How to ruin immunotherapy drug effectiveness and cause Liver Toxicity

Antibiotics, PPIs and chemotherapy drugs each damage the microbiome and the immune system, reducing the effectiveness of immunotherapy drugs and increasing the potential for Liver Toxicity

Let me give you some examples of the problems patients are facing.

Example 1: About two years ago, I reported on cancer patients being given a double immunotherapy - Nivolumab and Ipilimumab, or Nivolumab plus a PD-L1 monoclonal antibody. It might have been a clinical trial. What happened was that two of my patients had a liver toxicity problem, albeit mild. and had to stop the drugs.The toxicity went away in two weeks. At about the same timeI had five male patients come to me. They had all had terrible Liver Toxicity problems following the double immunotherapy, necessitating not just cessation of the drugs but the use of the steroid Prednisolone for four months. They still had the problems In each case, whether they lived in Scotland or  Devon. They had been told by their oncologist that this was the first time the oncologist had ever heard of it happening.

Example 2: More recently we are seeing a new treatment protocol, which seems to be unique to Britain. Patients are being given two chemo drugs plus an immunotherapy for 3-4 rounds and then continuing with the Immunotherapy drug (Pembrolizumab) on its own. But here we go again. I've had a number of patients come to me with liver toxicity problems after the 3-4 starter rounds. And as a result they were offered Prednisolone and no longer allowed the immunotherapy option.. 

As regular readers will know, I believe immunotherapy drugs are the way forward. They can be excellent if used properly. I have written on how to make you immunotherapy drugs work properly. It’s not rocket science - it all comes straight out of immunotherapy research.

The problem is we are NOT using these great drugs properly. 

• Many oncologists seem oblivious to the fact that taking antibiotics with Immunotherapy drugs greatly reduces their effectiveness (1)

• Antibiotics prior to immunotherapy is also linked to poorer outcomes (2) 

• We also have a recent meta-analysis research study that taking Proton Pump Inhibitors at the same time as immunotherapy drugs reduces their  effectiveness.

Why then would an oncologist believe taking chemotherapy drugs at the same time would not also reduce the effectiveness of immunotherapy drugs? At this point I hear oncologists  shout, “Yes, but we have a clinical trials.” 

My patient expressed concerns to his oncologist about having chemo drugs at the same time as an immunotherapy drug. He was told by the oncologist that in the Clinical trials, the Pembrolizumab didn’t work on its own, but when the researchers used two chemo drugs with it, they found a significant response after 3 months.

So I went to read the clinical trials.This is NOT what they reported. The immunotherapy worked reducing tumours by about 23 per cent after 3 months; adding the chemo drugs to the immunotherapy increased the tumour reduction to 36%. 

There were warnings on liver toxicity.

I would like to make a couple of points:

• Immunotherapy drugs are like Long Distance Runners. They start at a certain pace and would expect them to perform right through the 2-year race. That’s what it is. A two-year programme; and patients of mine have been cured by Pembrolizumab at the end of the two years.

• But chemo drugs are like sprinters. They run really fast for three months, then they start to tire.

• Would you race sprinters against Mo Farah? Who would be leading after 2 miles? Who would win the whole 26 mile race?.

• And if you read my researched piece on how to get the most out of these excellent immunotherapy drugs, you would understand that chemo is like antibiotics and PPIs. It totally damages the effectiveness of the long distance runner.

Immunotherapy is capable of doing something most chemo drugs cannot. Immunotherapy can cure a cancer - I’ve seen it with Colorectal cancer and ‘mis-match” genes; with Melanoma, and with NSCLC.

If you want it to work at its very best, your patient needs a wonderful microbiome and high levels of activated T-cells. Unblocking a weakling is not going to do much for you, is it?

We have research from the USA - 2 drugs taken for 4 rounds, then antibiotics for 2 weeks. One year later how much of a microbiome would the patient have. An oncologist guessed that after a year it would have recovered 85%; I said 40%; the research said 27%. 4 rounds of chemo and 2 weeks of antibiotics destroy three quarters of a healthy microbiome. Without one, immunotherapy will not work to its potential.

Liver Toxicity

But this is my second concern. Liver Toxicity. And it is equally important. The oncologists damage the microbiome and the liver. Liver toxicity can occur with chemo; it’s one of the reasons oncologists do blood tests. But it can also occur more with immunotherapy drugs or Immune Checkpoint Inhibitors (ICIs) to give them their correct oncology title; Ipilimumab seems worse than others. In one study, ALT was elevated in 6.2% in the nivolumab group and 14.6% in the ipilimumab one; the most aggressive toxicity was found in 1.15 and 5.7% patients respectively. AST was elevated at 0.4% and 4.2% respectively. Pembrolizumab seems the weakest for liver toxicity.

Research reviews talk of an ‘overactive immune response’. ICIs boost the immune system by unblocking the blocks that cancer has put in place, causing increased inflammation and cytotoxicity against the cancer (and the liver). In my opinion, this is because you have to take things slowly BEFORE you use immunotherapy drugs. If oncologists understood the microbiome and its effects on the immune system, they would realise why I like to rebuild the patients microbiome, their soluble fibre consumption, butyrate and vitamin D levels. There’s research on all of this. Rebuilding the microbiome gets an improved immune system working, so the immunotherapy drugs DON’T cause such a shock to the system!

Correcting Liver Toxicity - Prednisone, Prednisolone

Steroids are considered ‘First Line Treatment’ for Liver Toxicity - the dose depending upon the grade. Hepatitis is a serious issue and guidelines in the USA include  investigation for viral hepatitis,  history of alcohol use, iron stores, and liver imaging (in case of potential liver metastasis). 

If the patient has high liver toxicity, the Doctors reach for the Prednisone. Doses up to 60 mg are given. There is a very useful research review (3) on ICIs and liver toxicity. 

On the subject of Prednisone, one study (4) showed that the steroid didn’t seem to add anything to recovery times. .Wose, the people who did not take Prednisone, on average recovered after 4.7 weeks; those who took the drug recovered after 8.6 weeks on average. So much for the steroid!

Prednisolone doses greater than 60 mg don’t improve the recovery time either. And having had both Nivolumab and Ipilimumab actually extends it. 

NB. Both Prednisone and Prednisolone are synthetic versions of cortisol, the stress hormone! Prednisone is the precursor of prednisolone.

Go to: Overcoming Liver Toxicity - eight natural compounds that can help

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References

1. Influence of Microbiome and Antibiotics on the Efficacy of Immune Checkpoint Inhibitors; Priyanka Patel et al; Cureus. 2021 Aug; 13(8): e16829.

 2.‘Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer; David Pinato et al.  JAMA Oncology. DOI: 10.1001/jamaoncol.2019.2785

3. Immunotherapy-induced Hepatotoxicity: A review; Teresa Da Cunha J Clin Transl Hepatol. 2022 Dec 28; 10(6): 1194–1204.

4. Immune-related hepatitis with immunotherapy: Are corticosteroids always needed? Marie-Léa Gauci et al; J Hepatol 2018, Aug 69 (2) 548-550

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