All the research on PD-1 immunotherapy drugs like Pembrolizumab and Nivolumab points to the need for a healthy microbiome to make them work to their fullest potential - high fibre diets, vitamin D and certain probiotics each and all help make more active T-cells, the cells that these drugs aim to ’unblock’ so they can attack 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 their patients not to take probiotics with immunotherapy drugs or, even, that they inhibit the drug. As we shall see, the issue is to understand that certain bacteria really do help, but these are not necessarily the strains in mass market products.
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 the crucial role it plays in the immune system. And many also think that an immunotherapy drug is just another, albeit cleverer, drug, which works sometimes and not others. But one of the major reasons for this is that they rarely tell patients how to maximise the immunotherapy's potential.
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 cancer 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 another patient, George. This man had 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 the help they can get, not hindrance.
First you need to have lots of T-cells!. And T-cell development is linked to the strength of your gut microbiome.
But just how bad is chemotherapy (and/or antibiotics) on the microbiome? Research from the USA about 2 years ago showed that just 4 rounds of two drugs left patients with only 27% of their full microbiome, a year after finishing the drugs! In other words, the microbiome was in terrible shape - three quarters of it destroyed - after the drugs and didn't recover after a year of normal life as doctors assume. 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 families and strains.
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 to its fullest potential if the patient is given it simultaneously with a chemo drug, or immediately after one? This is not just my observation but weas a conundrum pointed out recently by oncologists at North Western in Chicago and at MD Anderson in Texas.
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 one strain. When people eat soluble fibre, they increase their levels of a major family of bacteria - Ruminococcaceae. And this is proven to produce greater survival benefits in melanoma. Ruminococcacae have major immune benefits; not least, some members produce a Short Chain Fatty acid called butyrate.
The family, Ruminococcus is present in large numbers in a healthy gut, but members are fragile and known to be damaged by drugs and antibiotics. Members, or strains, are happiest when they are feeding on soluble fibre - oats, vegetables, nuts and seeds, pulses or legumes and psyllium. The grow and they multiply. But they like a slightly acidic environment and this comes mainly from Lactic Acid Bacteria - particularly the families Lactobacillus and Bifidobacterium, both also known to be severely damaged by drugs and antibiotics.
People who consume the highest levels of soluble fibre have the best immune systems.
Arming your T-cells
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 vitamin D but recently it has been shown that a chemical called butyrate activates it (7). And butyrate is made by our Ruminococcaceae that could have been wiped out by the chemo drugs or antibiotics taken before the immunotherapy!
We often give people butyrate after chemotherapy to restore balance!
Ruminococcaceae are stimulated to produce butyrate by the action of chemicals on the gut lining - and this is also a big 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).
On top of this mess chemo drugs are also known to reduce 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; and let it all re-establish for 2-3 months. It's a sensible course of action to take to improve the success of your (expensive and powerful) immunotherapy drugs.
PD-L! Immunotherapy Drugs - unblocking cancer cells so they can be seen
There is another group of immunotherapy drugs - called PD-L1. These inhibit the blockers 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 blocks - you can find beta glucan in medicinal mushrooms and mothers' milk (e.g. colostrum). Heparin also works, and this maybe one reason why patients who have Heparin during cancer surgery seem to survive longer.
There is so much you can and should do to get the maximum potential benefit from your immunotherapy drugs.