Microbiome influences response to PD-1/PD-L1 drugs - specific strains affect the efficacy

[Olga]

Before Ivan was about to start the Keytruda therapy, when we were still hoping for the surgery, Kathy, Tom wife, posted on her Facebook page a link to an article where cancer researcher Jennifer Wargo of the University of Texas MD Anderson Cancer Center in Houston explained that the gut composition appears to be an important factor in the body response to the PD-1/PD-L1 drugs https://www.nature.com/news/gut-microbe ... py-1.22938 This is when we started to research this subject. Ivan even wrote a pretty comprehensive review article that I copy/past here partially:

"Gopalakrishnan et. al (2017) identified Ruminococcaceae and Faecalibacterium among those promoting a response to PD-1 therapy in human melanoma (see Figure 1 below for full breakdown).1,20 The patients with those abundances were said to have “enhanced systemic and anti-tumor immune responses mediated by increased antigen presentation, and improved effector T cell function”.1 A study of a CTLA-4 blocker in melanoma patients also found Faecalibacterium and Firmicutes associated with a better response, as well as higher rates of colitis.31 Therefore, similar microbiome abundances were shown to be strongly associated with immune responses achieved by both PD-1 and CTLA-4 blockers in melanoma. Among other things, this suggests that other ways of potentiating the immune response, such as the abscopal effect from radiotherapy, may be aided by the right microbiome composition, and warrants further investigation.
Routy et. al (2017) identified Akkermansia muciniphila in promoting a response to PD-1 therapy in epithelial tumors.2 These bacteria could be responsible for releasing IL-12 cytokines that are required for the expansion of tumor-reactive CD8+ T-cells.5,6 CD8+ T-cells activated in the presence of IL-12 were shown to provide better tumor control in a mouse study.7 Correspondingly, an increased tumor infiltration by CD8+ T-cells in responders was noted.2 This mechanism could be beneficial in other tumor types, and should be investigated further.
Sivan et. al (2015) identified Bifidobacterium breve and longum in promoting a response to PD-1 inhibition in mouse melanoma.3 Treated mice displayed significantly improved tumor control, accompanied by robust induction of tumor-specific T-cells in the periphery, and an increased tumor infiltration by the CD8+ T-Cells. Bifidobacterium may not have a similar effect in stimulating an immune response in humans due to differences in TLR9 expression.32 However, a 2017 study showed B. longum supplementation increasing the abundance of A. muciniphila, which could be useful.22
Vetizou et. al (2015) identified Bacteroides fragilis and Bacteroides thetaiotaomicron in promoting a response to CTLA-4 inhibition in mouse sarcoma.35 The authors also tested the effect of microbiome depletion via antibiotics on melanoma and colon cancer CTLA-4 treatment in mice. Consistent with other studies, treatment was thwarted by antibiotic use.
Analysis
In all four cases, study designs and findings suggest a causal link between specific bacterial abundances, and the magnitude of the immune response. Two of the studies show that a general lack of microbiome diversity negatively impacts treatment effectiveness in various tumor types. Therefore, strong recommendations can be made to immunotherapy patients:
Avoid antibiotics whenever possible, or attempt to counteract their effects on the microbiome.
Eat a healthy diet that promotes a diverse microbiome.
These two simple recommendations can play a crucial role in treatment decisions. Any surgery is usually accompanied by prophylactic antibiotic use, and could therefore be highly detrimental to immunotherapy. Something as simple as a routine infection treated with antibiotics could lead to devastating tumor progression. A poor diet low in fibre and variety could deplete microbiome diversity, wiping out bacteria crucial to the mounting of an appropriate immune response."

We also researched and kind of set some diet modifying strategy using commercially avail. supplements that I am not positing here, because all the dose funding studies were done in mice and gut metabolism in mice is very different from the human in calcium digestion, the studies in human were mostly done in a very unhealthy disease specific population (like obese or diabetic) with very specific metabolic problems, and in healthy population small groups the strategies were not producing an uniform result - in some people the result was negative, not improving but reducing the needed numbers. Also higher doses needed to be used in human were found to cause a gastrointestinal distress with acute symptoms of vomiting and diarrhea causing the loss of the needed bacteria.

My current understanding as of now that the best strategy is as follow:
- some people have a very good gut composition without the need for modification. Start from testing if possible.
- avoid antibiotics if possible, if not take the probiotics with Bifidobacterium breve and longum, do not try to get the extremely high doses, there were some issues with the viability when they try to compress the higher amounts in one capsule, smaller doses may work the same good or even better.
- eat more food with the insoluble fiber that the gut microbiota eats after the food passes the stomach and intestines - all fruits with the seeds, skin on, unbleached nuts, whole grain of different types - millet, barley etc. that has some hard shell component left. Apple pectin, grape with the seeds and skin, pomegranate, guava with the seeds etc. Legumes have a very good nutrition profile that should be good to feed them, with chick peas preferable due to low iodine content.

[D.ap]

Hello Olga
I was reminded of Josh being prescribed a z pack this time last year , and Breelyn Wilky tweeting the down falls of antibiotics while on immune therapies, so we consulted a natural path doctor. (Found my email and was reminded)
http://www.cureasps.org/forum/viewtopic ... ics#p10425



The natural path had been employed as an integrative oncologist of at the university cancer center , and went into practice of natural pathy here in our home town.
She has been pivatol in Joshua’s care from the get go, aided us in the choice of the probiotic .
She prescribed -

https://www.pureformulas.com/hmf-intens ... royal.html