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Angus Dalgleish, MD - The Role of LDN in the Management of Cancer (2017 Conference) (LDN, low dose naltrexone)
Prof. Angus Dalgleish: Well, I'm going to talk about LDN and cancer, and I'm coming from a very different, way of doing things. I was trained in some of my research at the Institute of Cancer Research, where you basically design drugs, put them in mice.
Other animals. And then you try and phase one trial in humans. And, I'm just going to give you a bit of my experience where it's really quite the opposite way around. Is that I came across LDN by, um, a completely different, uh, this is a. Oh, it's come back. Sorry. Right. That's that's it. Absolutely. As long as you're writing so, I can eat it.
Now, I came from a different way, and I was dealing with melanoma patients. I had a patient, who was doing incredibly well and we didn't have the drugs that we had at the time. This is, well, it was 13, 14 years ago now. And, I was just quite amazed, and I'm quite nosy. And I kept saying, you're taking something, and I don't know about it.
And, eventually, she confessed that she was taking this drug low dose naltrexone. And I said, what's that? Apart from naltrexone, I knew it's an antiopiat, but what's the low dose. I'd never heard of it before. And she explained to me that she had friends in New York, that she went to Dr. Bihari there. And they'd received low dose naltrexone for various things and that it worked.
And I said, well, how does it work? And I didn't know, but, Dr. Zagon's name was mentioned. And, so I had a look at a couple of the papers cause they are, they are published, and I showed an interest in. So next time I went to New York, she insisted, I went to Dr Bihari's clinic. So I went through the clinic, and I went through all his notes.
It was a card system. It's not computers. And counsellor notes were absolutely confusing. I couldn't possibly come to a conclusion or a decision at all. And I believe that somebody went on behalf of the NCI, did something rather similar and came away also a bit confused, but the message for multiple sclerosis was very clear.
And that there, there appear to be a really whole host of patients who had stopped progressing after they'd gone on low dose naltrexone. Anyhow, then there was another patient came, who was also an incredibly well, this patient actually had, breast cancer with widespread breast cancer metastasis, and the history showed that they'd get basically frozen and stopped progressing.
And this patient also admitted to that this coincided with going to New York and taking low dose naltrexone with, from Dr. Bihari. So I was very, very interested in this. So. We started to look at giving low dose naltrexone, to patients who are in that period where they've come off chemotherapy. They can't take chemotherapy anymore, and it's too early, really for palliative care.
So they're in that area. And I was really impressed with patients with a melanoma liver mets, and then for other liver mets who no longer able to take chemotherapy, but seemed to stabilize, on that the low dose naltrexone. And this was really first brought to my attention by my secretary who was saying that they want another repeat.
And that's how we started to notice that the patients were doing very well just on the low dose naltrexone. And some of them even I referred to it as happy pills. So yeah. When you've got a counsellor heading to palliative care to have something that makes you feel better and a better outlook in life.
From my point of view, that is well well worth considering as part of the management. Now I'm just going to go through cases because this is not something I developed and took through to the clinic, but the other way, just rather astounded at my clinical experience. One girl here who really did impress me, he was a 27-year-old girl with melanoma who, when I was looking at the various treatments that we were using, also had Crohn's disease and required increasing steroids and anti-TNF.
And it was clear that this treatment was interfering with the melanoma because she started to get the metastatic disease. And I'd been aware from my research is in with Dr Bihari, that it was also active in Crohn's disease. So I thought for the melanoma and crones, perhaps we could try and switch to LDN. And this was quite remarkable because she said within 48 hours of starting the LDN, it was the first time she'd work up in the morning without having to address the problems of diarrhoea. And the whole time I looked after her, she basically was able to come off the actual anti-TNF and stabilize the melanoma. Unfortunately, it just reduced the inevitable. In retrospect, we started probably the LDN far too late.
But another index case. And I'm a great believer of the well-observed anecdotes, which I've actually gone out of, um, uh, uh, fashion, uh, Two or three decades ago when I started doing clinical research people that said it was just full of areas, you had to have large randomized controlled trials. Otherwise, you wouldn't learn anything.
Well, I disagree. And this fellow here, as a 70-year-old man with a head and neck melanoma, he went on one of my nonspecific vaccine studies. And then he got increased metastases in his head and neck, he was a head and neck melanoma. They usually progress within six months a year. So the fact he did four years was, was very good for the vaccine treatment.
But when he progressed, he refused chemo. He was a GP, but he did agree to accept low dose naltrexone. So he took the low dose naltrexone. And when I saw him, it was two or three weeks later. I asked him how he felt on it, whether it was going to do any good. And he said, yeah, Look at me, it's a bloody disaster.
Stan took his shirt off to reveal vitiligo. Well, vitiligo is white patches you get, and if you're in the melanoma field to induce, have a treatment or a vaccine that induces vitiligo, you know, that patient is going to do very well because you've induced highly specific cytotoxic T killer cells against the tyrosinase, which is a major constituent of the melanoma.
Anyhow, he was very upset by this, but he's still here ten years later. I mean, it's quite incredible. He no longer mungs about the vitiligo, however. So, this way, it's not going. There we go. So the LDN induced specific CTLs, which does not activate with the previous vaccine, which was fascinating, the fact that you seem to be controlled there, that vaccine boost the innate immune response greatly, but you usually get CTL cytotoxic T cells, uh, induced if they exist there, but they're in dormant and sleeping.
Um, essentially the LDN was able to do something that activated these cells that were dormant. This, by the way, is the mechanism of these checkpoint inhibitors that you hear so much about the ipilimumab in the pembro and the nivo. What do they do? They take the brakes off the system. They don't make a new vaccine field system.
Basically, we now know that there are T-cells there, which would attack your cancer, but they've been suppressed. And I'm going to come to that in a, in a few minutes. But this was, um, essentially we decided that this change was difficult to explain just with modulation of the opiate receptors. It could be excepted.
That could be, I didn't fully understand opiate receptors and their role in the immune system, but I decided that there had to be another, um, mechanism of action. And I had worked with other things. I will actually give you some, some background very briefly as to why I asked, naltrexone specific designed to be a high affinity interacted with the opiate receptor.
Could it also act with something else because? Steven, so rightly said there's no drug that has one clear action. And, uh, we, uh, um, got to know that very well. I'll just step back a little bit because I was going to start looking for a receptor that we didn't know existed. And, uh, I had a history. I had discovered the CD four molecule the receptor for the HIV virus in the very early days of HIV research. And we did this by developing screens. Once we could tell the virus interacted with a cell, uh, we developed screens where you use just literally hundreds of antibodies to see if any of them would prevent the interaction and infection of the cell.
And all the ones with CD for inhibiting, um, attracting inhibit properties blocked the activation and entry of the virus. So I decided that we would try it and use the same approach for the low dose naltrexone. So we went looking around for all the assays for all the different immune receptors, which did include the Toll-like receptors.
And one thing I would disagree with Steve, whereas that isn't the literature about TLR four, but what we came up with and we couldn't repeat the four-story at all, but it became up with TLR nine, and I'll come into that in a, in a minute. Um, There we go. Uh, I just mentioned the HIV thing for a minute, because even when you get a very, very clear receptor interaction, I use this as a biological demonstration of just how complex disease and the immune system is, is that, um, we've found that if you look at this chart here, you see that the blue represents the CD four cells, and then the red, the virus load and the conditions, you can see a very nice fall off in the CD four cells and arise in the virus load and the conditions. And that was initially thought to be a lovely explanation for the CD four receptor. The virus enters via the CD four receptor kills all the CD four cells, and then you have no immune system. The actual fact, we found that a, if anything, this was very, very, very simplified, um, over-simplistic and fact that the disease, and if this is now accepted is really one of activation.
So that HIV induces chronic activation of the immune system. And it's the chronic activation, which acts as a noise and drowns out the specific signals. And that's what causes the, um, the disease. And we found. And Gene Shira mentioned in America that the disease was very, very similar to the graph versus host disease.
I don't want to get into this, but it's a disease of just overwhelming activation of the immune system. So it no longer works. And we think that that is the mechanism and that the mechanism is due to another receptor, which wasn't very well defined at the time. Now, why am I saying this? Because it actually gave us some insight into what was going on in cancer, because we knew in cancer, the Gene Shira was the work that the National Cancer Institute had shown several different cancers, that there was an immune suppression going on, which you could detect just taking lymphocytes from the arm, not as marked as in HIV, but it was in cancer.
So this is the classic National Cancer Institute, a progression of cancer. And I have a. pointer here. And basically where one change leads to cell surviving or not dying. Another change will lead to growing bigger and better. Another one will allow it to really get ripping and then another few and they get out of control.
And do you develop cancer? And basically out of the work that I've just been talking about with the first of the HIV, um, the particular receptor and the fact that that particular sector interaction doesn't account for the disease at all, we started to look, um, this is, uh, can I burn? And I realized that what was going on and his cancer developed.
Was that they were developing in the area of chronic inflammation with all the growth factors that are required for angiogenesis and the suppressed immune suppression that you get with this chronic inflammation allows the initiation cell to be to escape the CTL killers, which we know are there. Now we can give these checkpoint inhibitors and that, but they can't see the treatment, which is why a lot of the checkpoints don't work.
And just to put this into context, we're able to show, this is one of the very few, little bits of science. So going to show you, but this is so clear. We measured the immune response here by producing interferon-gamma from patients with colorectal cancer before the surgery. These are controls non-cancerous about surgery, and this is the patients amongst afterwards. Are they'd all come back to normal. So the only conclusion of that is the colon cancer caused immune suppression, which we could measure very easily and it came back. There's a slight twist to that earlier. I don't have my press there now.
There you go. There's a slide. There's a slight twist for that. Anyhow, that's data showing that the, uh, the more the patient came back to normal, the longer they lived. And we went on to, uh, to realize that, um, with this, there was a balance of the immune system, and this is where they're coming back to, um, uh, low dose naltrexone.
So important. It's a balance between the cell mediator and the humoral response, and that they. They balance each other up. And if you put a bait them, they come back rather lightened Lorenz, attractor, which is very one of the seminal components of nonlinear mathematics, how things can repeat time and time ago.
Never. I go exactly the same way it's nonlinear, but very consistent, reliable around these attractors now in disease and HIV, chronic disease and cancer, this cell-mediated response is suppressed, and the humeral is increased. And what we found was that. You cannot. You can correct that by removing cancer.
You cannot correct it in diseases where you can't remove all the cancers. So you're dealing with that. And that brings me to the other work that I'm involved in very early on. And this is another case of seeing patients improve with a drug that was said to be awful for living. And right now for thalidomide, which comes in left and right.
Um, it's very interesting because the left is good. And the right is bad. I think it's that way around. Isn't it. And, uh, I was very interested in the patient who responded fantastically to thalidomide for who couldn't respond to steroids. I mean, basically, it was a very, very bad form of the disease with vasculitis and everything they absolutely could by thalidomide, even though that being in intensive care, completely steroid-resistant.
And I wrote an article saying this drug is fantastic. We must resurrect to do something about it. And they a fellow. I replied to this article chat called Steve Thomas. He used to work for Cairo. He said he spent ages making the thalidomide, the left drug. And in order to avoid the right, that was the bad bit.
But as soon as you put it into the human, the liver flicked it over it. Right? So that was obviously not the way, but the good bits of thalidomide ever so good that you suggested we did another way. And that just makes analogues. Well, the first of these analogues, lenalidomide. It's one of them, I think it was the second biggest seven drug of the in oncology last year for myeloma lymphoma.
And that's how you started it. Now, what was interesting is we had no idea how these drugs worked on the receptors. In fact, the only one that they really, uh, thought that, um, would work on, uh, was anti TNF. And I don't need them, so the one there on the left, this was the mechanism of action. When I'm putting this up to say, is.
Especially when we're talking about specific receptors, we really don't have a clue with regards, which is the most important cause there's so many and now it's, there's been beautifully elucidated how it does all this. The Lenalidomide sticks into a thing called cereblon and that alter the way the, um, the other part that doesn't stick in
interacts with cascade signalling pathways, which gives it the reason why it's been so effective in so many conditions. Now, why have I spent all this time telling you about these things? Because. This set the template for me, understanding the low dose naltrexone, low dose naltrexone is clearly doing something it's not just as simple as an opiate receptor.
There are massive knock arms. And so this is why we went looking. That just shows how effective a little light is. So with the receptors, we screened all these receptors, and we hit upon a positive hit. The screenprint is a very strong signal to TLR nine toll-like receptor nine, not four as previously reported.
And we spent ages trying to get signal on four and, um, that the result was the paper spent ages trying to get a review that didn't lock it cause they worked in four and we finally got it in Frontiers in immunology. And what is important to see is that the toll-like receptors two, three, four, five, six are external cell membrane-based.
These are the ones that our vaccines work on. The toll-like receptors, seven, eight, nine, are normally internal receptors, but they are overexpressed in certain conditions, TLR nine and here is the basic data. It's in the morning, and it's very, very hot in here, and very hot and in the Glasgow out.
I don't expect you to go over this. I'll just tell you what it shows, but just to show us, we did very fine, uh, very didactic experiments. We repeated the many times that we did all sorts of controls, but it is TLR four, a TLR nine, which has affected. We looked at the inhibition of the aisle six production, which was a very, very strong inhibition through the TLR nine it's mentioned the paper that shows all these cytokines, and inflammatory cytokines increase.
No effect was seen a tall TLR four and no effect we've seen for IOL one, which shares the main TLR signalling system. And, uh, we are able to show the inhibition of these cytokines. I'm not going to go through the details. Again, just to point out that here, we were able to show that there is a complete, um, inhibition with a T and TLR nine, but not with a TLR four.
This is all published. So I'm not going to, uh, go through it further in detail. And also to point out that we looked at naltrexone does not reduce the overall. Uh, um, cell viability, um, peripheral blood mononuclear cells at all. So it's acting through the signalling, and it's not actually having any particular effect on survival.
Now, why was TLR nine? Very interesting for me because it was, it's a highly reproducible, we did it through many different techniques. We did it doing, we, we also sent it out to other laboratories. Blindly. And they were able to get this back because I was so worried about the TLR four being out there. So we know this is a very, very important.
So TLR nine for me. Why is it important? It is important because the goal I had with the Crohn's disease who responded within 48 hours, we now know TLR nine is grossly overexpressed in Crohn's disease and actually psoriasis. It's fascinating. I had patients with psoriasis, unbelievable response, and I think that's due to the fact that it's a TLR nine and the other thing it's overexpressed and several achiever types, including pancreas in gliomas.
And there are several reports as you know, out there of improvements and pancreatic cancer to low dose naltrexone, but it's also important in dendritic cell activation and antigen expression. Nah, just, just, uh, really push it very carefully. Is this TLR nine? I was expecting it to be an agonist. No data was highly antagonist, but it is interesting because I used that immune modulation, I mean, had a complicated mechanism of action of an HIV and known receptors and it doesn't explain it doesn't work out like that.
And then we had the wonderful examples from thalidomide. Showing just how amazing that drug is at correcting the immune system. In fact, we call those drugs in modulators, uh, specifically, and I think low dose naltrexone is actually an immune modulator. Um, and it probably, and we haven't got the data yet.
I am only presenting stuff. I'm only allowed to present stuff that I've published, but I think that the, um, that the dendritic cell thing is affected by low dose naltrexone and Zagon's data would be consistent with that. So you really have a new modulator, and the thing that's overexpressing TLR nine is brought down, and anything under expressing it to the actual presentation is brought out that that's my current thinking.
Now I'm just going to. Um, they play a fundamental role in the immune system. I am just going to go on to one last little bit of, uh, of lab data, because I was very, very concerned that low dose naltrexone amongst the doctors, et cetera, then either never heard of it, or even one of my best friends who's in neurologists.
And, um, it has multiple sclerosis patients on it. It's so cynical about it. I thought we really got to bring it as much science into it as you possibly can. And this one was work done by Wai Liu who's senior postdoctoral fellows and his particular interest in this and the cannabinoids, which I notice is also out there, but I'm not going to talk about this.
He was basically involved with doing gene chipping, uh, for drugs and, uh, I said, that's fascinating. So, you know, see what you feel. And, uh, basically you get these genes express, and you can put them in a Venn diagram. And, uh, what he was looking at his tumour cell lines before and after cytotoxic drugs were added as which, which pathway is doing effects, you know, like say B RAF inhibitors, the term of the B raffing, et cetera, et cetera.
So I said to him if he got some more chips, perhaps we could look at the expression of low dose naltrexone and normal dose naltrexone and see if there's a difference. And that basically is exactly what we found. Um, we found the genes that there's, there's an overlap, but it's the minority, but there has a tremendous number of unique genes, which are expressed by low dose naltrexone, which then switched off as you raise the dose. And once again, we've had that, we've done this ad nauseum and the interesting genes in the top 10, uh, are, um, completely reproducible with the low dose. The switched-on energy takes the, uh, um, OSAP they're switched off. And these have a unique one on the cell cycle and the immune system.
So, this actually is very in keeping with what I think is a, an immune modulator. Uh, all this is just wonderful work. You can go to it. It's all published. And we're looking through all the cells, pathways, cell cycle perturbations, and finding some very, very interesting observations. And one of them, which, uh, we've done is actually even better for the cannabinoids is that the cell death is better on withdrawal.
And this has led to a lot of discussions, which I like to do. The discussion is with low dose naltrexone and seeing gains coming to an end in a minute. Um, how do we actually use these drugs? We've we think that the, uh, cell death induced by a cannabinoid is so strong that it should be used intermittently.
This has been suggested to, for low dose naltrexone, which we've shown here in the washout, but. I think that this is where I really like to have a, you know, we're all here to have a discussion about it. I think that low dose naltrexone given daily is very intermittent because it has such a rapid washout period.
So you're basically only exposing the patient for a few hours. And so I'd like to discuss that further. It's one of the great things about having these meetings. Um, I would just like to end on a couple of other more recent, uh, patients. And, uh, just to say that I've been very, very impressed with, um, glioma patients who've, uh, been seen because of the, uh, progressed and radiotherapy.
And temozolomide, in fact, I don't do gliomas in the NHS. So melanoma is what they've given me to do, but I was rather horrified if I. A close cousin and a friend of a friend and a colleague work all developed gliomas in a very short time to realize just how a little progress has been made in this field in the last 30 years.
And, um, with the LDN, uh, um, and the other thing I wanted to really emphasize. Here is you had it on your list too. And I've asked you about talking to Steven here. Is the importance of vitamin D and the number of patients I see with cancer who got low vitamin D, and we know that vitamin D we did these experiments ages ago.
You need vitamin D in all our cancer experiments in order to get any significant killing, and you need vitamin D to get any kind of immune system to work. So always do the vitamin D low dose naltrexone. And we did some of these other drugs Metformin. Because it's an inventory inhibitor and that pathway is very important in gliomas.
And I'm just amazed that some of these patients have improved. This one here has improved dramatically, um, and all the areas after just putting them on this treatment without having any other, um, so-called conventional treatment. So it's a signal. It's several patients than that. So this is the end of my talk.
So in summary, Uh, LDN has direct and indirect, uh, activity in cancer, different effects in cancer cell lines. The gene expression to me means it is an I've claimed it's a new clinical entity because of the gene expression at low dose. This is completely different from the high doses. It has the indirect infirm activity of inflammation and shin presentation, and it acts as an immune modulator as well as being an antagonist TLR nine.
That's my last slide and F. Totally Lisa I'm on time. And I really want to thank way Lou and Kathy Scott. He did all the work. I mean, I flashed through those, um, presentations because I know it's really hot and it's a Saturday in glass, but it's all published, and it's all been prepared review. And I think that, that the gene expression work and all the withdrawal work that way.
Lou and Kathy Scott did, who actually also did something I haven't, uh, Um, shown here. They also showed that the cannabis, uh, preparations, radio sensitized, the gliomas, which is wonderful, but it wasn't part of the LDN, but they are really, really fantastic operatives. And Rachel Canton, Rachel Allen, who did all the TLR studies with me, um, basically, um, did.
Every which way we could to show about a TLR interaction or that result is really real. And through the IC VI formally the cancer of accident Institute for funding and, uh, prime protect the work so we can continue with it. Thank you very much.
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