Nasha Winters, ND - Quelling the side effects of immune therapies with LDN (2019 Conference) (LDN, low dose naltrexone)
Nasha Winters, ND: Hi, wonderful to be here. I'm sharing what I've learned to utilize with my patients undergoing cancer therapies, with the newer modern immune therapies and how low dose naltrexone can be a very powerful tool. So our discussion today is quelling the side effects of immune therapies with low dose naltrexone.
And I have nothing to disclaim. As far as any financial involvement, I received nothing except for the joy of sharing my knowledge with all of you and learning from you this on our outline today. On slide three, you'll see that we will be covering an extensive background into the review of the latest class of immunotherapy medications, indications, and adverse events. We'll also be discussing the concept that this is very much a balancing act and how to start to look at how low dose naltrexone can enhance the outcome.
And then we'll look at the who is a candidate for these drugs because these are considered now sort of the creme de la creme of treatments in the world of oncology with the expectation that this is where we're going to go in our future. And yet you will find very soon in our future slides that many people are actually not a candidate for these drugs and why we should shy away from using these drugs in the inappropriate times.
And then finally, how to incorporate low dose naltrexone into the immune therapy arena where I think it rightfully belongs, where we can really help patients understand and use these therapies much more effectively.
So on slide four, we are actually starting with our conversation around immune therapies. Are these interventions in the cancer condition a friend or so, and in the dawning of the immune therapy is of where we are today, nearly 80% of patients undergoing these treatments will actually experience adverse side effects. And understanding what is happening in the immune system when met with these medications, and then knowing what to do to lower the risk and negative outcome is how LDN will be discussed and how you'll very quickly see that these therapies can be made into a friend.
So just a quick little background here. Cancer immunotherapy, also known as Immuno oncology. It is a form of a cancer treatment that uses and harnesses the power of the body's own immune system to prevent, target, control and even eliminate cancer. And immunotherapy, when done properly, can help educate the immune system to return to its three RS.
The ability to recognize, respond and remember in a specific application of attacking specific cancer cells. It's also been utilized to help boost immune cells and then help eliminate cancer altogether.
And, along with that therapy it can be used. What we're finding now is using an immune therapy as a standalone therapy may not be as effective than if we combine it with other therapies such as chemo, radiation, or other targeted therapies.
But one thing that's very important to keep in mind before we move on to the next slide and talk a bit about what is the immune system is that our standard of care approach today utilizes a concept called maximum tolerated dose, and this is applied to whether it's chemotherapy, radiation, targeted therapies, and even immune therapies, so when we do our research, our huge studies are phase one, two, and three clinical trials before we bring it into the average population, we're actually looking at the first level one and two of the clinical trials of how much we can give a patient before frankly, killing them is a safe dose. This is the concept of maximum tolerated dose, and yet this approach actually backfires. Especially in the realm of Immuno oncology and with immune therapy is now this billion-dollar industry as a very hot topic of the day, expected to take over our standard of care in the future.
We're in our infancy of understanding and frankly, using these therapies in the proper way. We're often using them far too late and at far too high of doses simply because we don't have a good understanding of the immune system. Because frankly, none of us was trained very well in this and medical school. part, in fact, because we didn't know. The information, but also because we didn't really think of the immune system as something important when we started working with folks with cancer and autoimmunity and other conditions that low dose naltrexone itself has become very helpful in supporting.
So onto slide number five. Before we dive into what these drugs are and how low dose naltrexone can help. I think it's actually very important to take a very basic review of the immune system. So the immune system spans several organs and tissues and regions of the body and includes things like our lymph nodes, spleen, the bone marrow and the thymus gland and its far-reaching influence supports the overall wellness of the body, of the organism by combating infection and other harmful substances such as viruses, bacteria, parasites, pre-cancer cells, and even rapidly growing and proliferating cancer cells.
So different aspects of the immune system found in different regions of the body help the body deal with what it's being exposed to. And so there are three primary tasks, as I mentioned earlier, that the immune system's in charge of identifying the threat. So there's that recognition, neutralizing those, those threats, which is the response. And then recall, remembering. So if the body is exposed to those threats again in the future, it already knows what to do. And so simply put, immunologists, break down the immune system into two main branches. Our innate, so nonspecific immune response and our initial immune response. It's our natural barrier, such as our skin and our mucous membranes and our inflammatory responses. That is kind of kickoff things like our monocytes and our phagocytes to start to go into the system and scavenge and clean up the debris, the unwanted debris, and clear it out of the body. And then we have the other aspect of the immune system, which is the adaptive, the acquired immunity. And this is based on the exposure that our innate immune system is that frontline defense that sees first, and once that frontline has done its job. It will stimulate this delayed response. It's adapted more specific immune response, which harnesses cells like our T-cells and our B cells to do their job.
So just a quick reminder. Lymphocytes or lymph nodes, I should say specifically, are kind of like your filter. Okay. They're located throughout the whole body, and they're also the site where our T cells are educated to destroy harmful invaders in the body. The appendix, which is often overlooked and removed too quickly is basically, we still don't quite know exactly
what it does, but we think now more than ever, especially with our understanding of the microbiome, that it's a storage site for sort of our backup good digestive bacteria.
So when things get off-kilter, say from exposure to an antibiotic, the appendix can do its job by the sort of releasing extra good digestive bacteria and microbiome into the system, which will, of course, help our immune system function better. The thymus gland is that small gland that's situated in the upper chest, beneath the breastbone. And it's much larger when we're younger and it sort of shrinks and, kind of dries up as we age. But it functions as the site where our key immune cells, specifically our T cells go to mature. Then those are the cells that start to fight infection and cancer. And then the spleen, a lot of people don't think about the spleen as one of our main immune organs. It's located on the left of the stomach. And it's where we filter all the blood, and it provides storage for platelets and white blood cells. It also serves as a site where the key immune cells, such as the B cells multiply in order to fight harmful invaders. And then the bone marrow. This is the thought spongy-like material found inside of all of our bones, and this is what contains the immature cells that divide to form more blood, forming STEM cells and mature into red blood cells and white blood cells that later developed into B cells, T cells and platelets.
So hopefully your thinking now, as we move into slide six, the importance of these cells in our immune system. Hopefully, you're also making a few aha moments when you recognize that many of our standard of care therapies, especially things like chemotherapy and radiation, very much damage and destroy and eradicate all of those cells we just went through. So a little more specific on the cells of the immune system. On slide number six, this is where I had a list of things like the antibodies, the B cells, the cytokine, but dendritic cells, the regulatory T cells. These are some of the more advanced, sophisticated immune cells of our body.
And for those of you who want to do a deeper dive, there's an excellent book by Lopez et al from 2016 called “Immuno oncology from bench to the bedside.” And it really takes a lovely deep dive more into the specifics of some of these cells. And just a reminder. We need to have both an intact innate system, which is that first line of defence and a good intact second line of defence.
I'm bringing these up to you now so that you can be thinking about this as we dive deeper into the therapies that we're using today to treat cancer and another immune condition, but first, let's talk about on side number seven, the history of immune therapies in the United States alone. Now. I believe that the rest of the world is a bit more years, in fact, 30 to 40 years on average ahead of the United States with regards to the immune system, immune system therapies.
But what is important for me to share for people to understand, especially the modern use of immune therapy today is, is looking at some of the United States history. So I've also given you a link here on the slide number seven that takes you on the timeline of progress of our understanding of the immune system over many, many, many decades.
And this is a great kind of review for folks who like to dive deeper to understand, for instance, when was the first time we started talking about natural killer cells and etc. But basically in the 1890s in the United States, Dr William Coley of Memorial Sloan Kettering cancer centre inaugurated the first immunotherapy after losing a young woman to sarcoma.
It was devastating for him and for many of us that are involved in utilizing low dose naltrexone in our patient population. We have arrived at using this off label drug in this way because of needing an alternative to things that were not working, and Dr Coley was no different. He was devastated to lose this young, otherwise healthy woman to a devastating disease process and went on the search for another way.
He stumbled upon a man that was currently living during that time named Fred Stein, who was a German immigrant who had recurrent cancer that was completely resolved following a high fever secondary to a streptococcus pyogenes infection.
And on a deeper dive, that doctor Coley took, he started to look into
the work of Dr Bush and Dr Fedelheisen?, sorry if I'm slaughtering that, that in the 1860s and entity early 1870s started to inspect their first cancer patients deliberately, with good outcomes. And so the work of Dr Coley, he was paying attention to what was happening 30, 40 years prior to his work, that started to influence our modern therapies today.
So Dr Coley hypothesizes that fever and Bolden, the immune system. So did, uh, Hippocrates, by the way, who basically said, give me a fever and I can cure any disease. But Dr Coley in the modern times in the 1890s thought that if you could embolden the immune system with a fever, that those cells would take action against the tumour.
His observation, though, he had some very interesting ones and his daughter later published papers on his work. His author's observations basically went ignored. Or dismissed in favour of a standard of care and the standard of care being the cuts, burn, and poison that we're still accustomed to using today in our therapeutic interventions.
And so let's fast forward to the fall of 2018 when what a man who was considered sort of a renegade and a bit of an outcast and a little bit kooky. Dr James P Alison, a PhD. Immunologist from Texas started doing some interesting work with the immune system back in the 1970s and this man, despite him being kind of an outcast and a renegade, which of course I think many of us are who are practising low dose naltrexone and other therapies.
He was given the Nobel prize in physiology and immunology this past fall for his work. With checkpoint inhibiting drugs. So that's where we kind of bring ourselves up to this modern application where we're now going forwards to a well thought out, thought leaders in, in bringing immune therapies to the forefront in the way we think about and approach cancer today.
So cancer immune therapies come in a variety of forms as noted here on slide number eight, and these include targeted antibodies, cancer vaccines, adopted cell transfer, tumour infecting viruses, checkpoint inhibitors, sibo, and other adjuvants. So I just don't want to spend a large number of our time here cause I want to get to the crux of it.
But know that these therapies are where we're putting our time, our energy, billions of dollars of resources into research. And the ones that you're probably most familiar with are the checkpoint inhibitors. Drugs like Keytruda, Opdivo, Yervoy. As many of you might be running across the car T therapies, these antigen receptors, they're showing up in a lot of therapies with regards to blood-based cancers like leukaemias and lymphomas.
And for many years, we've utilized things like the cytokine therapy, fever therapies that interleukin two, which was used quite extensively with melanoma and renal cell carcinoma patients as they continue today.
However, why I bring this up is that on slide nine, immune therapy comes with a high price.
Specifically, these therapies have, on average, 80% of the population will be exposed to immune adverse events such as infection, malignancies, cytokine release syndrome. tumour lysis syndrome, autoimmune triggers, hypersensitivity and toxicity, and the area of most common affected by these drugs are the skin.
We happen to see a lot of rashes and very odd skin conditions that that happened with these medications. A lot of GI issues. But cynically, this kind of gas, right as eosinophilia, extreme, kind of like turning the GI tract into a big hamburger helper. Unfortunately, lung issues, so a lot of issues around, shortness of breath as well as fibrosis and damaged lung tissue, liver and endocrine organs such as pituitary and thyroid gland tanking on these medications.
And so most of these side effects are mild to moderate and reversible if detected early. And addressed appropriately. Typically they do so with suppressive medications such as steroids, which in the cancer population never has a good idea cause you're just going to increase things like Luca neogenesis depleting the immune system further and cause a weakening of the tissues in general or the body.
And then some of these side effects of these medications can be irreversible and in fact, result in death. And so an example of this is when these medications started really hitting the research, I had a lot of patients that signed up for a lot of these trials that were otherwise dealing with sort of ongoing managed disease processes.
But because they still had tumour burden on board, their doctors wanted to give it a, give it a good old try on these medications. And unfortunately many of those folks that come to the early research days, because we didn't understand the things that we're starting to understand today. Like I said, about 80% of the patients will have anywhere from a grade one to a grade four immune oversell at some numerous spots.
Five, ten cytokine release syndrome. It's often called CRS for short. not to be confused with the, can't remember to shoosh as many of us have gotten to know, but cytokine release syndrome is a large rapid release of cytokines, which are these immune substances that have many different actions in the body and may result in symptoms like fever and flu and nausea, aches and pains, sweats and chills, even down to low blood pressure crashes. autoimmune organ failure, such as liver issues, kidney issues, lung issues. All of this is secondary to immune therapy, including things like mistletoe, including things like these immune therapies we talked about. So we need and want to be very careful and cautious when we're looking at and dealing with cytokine release. There are various degrees of this and low dose naltrexone can be very helpful support for this process.
Slide number 11 is folks like Dr Tyler Jacks. He's a PhD at the Koch Institute for integrative cancer research at MIT. You know, a pretty smart guy here. You know, he talks about the problems of these very powerful, powerful therapies that are really starting to hit the market left and right. Initially, we use them more in therapy and not conditions like melanoma, very immunogenic type of cancers, but they're now starting to breach across all cancer types, all tissue types, all stages. And basically not discriminating on what type of cancer we're using them in.
But Dr. jacks, it goes on to say, that the challenge is that if you stimulate your immune system. It might get overstimulated, and it might actually start causing harms normal cells in the body. So we have to work a balance between attacking cancer and not attacking yourself. This will likely sound very familiar to all of us here in the low dose naltrexone camp because we have been utilizing this powerful therapy for many, many years now, especially in the autoimmune population. So wouldn't it makes sense that this drug, this off label drug could be a very helpful ally with these very powerful, potent chemotherapy, immunotherapy treatments.
So one of the cool things in preparation for this presentation that happened, since I first signed up to even view this presentation was we now have per slide number 12 here, per MD Anderson, they created a prognostic scoring system. Ironic and that for about a decade, I've had my own internal prognostic scoring system and I was looking at and seeing the use of these, possibilities in patients as these medications started to come down the pipeline. And I've also been able to really warn or heed the warnings that my patients to say, Hey, these drugs might not be appropriate for you, or, Hey, let's do some work before we start on these medications. Or, Hey, let's watch you very carefully because you've had a lot of risk factors that will make these drugs even more toxic for you. I sounded like the crazy person for all of those years, and yet, unfortunately, I was correct every single time and assessing this, and thankfully, our colleague, Dr Ralph Moss, had a paper come out back in October that highlighted this new MD Anderson prognostic scoring system of which I have outlined for you on slide number 12 and so on.
This is a question every patient who's considering utilizing one of these powerful immune cancer therapies is, will they even work? Are you even a candidate for these? And though we've had this information out for months and months now, I have still not seen it being applied clinically, which I think is very, very frustrating because it's really damaging to watch the number of patients that have terrible reactions to these medications.
So the first thing you want to look for does, does the patient have an absolute lymphocyte count. Under 1800 cells per microliter. Basically what we're looking for are these cells, their number too low because if they are, that's a problem, and frankly, the most important risk factor for failed response and adverse reactions to these medications.
Number two, on the MD Anderson prognostic scoring system, is an ECOG score greater than one. ECOG. For those of you who don't know stands for Eastern cooperative oncology group, it's basically a score to determine the ability of a patient to tolerate any therapy given their status, given their condition.
And so basically, the higher your score, the sicker the patient, and the less likely they'll have a good response to any therapies because they're so kind of beaten up by the disease process or the previous treatments that their response rates to these medications tend to not be very good. Number three, an elevated neutrophil count greater than 4,900 and what I've been watching in patients for decades now is something called an NLR neutrophil to lymphocyte ratio.
When we have more than two and neutrophils to every one lymphocyte, what we end up with is a poor functioning immune system. And a system that is scoring on this MD Anderson prognostic scoring system to make for a worse outcome. So basically, as we noted before, too low with lymphocytes, too high of neutrophils become very prognostic.
If you even do your own pub med search on an NLR ratio across all populations, whether you choose to do immune therapies or not, or even whether you have cancer currently or are aware that you have cancer currently or not, a poor NLR is an indicator of something that is terribly amiss in the immune system, and we can see this in autoimmune conditions as well as cancers.
And for patients that have poor NLRs that are dealing with cancer, going through cancer care, their prognosis is much worse when the NLR is off and the number for an elevated serum lactate dehydrogenase. My patients have gotten really accustomed to running an LDH on them for over 20 years now because a serum LDH is one of our key markers.
It's actually the cancer marker for things like lymphoma, certain melanomas, and multiple myeloma, and yet it's readily used. It used to be part of all of our comprehensive metabolic profiles, but about 15 years ago, we stopped using it for some unfortunate reason. But a level of a serum lactate dehydrogenase above 466. So this would be elevated on both of the quests or the lab LabCorp diagnostics. But if that's elevated this is a frank measurement of mitochondrial status. And if our mitochondria are, are foundering, if we don't have enough or they're not working well enough, we don't induce apoptosis. We do not have programmed cell death, which is under the direct supervision and a rule of mitochondrial status.
And so when the LDH is quite high, that can show us mitochondrial dysfunction, metabolic dysfunction that can also show us damaged tissues such as lung, liver and kidneys. And then that leads into number five on this going system, the presence of liver mass, which makes for a compromised liver and a compromised LDH. But I would also add kidney and lung issues here as well, because the basic if you've got some already established disease process in those, organs, the autoimmune flare, the autoimmune destruction with one of these medications is devastating. It can really create an immediate breakdown of going into liver failure, kidney failure with these medications. And then number six, if patients have an elevated platelet count over 300,000 that's this sort of process of having really thick, sticky blood, viral issues, macrophage issues, and frankly, again, another simple Pub Med search, high platelets alone are prognostic of cancer. And if you're somebody who doesn't have cancer, at least knowingly, and you see chronically elevated platelets over 300, you know, that you're likely dealing with a cancer process or an immune system that's lending itself to that. So it would be worth looking into and supporting yourself. And then finally, number seven on this list of the MDA, prognostic scoring system is being over the age of 52.
Now that's significant because of our longevity and our vitality, and our health is based on our mitochondrial function. So basically our ageing process is based on the nature of our mitochondria, and over the age of 50 our mitochondria start to kind of slow down and become a little bit weaker anyway, but especially the patient population that’s looking to be put on these medications have already had their mitochondria beat up by previous treatments.
And so that coupled with an elder, an older age, about 52 makes for much less response to these medications. So basically of these seven scores, to look at, the more risk factors you have, the more yeses you have to those seven questions, the lower the response to these medications of the immune-oncology medications, and the higher risk of adverse events to these drugs.
So. What do we do about it? Right? Because there are common, they're not going away. These drugs are only picking up momentum. And yet probably about 5% of the patients that are being put on them are even a good likely candidate.
And there are many, many more, not like the candidates that have been put on these medications. So on slide 13, this is my extremely oversimplified image. Of where low dose naltrexone can come in and, and weigh in on the balancing act of all of this is the idea that for many, many years now, we have already had a powerful immunomodulating therapy that has already been shown to enhance the standard of care, that's already been shown to prevent, oversell zealous immune reactions, whether that's too modern immune therapies, to autoimmune conditions in general, that overall supports the whole terrain and that condition and the quality of life of our patients, that has been shown to already lengthen survival times of cancer patients and the studies that have happened thus far, and it's at a fraction of the cost, and it's been in continuous use now for many decades in the arena of immunomodulation.
So my feeling without further ado is that this is a therapy that should be considered as an adjuvant therapy to any immune therapies utilized in the oncology patient on slide 14 I'm not going to spend any time here. Except for the fact, because all of our previous speakers and there are many between the book, the low dose naltrexone book in between.
Many of our colleagues, we've already discussed ad nauseum the mechanism of action of low dose naltrexone.
But basically I see this therapy as the treatment that sits between the extremes of the pharma co chemical paradigm at the modern immune therapies, along with sort of the old adage, fever therapies if things like hyperthermia or mistletoe or some of the other, even interleukin two that creates these sort of fever patterns so utilizing more of a low dose. The cumulative benefit of low dose naltrexone can be just the perfect, perfect addition to the kind of keep that Teeter totter of the immune system in balance.
And so on the slide 15, I go further. A quote for me that I've become known to say is that we treat the immune system like an on-off switch with regards to the modern immune therapy that’s being offered to patients today.
However, the elegant system needs a bit more finesse, treating it much more like a volume dial that needs to be adjusted accordingly. And so changing that score, changing that MD Anderson scoring system on slide number 16 I go into detail about what needs to happen with every patient that's considering this as a therapy, as a therapeutic intervention for their cancer process.
So changing the score, we can change that score. So exploring the MD Anderson prognostic scoring system before consideration of implementing an immune therapy is step number one. Dot. Step number two, explore the rest of the terrain to see what else needs to be addressed. Which I've talked about ad nauseum at other low dose naltrexone presentations and beyond.
So you're welcome to go back and explore what that looks like a bit as well. Number three, get a baseline vitamin D 25 O H level. Having a level greater than 50 nanograms per millilitre will enhance treatment outcomes of all immunotherapies, but also know that low dose naltrexone is basically ineffective if vitamin D therapies are not at a good level.
I'm hoping that my husband will be doing a presentation on this for future low dose naltrexone conferences as well. This is one of his areas of expertise and understand the implications of vitamin D with immunomodulation with LDN outcomes, and even how our epigenetics snips our BDR 2R 1 snips, in particular, interface with this can make or break our response therapy and even enhance our low dose naltrexone populations, responses for all therapies, not just with cancer immune therapies.
And then educate the patient on what to watch for with regards to side effects and symptoms of those immune therapies so you can intervene accordingly. So they don't end up with some of those life-threatening issues. And then prior to any immune treatment, I believe it's worth introducing low dose naltrexone, per the usual dosing schedule to just sort of getting the playing field balanced out before we start to add these other extremely potent therapies into the mix. And just like we use titration with low dose naltrexone, I believe we should be working much more in a, in a titration, a dose-escalating process with the immune therapies as well. We'll have much better outcomes than when we're trying to put everybody on that maximum tolerated dose that we have come so accustomed to as a standard of care conventional therapies.
And so finally, the take-home points of the discussion today was just to review the definition of the immune system, the types of immune organs and cells involved and our key players in our immune system.
The history of the immune therapies in the United States and our current modern applications, the side effects of these modern immune therapies and how we can do much better with regards to low dose naltrexone, as a key partner in these medications. So with that, I leave you more things to ponder for our next time we all get together.
Thank you. And be well.