Thursday, June 22, 2017

ASCO 2017: Melanoma, anti-PD1 and the microbes in your gut

I've been posting about our intestinal flora and its possible interaction with immunotherapy for some time.  This is from 2015: Cooties in our gut keep us skinny, smart and cure cancer!????? where bifidobacterium is thought to enhance efficacy of anti-PD-1.  There was this in 2016: Intestinal bacteria as a way to determine risk for ipi induced colitis!  in which it was suggested that the presence of "bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis" in patients taking ipi.  And this year, I posted Antibiotic use MAY decrease effectiveness of immunotherapy????? which, if the prior studies are accurate, would make sense as antibiotics drastically change the microbes in our intestines.

"Right there I had it, and right here I lost it"... cause, now ~ there's this:

Association of the diversity and composition of the gut microbiome with responses and survival (PFS) in metastatic melanoma (MM) patients (pts) on anti-PD-1 therapy.
ASCO 2017. J Clin Oncol 35, 2017. Wargo, Gopalakrishnan, Spencer, et al.

Background: Significant advances have been made in cancer therapy with immune checkpoint blockade. However, responses in pts with MM are variable, and insights are needed to identify biomarkers of response and strategies to overcome resistance. There is a growing appreciation of the role of the microbiome in cancer, and evidence in murine models that modulation of the gut microbiome may enhance responses to immune checkpoint blockade, though this has not been well studied in pts. Thus we evaluated the microbiome in a large cohort of pts with MM, focusing on responses to anti-PD-1. Methods: We collected oral (n = 234) and gut microbiome samples (n = 120) on a large cohort of of MM patients (n = 221). Of note, the majority of pts were treated with PD-1 based therapy (n = 105). Pts on anti-PD1 were classified as either responders (R) or non-responders (NR) based on RECIST criteria, and 16S rRNA and whole genome shotgun (WGS) sequencing were performed. Immune profiling (via immunohistochemistry, flow cytometry, cytokines and gene expression profiling) was also done in available pre-treatment tumors at baseline. Results: Significant differences in diversity and composition of the gut microbiome were noted in R vs NR to anti-PD-1, with a higher diversity of bacteria in R vs NR. Differences were also noted in the composition of gut bacteria, with a higher abundance of Clostridiales in R and of Bacteroidales in NR. Immune profiling demonstrated increased tumor immune infiltrates in R pts , with a higher density of CD8+T cells; this correlated with abundance of specific bacteria enriched in the gut microbiome. Other features of enhanced immunity were also noted, and WGS revealed differential metabolic signatures in R vs NR. Furthermore, diversity and abundance of specific bacteria in R was associated with improved PFS to anti-PD-1 therapy. Conclusions: Diversity and composition of the gut microbiome differ in R vs NR pts with MM receiving anti-PD-1 therapy. These have potentially far-reaching implications, though results need to be validated in larger cohorts across cancer types.

Okay - oral and gut microbiome samples were taken from 221 folks with metastatic melanoma who were treated with anti-PD-1 and those patients were classified as responders (R) or non-responders (NR).  Per this study, responders had an abundance of clostidiales and non-responders had mostly bacteroidales in their respective flora. Also, "Diversity and abundance of specific bacteria in R was associated with improved progression free survival to anti-PD-1 therapy."  Well, hmmm....  Not too specific here about exactly WHAT bacteria and how one is to attain them in our gut in order to improve our chances.  A little googling told me that "Clostridiales" (the cooties we want) are of the genus "Firmicutes" and the class "Clostridia".  (I'm glad there is a cuteness quotient cause the "clostridia" class is not sounding cute at all!)  From wikipedia there is this:  
"The Clostridia are a highly polyphyletic class of Firmicutes, including Clostridium and other similar genera. They are distinguished from the Bacilli by lacking aerobic respiration. They are obligate anaerobes and oxygen is toxic to them. Species of the genus Clostridium are often but not always Gram-positive (see Halanaerobium hydrogenoformans) and have the ability to form spores.  Studies show they are not a monophyletic group, and their relationships are not entirely certain. Currently, most are placed in a single order called Clostridiales, but this is not a natural group and is likely to be redefined in the future.
Most species of the genus Clostridium are saprophytic organisms found in many places in the environment, most notably the soil. However, the genus does contain some human pathogens (outlined below). The toxins produced by certain members of the Clostridium genus are among the most dangerous known. Examples are tetanus toxin (known as tetanospasmin) produced by C. tetani and botulinum toxin produced by C. botulinum. Some species have been isolated from women with bacterial vaginosis.
Notable species of this class include:

Heliobacteria and Christensenella are also members of the class Clostridia."
Okay...that's weird.  Cause some of those cooties are really bad shit!  (Sorry, sometimes I can't help myself!)  

So...what are the Bacteroidales?  Well, wiki ain't touching this one with a ten foot pole.
However, this article: Genomic characterization of the uncultured Bacteroidales family S24-7 inhabiting the guts of homeothermic animals.  Ormerod, Wood, Lachner, et al.  Microbiome 2016.

Provided this insight:  "Our view of host-associated microbiota remains incomplete due to the presence of as yet uncultured constituents. The Bacteroidales family S24-7 is a prominent example of one of these groups. Marker gene surveys indicate that members of this family are highly localized to the gastrointestinal tracts of homeothermic animals and are increasingly being recognized as a numerically predominant member of the gut microbiota; however, little is known about the nature of their interactions with the host.  Here, we provide the first whole genome exploration of this family, for which we propose the name “Candidatus Homeothermaceae,” using 30 population genomes extracted from fecal samples of four different animal hosts: human, mouse, koala, and guinea pig. We infer the core metabolism of “Ca. Homeothermaceae” to be that of fermentative or nanaerobic bacteria, resembling that of related Bacteroidales families. In addition, we describe three trophic guilds within the family, plant glycan (hemicellulose and pectin), host glycan, and α-glucan, each broadly defined by increased abundance of enzymes involved in the degradation of particular carbohydrates. "Ca. Homeothermaceae” representatives constitute a substantial component of the murine gut microbiota, as well as being present within the human gut, and this study provides important first insights into the nature of their residency. The presence of trophic guilds within the family indicates the potential for niche partitioning and specific roles for each guild in gut health and dysbiosis."

For those of you who think I know stuff....I'm pretty floundered on this one!!!  Have to say I've never seen a study where the ratties included were:  peeps, mice, koalas, AND guinea pigs....all together!! (Koalas?  Really??? I mean...there's their cuddly appearance, their life exclusively down under...and most germane to this discussion, as I understand it, they feed exclusively on eucalyptus plants!!!  I would assume the intestinal microbiome needed to digest this food source would be one more in keeping with that found in a termite than a human!!!!!)
But, back to the ASCO study, have to say that it makes me feel a little sick to my stomach thinking that if I am to be a responder to anti-PD-1 clostridium difficile, tetanus, and botulinum cooties need to be part of my make up.  Maybe it just means that if we can survive with that crap in the old poop shoot, melanoma doesn't stand a chance?  I wonder if the asbstract has a typo and mixed up the names of the organisms associated with R and NR.  Oh, well...

Don't really know where this line of investigation is going!  I think I'll just keep eating my sauerkraut, kimchi, yogurt, and kefir!  In case you are interested in more handy dandy, readily available, and delectable cures for melanoma....I've been keeping up with the data on all that jazz for years, too. Here's the last post on that front:  Everything Cures Melanoma: Installment #6

Hang tough ratties - it's a pretty toxic world without and within....apparently!!! - les

PS ~ Not sure many of you grew up reading the folktales of Richard Chase, but if you did, I'm sure you recognized, "Right there I had it.  Right here I lost it!" as the refrain the main character used in his story:  Soap, soap, soap!  If you want a trip down memory lane or have never heard is an abbreviated, 'cleaned up' version...and after all that may be just what we need:  Soap, soap, soap. Revised by: Eldrbarry

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