The gut microbiome AGAIN - as it relates to immunotherapy for melanoma, other cancers, antibiotic use, and fecal transplants!

We have known that the bacteria, good and bad, within our intestines impact our health in ways, good and bad, for far longer than the current run of research and discussion of the microbiome sometimes remembers.  I posted this in 2015 - and it was old news then:  Cooties in our gut keep us skinny, smart and cure cancer!?????   For more on all things microbiome there are these:  The intestinal microbiome

Now, there are these additional reports:  

Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients.  Peters, Wilson, Moran, et al.  Genome Med. 2019 Oct 9.

Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community.

In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression

Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up. Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of L-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis.

This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.

NOTE:  While what follows is positive news, many reports have shown that taking probiotics from a bottle do not provide the help our intestinal microbiome really needs, while a diet high in fiber and live cultures like those within yogurt, kefir, sauerkraut, and kimchi does.  Now, this:

Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth.  Li, Elmen, Segota, et al.  Cell Rep.  2020 Feb 11.

Growing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor immune responses and inhibition of BRAF mutant melanoma growth in a subcutaneously implanted syngeneic mouse model. Mucin fails to inhibit tumor growth in germ-free mice, indicating that the gut microbiota is required for the activation of the anti-tumor immune response. Inulin and mucin drive distinct changes in the microbiota, as inulin, but not mucin, limits tumor growth in syngeneic mouse models of colon cancer and NRAS mutant melanoma and enhances the efficacy of a MEK inhibitor against melanoma while delaying the emergence of drug resistance. We highlight the importance of gut microbiota in anti-tumor immunity and the potential therapeutic role for prebiotics in this process.

When you need your cooties to work for you, it makes sense that killing them off with antibiotics would not serve you well.  Clearly, the development of antibiotics has prolonged and saved untold lives.  However, when they end up in the food chain, are used to treat viruses (for which they do NO GOOD) or are otherwise used inappropriately, real harm can result.  Not the least of which is a poor response in melanoma patients to immunotherapy.  There have been many concerning reports - Antibiotic use may diminish the positive effects of immunotherapy  

Now - there's this:

Antibiotic administration shortly before or after immunotherapy initiation is correlated with poor prognosis in solid cancer patients: An up-to-date systematic review and meta-analysis.  Yang, Wang, Yaun, et al.  Int Immunopharmacol.  2020 Aug.

Objective: Immune checkpoint inhibitors (ICIs) have recently achieved inspiring performance in improving the prognosis of various solid tumors. Gut microbiome plays a crucial modulatory role in the efficacy of ICIs, which can be influenced by antibiotic (ATB) administration. In this meta-analysis, we aimed to clarify the correlations of ATB administration with the prognosis of solid cancer patients receiving ICI treatment.

Method: The eligible literatures were searched using PubMed, Cochrane Library, Web of Science, and Clinical trials.gov databases before 29 February 2020. The correlations of ATB administration with overall survival (OS) and progression-free survival (PFS) were determined using Hazard ratios coupled with 95% confidence intervals.

Results: A total of 33 studies enrolling 5565 solid cancer patients receiving ICI treatment were included in this meta-analysis. As a whole, ATB administration was significantly correlated worse OS  and PFS. This significant association was then observed in the subgroup analysis based on region (except for OS in Europe), sample size, age, therapeutic strategy and ICI type. The similar results were also found in subgroup analysis for lung, renal cell (except for OS) and other cancers (such as melanoma) but not for mixed cancers. In addition, the ICI efficacy was more likely to be diminished by ATB administration within a time frame from 60 days before to 60 days after ICI initiation.

Conclusion: ATBs should be used cautiously in solid cancer patients receiving ICIs. However, further validations are still essential due to existing publication bias.

And this:

Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI).  Creen, Bertrand, Deley, et al.  Oncoimmunology.  2020 Nov.

Background: The gut microbiota has a key role in the regulation of the immune system. Disruption of the gut microbiota's composition by antibiotics might significantly affect the efficacy of immune checkpoint inhibitors. In a study of patients treated with ipilimumab, we sought to assess the relationship between overall survival and in-hospital antibiotic administration. 

Methods: Patients having been treated with ipilimumab between January 2012 and November 2014 were selected from the French National Hospital Discharge Summary Database. Exposure to antibiotics was defined as the presence of a hospital stay with a documented systemic bacterial infection in the 2 months before or the month after initiation of the patient's first ever course of ipilimumab. The primary outcome was overall survival. 

Results: We studied 43,124 hospital stays involving 1585 patients from 97 centers. All patients had received ipilimumab monotherapy for advanced melanoma. Overall, 117 of the 1585 patients (7.4%) were documented as having received systemic antibiotic therapy in hospital during the defined exposure period. The median overall survival time was shorter in patients with infection (6.3 months, vs. 15.4 months in patients without an infection. In a multivariate analysis adjusted for covariates, infection was still significantly associated with overall survival. 

Conclusions: In patients treated with ipilimumab for advanced melanoma, infection, and antibiotic administration in hospital at around the time of the patient's first ever course of ipilimumab appears to be associated with significantly lower clinical benefit.

In 2017 I reported on the positive effects of fecal transplants in poor little cancer affected mice - Back to the cooties in our guts....again!!!  Now, there seems to be a real benefit of same, for melanoma ratties!

Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients.  Davar, Dzutsev, McCulloch, et al.  Science. Feb 2021.

The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy. Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients.

Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma.

 

Certainly something melanoma peeps who are not responding to anti-PD-1 might wish to discuss with their docs! 

And that brings us up-to-date with the most recent bits and bobs regarding the cooties in our guts!   Kefir smoothie, anyone? - c