How to make your immunotherapy drugs work properly

How to make your immunotherapy drugs work properly

All the research on PD-1 immunotherapy drugs like Pembrolizumab and Nivolumab points to the need for a healthy microbiome to make them work better - high fibre diets, probiotics, even vitamin D, each and all help make more active T-cells, the cells that these drugs aim to ’unblock’ so they can ’see’ the cancer.

The use of probiotics with PD-1 immunotherapy

I recently had an interesting conversation with Professor Robert Thomas of Addenbrook's before recording my Sunday Show on which he was my guest. The subject was immunotherapy drugs.

He was telling me how he'd been conducting research on probiotics and had found that they make virtually any drug work better, especially immunotherapy drugs. This is something I have been saying for nearly a decade.
 
However, some oncologists tell patients not to take probiotics with immunotherapy drugs, or that they don't work. As we shall see, the issue is to understand which bacteria can actively help. Maybe the strains sold in the high street are simply the wrong ones.
 
I have a view, that is certainly not meant to be rude, that the majority of oncologists in Britain simply do not understand the microbiome. And they also think that an immunotherapy drug is just another, albeit cleverer, drug.
 
Let's start with some basics from research.
 
First we have had research (11) from Georgia Medical School showing that the simultaneous use of antibiotics wipes out the effectiveness in three out out five cases of PD-1 usage. “Any negative impact of antibiotics on cancer treatment appears to go back to the gut and to whether the microbiota is needed to help activate the T cells driving treatment response”, according to Dr. Gang Zhou , Put simply, 'damage your microbiome and you ruin the effectiveness of PD-1 immunotherapiy drugs'. Simultaneous use of chemo drugs would have much the same effect. 
 
Last year I had a patient who was on Carboplatin and Taxol for about 3 months, then Avastin was added for another three months, and then the lady had Avastin only, plus an immunotherapy drug - Pembrolizumab. She was so pleased that she was having 'immunotherapy'. Unfortunately, it didn't work and a scan about 4 months later showed progression. If you understand the need for a strong microbiome to get the best results from PD-1 immunotherapy, you would understand that between the end of the chemo, and the start of the immunotherapy, you need about 3 months to rebuild your microbiome, before having the immunotherapy. This is exactly what I did for George. This man had so much chemo that he has ended up with chronic neuropathy in his feet. When his doctors suggested immunotherapy, I said simply. 'Give me three months to rebuild your microbiome before you start'. Here we are two and a half years later and George has been signed off, 'cured'.
 
PD-1 mmunotherapy drugs 'UNBLOCK YOUR T-CELLS'. They need all thre help they can get, not hindrance.
 
First you need to have some T-cells! And ideally lots. But just how bad is chemo? Research from the USA about 2 years ago showed that 4 rounds of two drugs left patients with just 27% of their full microbiome,12 months after finishing the drugs! In other words, the microbiome was in terrible shape after the drugs and didn't recover as doctors assumed. The research concluded Fecal Microbiome Transplants were necessary. Not surprisingly, there is research from the National Cancer Institute (12) showing Fecal Microbiome Transplants make melanoma immunotherapy work better.
 
Fecal transplants are not essential, if you talk to someone who understands how to rebuild a healthy gut over time. You need to do 4 jobs - heal your gut wall, repair/replace the ravaged gut lining, kill any pathogens, and replenish the microbiome with a diverse selection of lost strains and families.
 
High fibre diets and bacteria
 
We know categorically that PD-1 immunotherapy works better if you have a strong microbiome (1). How could it possibly be expected to work if given simultaneously with a chemo drug, or immediately after? This is a conundrum pointed out by Oncologists at North Western in Chicago and oncologists at MD Anderson.
 
A strong gut microbiome increases the numbers of T-cells (and B-cells that make antibodies). And the best way to get a strong microbiome is to eat a high soluble fibre diet and people who do this have the best immune systems and their immunotherapy drug WORKS BETTER (2)
 
There are about 5 studies that show that taking a probiotic can help immunotherapy drugs work better, and even a study that names the strain that seems to help the most (3). It was a bacterium called Akkermansia, a strain of bacterium known to promote the gut lining.
 
A world wide study lead by the University of Texas (13) however concluded that the issue was bigger than this. When people eat soluble fibre, they increase their levels of one major family of bacteria - Ruminococcaceae. And this alone produced greater survival benefits in melanoma. However, this family have major immune benefits; not least it produces a Short Chain Fatty acid called butyrate.
 
Arming your T-cells
 
But also T-cells cannot attack unless they are 'armed' by vitamin D (4).  T-cells have receptor sites on them for Vitamin D; it works as a hormone and activates the T-cells. 
 
80% of people diagnosed with cancer have extremely poor vitamin D levels (below 50 nmol/L) with another 10-12% still deficient and below 75 nmol/L.. The T-cells can't be activated unless the levels improve. Not surprisingly, for these deficient people, we know that Vitamin D supplementation increases survival (5).
 
The Endocrine Society, Harvard Medical School, Professor Michael Holick, and yours truly say you MUST be over 75 nmol/L and ideally between 100 and 150nmol/L to be healthy (6). 
 
But vitamin D in the bloodstream is actually in the inactive form as the liver 'processes' it, whether from sunshine or a pill. It was thought that the adrenals re-activated but recently it has been shown that a chemical called butyrate activates it (7). And butyrate is made by about Rhuminococcaceae that could have been wiped out by the chemo drugs or antibiotics taken before the immunotherapy! We often give people butyrate after chemotherapy! 
 
Rhuminococcaceae are stimulated to produce butyrate, by the action of chemicals on the gut lining - and this is most usually the biggest casualty of chemotherapy drugs and antibiotics!
 
And this is why we suggest to our patients to take 3 months off after their chemo, to allow us to rebuild the gut  - wall, lining and microbiome - and therefore the immune system. It's not just about adding in missing bacteria. Good food choices increase helpful bacteria that avoid illness and reduce inflammation (8), and good foods can restore the volume of good (commensal) bacteria (9).
 
And anyway, the chemo drugs reduced vitamin D levels in the body (10).
 
So, we would give you probiotics and probiotic foods, a high soluble fibre diet, vitamin D3 and butyrate. It's a sensible course to take to improve the success of your (expensive) immunotherapy drugs.
 
 
PD-L1 immunotherapy drugs
 
Of course there is another group of immunotherapy drugs - called PD-L1, these inhibit the inhibitors on cancer cells. Cancer cells don't want to be seen by the T-cells so they block their surface. PD-L1 drugs unblock the blockers. Ipilimumab is a typical PD-L1. There's a lot of research including four Nobel prizes on the subject of glycoproteins. Suffice it here to say that beta glucan can unblock the surface - you get beta glucan in Medicinal Mushrooms and mothers' milk. 
 
References
 
  1. Immunotherapy works better in patients with a strong microbiome - https://www.canceractive.com/article/immunotherapy-may%20work%20better%20after%20a%20fecal%20transplant 
  2. Increasing fibre intake improves immunotherapy - https://www.canceractive.com/article/increasing-fibre%20intake%20improves%20immunotherapy%20outcomes 
  3. Successful immunotherapy may be the result of one bacterium - https://www.canceractive.com/article/successful-immunotherapy%20may%20be%20the%20result%20of%20one%20bacterium 
  4. Vitamin D activates your immune T-cells - https://www.canceractive.com/article/vitamin-d%20activates%20tcells 
  5. Vitamin D supplementation increases survival - https://www.canceractive.com/cancer-active-page-link.aspx?n=3896&Title=Vitamin%20D%20supplementation%20increases%20breast%20cancer%20and%20colorectal%20cancer%20survival 
  6. Vitamin D? Shout out loud One-Two-Five - https://www.canceractive.com/article/vitamin-d%20%20say%20out%20loud%20onetwofive 
  7. Butyrate from gut bacteria activates vitamin D - https://www.canceractive.com/article/your-gut%20bacteria%20activate%20your%20vitamin%20d. 
  8. Gut microbiome enhanced by good foods https://the-rainbow-diet.com/the-colourful-mediterranean-diet/study-links-rainbow-diet-foods-to-good-health/ 
  9. Foods that boost good gut bacteria - https://chriswoollamshealthwatch.com/your-illness/gut-health/the-best-foods-for-gut-health/ 
  10. Vitamin D levels lowered by drugs - https://www.canceractive.com/cancer-active-page-link.aspx?n=4100&Title=Chemotherapy%20prevents%20vitamin%20D%20levels%20rising%20in%20the%20bod
  11. Antibiotics ruin immunotherapy success - https://www.canceractive.com/article/antibiotics-can-damage-performance-of-anti-cancer-drugs 
  12. Fecal microbiota transplants help patients with advanced melanoma respond to immunotherapy - https://www.nih.gov/news-events/news-releases/fecal-microbiota-transplants-help-patients-advanced-melanoma-respond-immunotherapy 
  13. High fibre diet important for best results with immunotherapy - https://www.canceractive.com/article/high-fibre%20diet%20important%20for%20best%20results%20with%20immunotherapy
 
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