The Roman poet Horace once wrote that the best way to tell a story is to start it in the middle.  To tell this story, let’s start in the middle, back in February of 2021.  On the fifth of that month the journal Science published results from two similar clinical trials that marked a change in how we thought about the checkpoint inhibitor drugs now common to use in cancer treatment.  One team of scientists was led by Diwaker Dawar.  The second team by Erez Baruch.  Both studies were small.  Dawar’s trial had only 15 patients enrolled in it.  Baruch’s had just 10. 

All the patients in both studies had malignant melanoma.  All had failed to respond to earlier treatment with drugs that inhibit programmed cell death protein 1 (PD-1), either, pembrolizumab (Dawar’s group) or nivolumab (Baruch’s group).^1,2

All the patients were treated with fecal transplants from patients who had responded well to the same PD-1 inhibitor drugs, which the study subjects had failed to respond to.  The patients then received an additional course of treatment with the same drugs.  Of the “… two proof-of-concept trials with a total of 26 patients, responder-derived fecal microbiota transplantation (FMT) overcame PD-1 resistance in a third of patients with melanoma, suggesting that microbiome modulation could improve responsiveness to anti-PD-1 ICB.” (John McCulloch et al 2022)

This was a big deal.  Even though a similar study had already been done in non-responding mice, giving them fecal transplants from human responders, no one could be certain the same response would be seen in humans.  People are not mice; their gut microbiomes are dissimilar sharing only about 4% of bacterial species.³ Nevertheless, the fecal transplants made a difference in a third of patients who had failed.  Initial treatment with these drugs generally only works in a minority of patients.

Our patients have been asking for treatments like this for as long as I can remember.  Patients newly diagnosed with cancer would say, “I don’t want chemo for my cancer, it’s all poison. I want to do something that triggers my immune system to kill the cancer.”

I would try to explain that the immune system wasn’t reliable at killing cancer cells because cancer cells had pretty much the same DNA they did, and it was hard for the immune system to recognize cancer cells as different from oneself. I would tell these patients about the historic methods used to stimulate the immune system to fight cancer.

The oldest technique is probably one attributed to the Egyptian physician Imhotep.  About five millennium ago, he treated patients by slathering river mud over the tumor’s surface and then used a sharp knife to slash the tumor through the mud.  The resultant infection would trigger an immune reaction so intense that sometimes it would also attack the tumor.

 William Coley came up with a somewhat similar strategy in the late 1800s. He used a bacterial culture derived initially from patients with diarrhea.  He’d either use these bacteria or strain off liquid from the culture tube and inject this into his patients.   This also often stimulated a rather intense immune response.  Coley’s method was unquestionably controversial and sometimes lethal, but cured 30% of treated patients, giving them 10 plus years of tumor-free survival.

Few of our patients who we told about these strategies to get their immune systems to fight the cancer were enthusiastic to try them.

Patients had to wait until scientists began to unravel the biology of the checkpoint pathways, in particular the work of James Allison and Tasuku Honjo.  These two doctors shared the 2018 Nobel Prize in Medicine; Allison for his work on cytoxic T-lymphocytic antigen -4 (CTLA-4), referred to as CTLA-4, and Honjo for identifying PD-1.

Once identified, monoclonal antibody drugs were developed to block these pathways, turning off these specific mechanisms that prevented the immune system from noticing and attacking cancer cells.  In some cases, the results were near miraculous.

Let Us Take a Moment to Review What We Know About Checkpoints

The immune system fights off threats within the body, including bacterial infections, viral infections, and to some degree, cancer. Specialized cells called antigen-presenting cells patrol the body and pick up evidence of potential threats. They bring this evidence to the closest lymph nodes, where they “present” the antigen evidence to T cells. If the T cells recognize the threat, they become activated, multiply, and go out to hunt and kill threatening cells wherever they are found.

Immune checkpoints are the “brakes” of the immune system. They play a key role in:

• slowing down immune reactions keeping them under control:
• helping to keep the immune system from attacking normal “self” cells (preventing autoimmune diseases);
• preventing excessive responses to everyday threats (like potential allergens) or for example, bacteria in yogurt;
• restoring order after a strong immune response to a threat (like post infection) has been eliminated.

While checkpoints serve as an important safety mechanism, in some cases, they may slow down desirable immune responses too soon.

The immune system may be able to recognize that cancer cells are dangerous and do not belong in the body, but checkpoints may slow the immune cells down before they are attack and kill a tumor that is forming. A growing tumor takes advantage of checkpoints to defend itself against the T cells, producing molecules that activate checkpoints to press the brakes on T cells and slow down their activity.

The US FDA approved these checkpoint inhibiting drugs for treating advanced melanoma at nearly the same time; pembrolizumab (Dawar’s study) was approved in September 2014 and nivolumab in December 2014. They are now approved to treat a range of cancers. PD-1 is a negative regulator of T-cell immune function; that is, it suppresses the immune system’s response. This suppression guards against autoimmune disease, but it also weakens the immune system’s ability to kill cancer cells. Anti–PD-1 drugs halt this suppression, allowing the immune system to recognize and kill cancer cells unrestrained. 

When these drugs work, they may work very well to extend patient survival.

Since these drugs came into wide use, the long-term survival for patients with malignant melanoma went from 5% to 50%.

“Before the introduction of checkpoint inhibitors, the average life expectancy for a patient with advanced melanoma ranged from 6 to 12 months, and by 2019 average survival has increased to over 6 years.”⁴

The trouble though is that these drugs don’t work as often as we want them to: “…approximately 40–60% of patients do not achieve significant therapeutic responses under anti-PD-1 monoclonal antibodies.” In other words, half the time they don’t help.⁵ When using single drugs “… 60-70% of patients do not respond to single agent immunotherapy.”⁶  This strategy shifted to using more than one drug at the same time, to target multiple checkpoint pathways.  This is referred to as an immune checkpoint blockade (ICB).  Nevertheless, the hunt was on to find ways to increase the response rate to these drugs and attention quickly turned to the role the gut microbiome might play in response rates.

Sophie Viaud and Laurence Zitvogel had pointed to the importance of the gut microbiome in immune responses first in 2013 for the drug cyclophosphamide,⁷ and again in 2015 for the platinum chemotherapy drugs. These French researchers were responsible for a paradigm shift in our understanding of how chemotherapy works.  Knowing that germ-free mice or mice treated with antibiotics were unresponsive to many of the classic chemotherapy drugs, Viaud formulated a new explanation for how these drugs kill cancer. Rather than poisoning cancer cells directly, these drugs compromise the intestinal integrity, increase gut permeability, and allow the selective translocation of bacteria into the lymph system. The presence of these bacteria in the lymph system primes the immune system to attack the tumor cells.⁸  Their work turned our attention to the fact that the gut microbiome played an important role in the immune response to cancer.

It was soon realized that these bacteria also played an important a role in checkpoint inhibition: “… gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies.”⁹

Back as early as 2015, we started reading studies that sought to identify the key components of the gut biome that control responses to checkpoint inhibitors.    Patients were recruited and their gut biomes were compared between those who responded to treatment and those patients that did not.  Remember that only a minority of patients, 40% more or less, respond to checkpoint drugs. 

Initially it was assumed that there would be one or two key bacterial players and once identified, the problem would be solved. In November 2015, a colleague of Viaud and Zitvogel, Marie Vétizou, reported that a specific Bacteroides species was necessary for cytotoxic T lymphocyte antigen -4 (CTLA-4) targeted drugs to work well.¹⁰ 

Then just a few weeks later, on November 27, 2015, Ayelet Sivan and colleagues at the University of Chicago reported on their work.  They had purchased what they thought were genetically identical mice from two different supply houses. Taconic Farms (TAC) and Jackson Laboratory (JAX)], Cancer tumors grew much slower in the Jackson Lab than mice in those purchased from Taconic farms.  Co-housing, letting the mice live together for a while, erased the differences in tumor growth rates.  The gut biomes of the two groups of mice were initially different.  Fecal material transplanted from the Jackson mice slowed tumor growth and passed along their greater sensitivity to PD-1 inhibitor drugs. 

Sivan and colleagues identified Bifidobacter as the key to improving response rates in their mice. Responsiveness to treatment could also be transferred from one group of mice to another by fecal transplant.¹¹

In 2018 Bertrand Routy furthered our knowledge by publishing his experiments with mice that again suggested that the immune checkpoint inhibitors were dependent on the gut microbiome. His team showed that primary resistance to the checkpoint inhibitors could be transferred. Antibiotic use inhibited the clinical benefit of these drugs in human patients.  “Fecal microbiota transplantation (FMT) from cancer patients who responded to immune checkpoint inhibitors (ICIs) into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so.” Their analysis of patient stool samples who had responded to treatment led Routy et al to treat their mice with Akkermansia muciniphila  and this restored the  efficacy checkpoint inhibitor drugs.  ¹²

You might notice that these studies had all used mice.  This changed in 2018 when Vidya Gopalakrishnan published human data.  Her team analyzed the microbiomes of 112 melanoma patients treated with PD-1 therapy and looked for differences between responders and non-responders.  The fecal biomes were analyzed in 43 patients (30 who were responders) and the biomes of responders showed significantly greater alpha diversity.  [Note, their findings are probably what led to the suggestion that patients should consume more than 30 different plant foods per week as doing so is associated with greater alpha diversity.¹³]  Gopalakrishnan also reported higher levels of bacteria from the Ruminococcaceae family in the responders.¹⁴

It’s not just what bacteria are linked to response.  Data have also linked the presence of certain bacteria with increased incidence of adverse reactions to treatment. MC Andrews reported this association in 2021 after comparing the gut biomes of 77 patients, about half of whom had significant adverse effects from treatment.¹⁵/p>

The problem with all these studies, as you may have noticed, is they all have reported different bacteria as helpful.  To quote Karla Lee, “However, translating experiences from the preclinical gut microbiome to clinical practice has been somewhat unsuccessful.”

The data are consistently inconsistent between trials.  And there have been a lot of different trials by now.

Dawar and Baruch’s clinical trials in humans using fecal material transplants told us that this would convert non-responders into responders in a third of melanoma patients.  Yet up until this point we do not know why.

One of the largest and most recent attempts to make sense why or how the microbiome helps some patients respond to treatment is John MacCulloch study from 2022.

To resolve the “… inconsistencies [that]exist between published microbial signatures associated with clinical outcomes…”  they evaluated a new melanoma cohort (Pittsburgh Cohort, N=94)  along with data from four previously published studies  (Gopalakrishnan,¹⁶ Matson,¹⁷ Routy,¹⁸ Chaput¹⁹).  This combined data set brought greater significance to their findings.

Certain patient characteristics were clearly associated with worse outcomes.  These included low basal mass index (BMI), low neutrophil/lymphocyte ratio (NLR) and use of proton pump inhibitor drugs (PPI).  Any type of adverse reaction to treatment was associated with longer progression free survival (PFS).  A number of bacterial species that might be associated with either disease progression or inhibition were identified. “Collectively, our findings hint that an unfavorable gut microbiome enriched in Gram negative bacteria may promote an LPS-dominated inflammatory signature in the gut, resulting in systemic inflammation manifested by elevated NLR and poor response to anti-PD-1.”²⁰

McCulloch introduced a new term to our vocabulary: “enteric microbiotypes,” suggesting that the human gut microbiome includes multiple discrete ecologically balanced communities that are distinctive of different geographical areas and affected by ethnicity and geographical origin, though still modifiable by diet, drugs, and lifestyle.

Analyzing his combined data, McCulloch defined 27 distinct microbiotypes of which there are four superclusters; broadly grouped microbiotypes with similar correlation between microbial composition and clinical response: two enriched in favorable taxa and two enriched in unfavorable taxa.  When viewed through the lens of these enteric microbiotypes, the inconsistencies of the previous cohort data seem to fade.

Our initial assumption that there would be one or two essential gut microbes that we needed to have for patients to respond to checkpoint inhibitors was clearly wishful thinking.  The real situation appears to be far more complex than we could have possibly imagined.

I imagine these variations in enteric microbiotypes analogous to forests in different parts of the country: as I look out my window at the trees there is no doubt that the trees I see would be different if I were in Seattle, or Florida or Phoenix.  Each geography has its own flora best suited to that climate and geography.  The gut microbiome is probably like that; it varies considerably with genetics, diet and geography.  There are many variations that can and will work.

How can we help patients undergoing treatment with checkpoint inhibitors? 

Eat more fiber: the goal should be 30 grams per day.  This suggestion comes from the study by Christine Spencer et al published in 2021. Dr. Spencer made a name for herself while still at MD Anderson.  While there, she presented some of her findings at a conference in 2018. Spencer and colleagues had gathered data about diet and supplements from 113 melanoma patients, along with stool samples from each. Spencer reported that patients eating high-fiber diets were 5 times more likely to respond to anti–PD-1 therapy than those on a low-fiber diet.

Surprisingly, taking probiotic supplements, things that we generally assume are good for everyone, stuff like Lactobacilli or Bifidobacter was associated with a lower chance of responding favorably to treatment, a full 70% lower chance.²⁵ These results were confirmed when published in 2021. This second study had more patients (n = 293 total; n = 193 responders and n = 100 non-responders. All had advanced melanoma). 

Adequate daily fiber was defined as 20 or more grams per day.  Those who ate 20 or more grams of fiber were compared to those who ate less and their PFS compared.  Patients who ate sufficient dietary fiber (every 5-g increase in daily dietary fiber intake corresponded with a 30% lower risk of progression or death).²¹

Antibiotics, probably because they disrupt the gut microbiome, are bad news.  Antibiotic use has consistently decreased response rates and worsened outcomes: figure that antibiotics will cut PFS and overall survival by at least half.²² The only good news in regard to antibiotic use is that the impact is temporary, the microbiome recovers in about a month.

Avoid proton pump inhibitor drugs. These drugs used to prevent acid reflux are associated with a 40% drop-in response rates, and a similar decrease in overall survival.²³ The good news here is that our profession is relatively proficient at weaning patients off these drugs.

Steroid drugs can be a problem as they clearly suppress immune function.  Patients who are taking the equivalent of 10 mg of prednisone per day have significantly lower response rates, progression free survival and about a 70% lower overall survival.²⁴ This is more complicated though as steroids are often used to treat the adverse effects triggered by checkpoint inhibitors, usually symptoms of autoimmunity.  Such side effects are taken as a good sign, an indicator that the drugs are working as desired.  Thus, when a patient is taking steroids to treat their reaction to checkpoint targeted treatments, this is associated with a better outcome.  So, with steroids we need to know when the patients started taking them and why, to know if they are good news or bad news. The longer the time between initiating the checkpoint drugs and initiating steroid treatment, the better the survival odds.²⁵  As interesting as this is, there isn’t much we can do to change this situation.

Something that we can change is diet.  The more closely a patient follows a Mediterranean style diet, the better their chance of responding to treatment.  In an analysis by Bolte et al, there was about a 35% increase in response rate between patients with a low compliance and those with an above average compliance following basic Mediterranean diet guidelines.²⁶  This is about the same degree of improvement seen in Dewar and Baruch’s fecal transplant studies.  One can ask patients the rhetorical question of which approach they would prefer, eating more vegetables and olive oil or swallowing capsules of fecal material.

Fecal microbiota transplants would still be a great idea for these patients to do if we could get material from individuals who have responded to treatment, ideally as Dewar and Baruch did, obtaining stool from cancer patients who responded to treatment.  The Catch-22 is that we can’t.  Fecal material obtained from cancer patients is not banked for use in others as there is a risk that their cancers will be passed along.  The only option to get such fecal material is to enroll in a clinical trial [clinicaltrials.gov].  Some patients may take a DIY approach, which I can’t encourage here.  If they were to take this sort of initiative though, there are two specific tests that might help them judge if they or their donor is likely to respond to checkpoint inhibitor therapy.  The first and cheapest is the lymphocyte-neutrophil ratio (LNR) that can be calculated from numbers reported on a complete blood count (CBC).  We want a NLR between 2.0 and 3.0 as these were “remarkably associated with optimal ICB treatment outcomes.”  Also decreasing (<2.0) or increasing (>3.0) NLR levels were indicators of worse ICB treatment outcomes.²⁷

There’s a lab that now claims that by analyzing a stool sample, they can predict if a person will respond to treatment.²⁸ One could use both tests first on the patient and if they look as if they won’t respond then on to potential donors.

Exercise probably helps.  There are indications from both mouse research and human trials that exercise levels are associated with progression free and overall survival benefits for these patients.²⁹

It also appears that vitamin D supplementation to those with initially low levels is also helpful.  So, test and supplement as needed.³⁰

On the other hand, cannabis use is associated with significantly poorer outcomes.³¹ Advocates seldom want to hear this.  The best approach might be to print out the graphs from this paper and share them and allow the patients to interpret these findings for themselves.

Severe emotional distress is associated with worse outcomes in these patients.³² It might be that psychological interventions or even medications might lessen this negative effect.

The initial failure of the multiple attempts to identify the specific bacteria that are crucial to regulating an immune system response to these immune checkpoint inhibitor drugs left me questioning why.  I brought my question to Heather Zwickey, PhD, from NUMN and she provided an informative perspective telling me, “The reason that bacteria data is inconsistent is  it’s not the bacteria that matter so much as it’s what those bacteria are doing. A paper by Visconti came out in 2019 that shows microbes are not highly conserved between people (40% at best), but metabolites are (84% and more). That means that in some people, Akkermansia may be producing a particular metabolite. And in someone else, Bifidobacterium may be producing the same metabolite. So, it’s the metabolite that matters and not the microbe that is making it.”

If one follows the most recent research on these drugs, the more recent publications are identifying a growing list of metabolites that increase effectiveness of these drugs.  Most of the research to date has been on mice.  One metabolite does stand out because we see it in human trials and that is butyrate.  There are several human trials that have increased gut butyrate levels by supplementation of the gut probiotic Clostridium butyrate that have demonstrated superior outcomes.^33-35 Though this probiotic has a long history of use in Asia, it is still not widely available in the US or Canada.  Patients seem to be purchasing it online though.

The time of day that patients are given infusions of the checkpoint inhibiting drugs may make a major difference.  The immune system is more responsive in the morning than the rest of the day and patients given infusions in the morning appear to have better responses.³⁶

This article keeps getting longer as new information keeps getting published. By the time you read this, there will probably be new things that might help these patients.

While hoping and praying for a miracle cure,  we can be proactive in helping our patients improve their odds of recovery using simple strategies that are coherent with naturopathic medicine.

References

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Published July 27, 2024