficacy of cyclophosphamide was partially restored, which suggests that antibiotics may influence the efficacy of immunotherapy by regulating the gut microbiota. Another study also found that antibiotic-treated mice showed a low response to CpG-oligonucleotides.
They found that TNF expression and frequencies of TNF-positive leukocytes induced by CpG-oligonucleotides were significantly impaired[42]. It is mainly because those antibiotics could affect the microbiota and further affected local and systemic inflammation and the tumor immune microenvironment.
Further studies showed that immunotherapy CTLA-4 and/or PD-1/PD-L1 efficacy could be improved by transferring patient fecal samples into germ-free (GF) or antibiotic-treated SPF mice[7].
In addition to the above animal experimental findings, several independent retrospective analyses in human cohorts of advanced NSCLC, RCC, and urothelial carcinoma have found contradictory results (Table (Table3).3).
An early study found that antibiotics do not affect the efficacy of nivolumab in NSCLC patients[43]. A total of 74 locally advanced or metastatic NSCLC patients were treated with nivolumab as a second- or third-line therapy, 15 patients were exposed to antibiotics, and the remaining 59 patients were not exposed to antibiotics. No significant difference was found in response rates and progression-free survival (PFS) between the two groups of patients.
Subsequently, another two independent studies with larger sample sizes drew inconsistent conclusions. Indeed, Kaderbhai et al[43] showed that in RCC patients, antibiotic use compared to no antibiotic use was associated with an increased risk of primary progressive disease (PD), shorter PFS, and shorter overall survival (OS). In NSCLC patients, antibiotic use was associated with similar rates of primary PD but decreased PFS and OS. In a study by Routy, 69 out of 249 patients were prescribed antibiotics. PFS and OS were significantly shorter in the antibiotics-treated patients when all patients were combined.
Furthermore, transplantation of fecal microbiota from patients who responded to ICIs into germ-free non-responders restored or enhanced the ICIs responsiveness. In univariate and multivariate Cox regression analyses, antibiotic use was found to be a predictor of resistance to PD-1 blockade, independent of classical prognostic markers in NSCLC and RCC[44]. Gut microbiota composition analysis found that A. muciniphila was the most significantly associated bacteria with favorable clinical outcome, which increased the recruitment of CCR9+ CXCR3+ CD4+ T lymphocytes into tumor beds in an IL-12-dependent manner.
The different studies come to different conclusions, which may be due to a combination of several reasons. First, the duration time of antibiotic usage is different.
Some studies allowed the use of antibiotics for 3 months before immunotherapy, while other studies used antibiotics for only 1 month before immunotherapy, and there is no unified standard. Second, the cancer type is different. RCC, melanoma, and NSCLC are more sensitive to ICIs. Third, all the studies were retrospective studies, which need to be further confirmed by randomized controlled clinical trials.
More information: David J. Pinato et al. Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer, JAMA Oncology (2019). DOI: 10.1001/jamaoncol.2019.2785
Journal information: JAMA Oncology
Provided by Imperial College London
