This module on cancer immunotherapy answers these questions:
–> How does the immune system work?
–> What are the different kinds of immunotherapies?
–> Who can have cancer immunotherapy?
–> How can you get cancer immunotherapy?
This is module 6 – Immunotherapy, and I’m going to talk a bit about the immune system. I’ll talk a bit about how immunotherapy fits into oncology. It fits in very badly, so I’ll explain a bit about that. I’ll talk about different kinds of immunotherapy, who can have immunotherapy, how to access immunotherapy and choose immunotherapy.
Immunotherapy is a whole branch of oncology, a whole branch of treating cancer. I’m not a doctor and I won’t give medical advice, but from a lot of conversations with research scientists, oncologists, radiotherapists, immunotherapists, surgeons and general doctors, a lot of conversations with patients over the 6 years of dealing with terminal stage 4 bowel cancer, I’ve got a lot of communication with patients, it does seem that all long-term response for late stage patients is immune-system related. I don’t necessarily mean that they’ve had immunotherapy and it’s cured them, or added lots of years to their life, but it does seem that immune response is the key thing. That also implies less immune suppression.
With my treatments, I’ve always tried to find treatments that don’t affect the immune system so much, that don’t damage the immune system so much, that don’t cause so much immune suppression. It seems that there are 4 things for long-term survival, and they’re all interconnected.
One is the state of the patient’s immune system- overall how robust is your immune system. That means taking treatments that don’t cause too much immune suppression.
The variety of treatments – again that relates to the immune system, because cancer hides from your immune system. It hides from the treatments after a while, like treatment resistance.
The total amount of treatment that you have – again that’s very related to the immune system, because unfortunately most cancer treatments weaken our immune system a lot. They make us sick directly, and often we get infections and therefore have to stop treatment, or take breaks. We might get infections after surgery that mean we can’t have chemo again for a long time – this kind of thing.
The fourth thing which ties it all together, is access to the new treatments. It does seem that a lot of the newer treatments cause less immunosuppression. They are often designed that way, but sometimes it’s just the nature of the new treatments. An obvious example of that would be molecular targeted treatments, which tend to cause less immunosuppression than chemo. Chemotherapy kills your white blood cells. When we talk about the immune system, we’re largely talking about the behavior and the number of white blood cells.
The gentler radiotherapies kill fewer white blood cells. The radiation cycles are shorter. That means fewer white blood cells in your body are exposed to the radiation. If you think about it, your blood is going all around your body, all the time takes. I think 14 minutes for the blood to pass around the body. So wherever you’re having that beam of radiation, blood is flowing past, taking white blood cells past that are getting zapped.
Newer treatments tend to cause less immunosuppression either by design, or just by the very nature of the treatment.
Those four things, I know it doesn’t sound very scientific, but I observe from 6 years of a lot of treatment, 5 years of chemo, lots of molecular targeted therapy, a couple of big cancer surgeries, a lot of radiotherapy – I did proton beam therapy and Tomotherapy, I’ve done possibly more hyperthermia therapy than anyone on Earth (Japan uses hyperthermia quite a lot, and I think I’ve had it more than any of us in Japan, so it’s quite likely I’ve had it more than anyone else in the world). It’s a very mild treatment, probably makes a small difference, but it’s very safe and very easy to do, so it makes sense to have it.
So after combinations of treatments, my observation has been that those four things are what really makes the difference, and it’s really about your immune system.
This is very contrary to the history of oncology, where the immune system has been ignored. The reason it’s been ignored is completely reasonable, which is that in the first 60-70 years of modern oncology, almost the definition of cancer is cancer is a disease that’s in your body, that your body can’t recognize as a disease, because it’s your own cells mutated and the immune system can’t get it, so the immune system plays no role in cancer.
Of course now we know essentially the opposite is true. It may in fact be that the immune system is protecting everyone from cancer all the time, and that maybe everyone’s walking around with little cancers, and the immune system successfully gets those. For those of us diagnosed with cancer, it means that cancer is formed in our body that the immune system couldn’t get.
So it’s incorrect to describe immunotherapy as new, which the media always do. They always describe immunotherapies like a “new cancer treatment, a new and promising cancer treatment”.
The inventor of immunotherapy, serious modern immunotherapy – he was starting his research in early 1980s, when for the cancers he was dealing with, the main treatment was amputation. That’s Dr Stephen Rosenberg who is at the National Cancer Institute in Maryland. He’s head of surgery there, and he has written a very good book about his work on the development of immunotherapy, called “The Transformed Cell”. That’s a very good book on cancer to read.
I always cringe when I hear a lot of people reading books on cancer by non-experts. “The Emperor of all Maladies” springs to mind – it is full of inaccuracies on every page. Just because someone’s a Doctor, doesn’t mean they know much about cancer. It’s a very big field. Just the disease itself is a massive field. Treatment is a whole other issue.
There’s still a huge problem that oncology misunderstands immunotherapy. It’s often thought of as a single treatment. Your oncologist may say to you, “Sorry but the test shows you’re not eligible for immunotherapy”, which doesn’t make any sense medically, because immunotherapy is a whole branch of medicine.
If you have an autoimmune disease, that does present a lot of issues with immunotherapy, because many kinds of immunotherapy are trying to get more immune response. So if you have an autoimmune disease like rheumatoid arthritis, you could get some serious complications from that. So that is one thing to bear in mind. It’s still probably worth talking directly to some immunotherapists about the risk and benefit, and how side effects could be managed. But it doesn’t make sense to say that someone’s not eligible for immunotherapy, because it’s a field of cancer treatment with many treatments within it.
Treatments that only work for a very small % of cancer patients, but work very well, are often being used in trials with people who shouldn’t respond well, but combining the immunotherapy with other drugs. The most famous example of this would be the checkpoint inhibitors which got a lot of media attention about five years ago – Keytruda being the most famous example (it was the first or second commercial checkpoint inhibitor).
The way the media describe it is, “the checkpoint inhibitor takes the brakes off the immune system, and then your immune system magically recognizes the cancer and kills all the cancer so everything’s wonderful”. That’s an exaggeration on many levels, but checkpoint inhibitors do make it harder for cancer to suppress the immune system, and make it harder for cancer to ignore the immune system, things that cancer is able to do to survive.
The reason that Keytruda got a lot of attention – it was approved in 2016, I don’t remember for which cancer, but it was then approved again in 2017 in the US by the Federal Administration for all hard tumors (solid tumors) for patients who have MSI High, which means that tumors are quite mutated, the cancer cells are quite mutated). It was the first time really that a cancer drug was approved for loads of types of cancers at the same time.
Cancer drugs need to be proven for each cancer type that they get approved for. That’s a long, expensive process and it’s one of the things that holds back some immunotherapies, because some immunotherapies work well for many different cancer drugs.
So it still is a big problem. You will meet resistance probably when you’re asking your oncologist about immunotherapy. It’s important to get access to immunotherapists, and I’ll talk a bit later on about how you do that, and the challenge of getting immunotherapy and choosing immunotherapy and accessing immunotherapy. It’s really a challenge after challenge after challenge.
Unfortunately there’s a lot of hype about it. We saw earlier this year, I think it was a checkpoint inhibitor trial for colon cancer patients. It was announced at ASCO (American Society for Clinical Oncology) at their yearly conference, the world’s biggest cancer conference. Some scientists or some researchers presented this paper, and they’d got a 100% response of total remission of all the patients in the group. This was picked up by the media, presumably promoted by whoever was running the research, and of course the details were they were early stage colon cancer patients, they were highly selected, so testing had revealed that these people had highly mutated cancer cells, which means they tend to respond very well to immunotherapy, and the research group was something like 31 patients.
If you can imagine, in the weeks after this was announced this summer, you had people at breast cancer clinics getting phone calls from the patient saying, “I’ve heard about this treatment, can I get this treatment?”, and the oncologist having to say “that’s for early stage colon cancer patients”.
We have to fight through the hype, but then there are lots of other issues as well.
Obviously some of these treatments are very new and fiendishly expensive. In some countries it’s quite unregulated, it’s usually done by private clinics. The people running the clinics may be quite new. So it’s really important if you’re going to do immunotherapy, you need to find people who’ve been doing it for quite a while. Ideally they should be research scientists as well. Ideally they should work with larger hospitals as well. You don’t really want to be getting immunotherapy from a biotech startup. I’m not a doctor but I would strongly advise against going to an immunotherapy clinic with big claims, a lot of marketing, and they’re usually refusing to give data, saying they’ve got lots of data but they can’t share it, giving weird reasons why they can’t share it. You want to avoid those.
Another big problem- if the immunotherapy involves human cells (either grown from a commercial cell line, or autologous – which means grown from your own cells), the processing and training of those cells is really important.
In my case, the immunotherapy I have is autologous, that’s made from my own white blood cells. Even so, when they’re taken from my blood- the process is called apheresis which is a little bit like kidney dialysis – some of your blood is pumped around in a machine, some white blood cells removed, your blood is returned to you) – then those cells are taken to a lab and over several weeks (in my case ~3 weeks), those cells are expanded. That just means they grow more cells from them. But they’re also selected. The lab should be selecting the cells amongst your cells that seem to be most active against cancer. They may also be doing things to increase the immune activity, so incubating them with various things, and maybe doing other things to make those cells the best possible cancer fighting cells.
In my case, I was fortunate enough to do surgery in Japan with a surgeon who agreed to freeze some of the tissue, so it could then be used for immunotherapy.
But many clinics, their cell processing is not going to be fantastic. So the quality of the cells make a lot of difference, and it’s very hard for a patient to judge these kinds of things.
In Japan, medical engineering is world leading, so the quality of the cells that I get is very high, and I think that may be one of the reasons why I’ve had such a good response. My immunotherapy clinic is very careful about the timing of the immunotherapy. If you have a kind of immunotherapy (I had so adoptive cell therapy – those are a family of immunotherapies where you get cells given to you, either growing from your own or grown from a commercial line. T Cell adoptive cell immunotherapy is relatively well known in the world). A lot of the cells that are put into your body are recognized as foreign, even if they’re grown from your own cells, and they’re destroyed. Yes, you’re given a huge number, and the idea is many, maybe most get destroyed, and hopefully there are enough to go and get the cancer.
But still, the timing makes a big difference. If you have that kind of immunotherapy just after chemotherapy or just after radiotherapy, you should get a better response, because chemotherapy and radiotherapy cause immune system suppression, which is usually a terrible thing. However it’s very handy if you’re introducing a whole bunch of cells into your body. It’s very handy to have some immune suppression, because then more of them are going to survive.
To continue describing the minefield of accessing and selecting immunotherapy, obviously the cost can be massive. Depending on where you are, if you’re in a country where maybe you have universal health care, but not a lot of choice in your health care, like the UK where I’m from. In the UK, access to immunotherapy is very poor through the public health system (the NHS). So you have two options within that. One is to get your oncologist to get you into a trial. Find an immunotherapy trial and get in via a trial. The other path is to get access to immunotherapy through what I think is currently called the Cancer Drug Fund.
I know I say this in every module, but the Cancer Drug Fund in the UK sometimes gets renamed, the government sometimes tries to scrap it. But the Cancer Drug Fund in the UK allows patients to access drugs that are not approved for use in the UK – not because they’re dangerous or ineffective, but because they’re expensive. So those are two options and I guess they apply to you wherever you are, if you’re getting treated within the public health system in your country. So you could either get your oncologist to try and get you into trial, or you could find another path.
For example in the UK, it is possible to be sent abroad for a treatment that’s not available in the NHS. That generally means being sent to Germany or the US. I guess the NHS is unaware of how affordable Japanese treatment is. In Japan, our treatment is very highly regulated, which is generally a good thing I think, because it makes the prices reasonable.
Another way to access it of course is private treatment. Now of course I know we have our friends in the US who don’t really have a public health system, at least not in the way that we generally think of public health systems. So in that case everything is private, although at least some hospitals in the US are non-profit but still seem to be incredibly expensive. If you’re in a country with a public health system like the UK, France, you could still go private.
That will generally involve crowdfunding, because the cost for this kind of thing can be very high.
In Asia the cost of immunotherapy is low compared to Europe, or at least low compared to Western Europe, and very low compared to the US. I’m very biased towards immunotherapy in Japan, because it seems that it is affordable here, and yet the quality is very high.
There’s a lot of immunotherapy available in Eastern Europe and Southeast Asia. I am not in a position to comment on those, but I would say, think of the things I’ve said about cell quality, about marketing and hype. My cynicism guides me. When I see an immunotherapy clinic that’s listing 50 different treatments on their website, that are pseudoscience stuff, I think, “I wouldn’t trust their immunotherapy.”
By the same rationale, if they’re claiming their one treatment treats loads and loads of different things, not cancer related at all, again that makes me a bit skeptical.
So you have to be a bit careful about junk science. Unfortunately with immunotherapy, a lot of the language that we see in the marketing is very emotive. These treatments are described as “natural”. They “naturally aid your immune system to wipe out the cancer” – it’s very unfortunate.
The immunotherapy I had uses NK cells. The scientific name for NK cell means natural killer cell – it does kill cancer but it’s still a very emotive and silly term.
There’s also the issue of amateur science. I’m in a lot of cancer Facebook groups, and we have a lot of people in the groups who claim that they’ve cured their cancer by a combination of various off-label drug use, or green smoothies and yoga every day, and this is boosting their immune system. I’ve never seen a scrap of robust evidence for any of that kind of stuff. I’d love to believe it but again, there doesn’t seem to be such a thing as immune-boosting foods.
The science around nutrition is complicated and probably mostly wrong. We’ll find out in some decades in the future maybe. With respect to cancer particularly, if you have something that boosts your immune system, that does not necessarily mean it’s going to boost your immune system and have any effect at all, because cancer suppresses the immune system. So if you did have something that boosts the immune system, then the cancer cells are able to just increase their level of immunosuppression. They don’t give up easily, partly because there are many of them, so some die and the surviving ones are able to survive, and go on to make more populations of cancer cells.
This is the problem we have for cancer treatment- this is why we get drug resistance ,this is why chemotherapy stops working after a while. It’s because cancer tumors, cancer cells evolve. It’s a big population of cells, they’re reproducing and dividing rapidly. That’s part of the definition of cancer. They’re under survival pressure, because we’re attacking them with chemotherapy or radiotherapy and other treatments.
So the tough cells unfortunately, they survive and go on to make the next cells. This is why it’s such an issue. This is why I’m very skeptical, when you hear these people saying, “ I take these 10 things every day to boost my immune system, and it’s doing wonders for the cancer.”
I’ve looked a lot for evidence, and I’ve not found any robust evidence for that at all. That is part of immunotherapy, as treatments that generally boost the immune system – some of these are based in strong science, with reasonable evidence.
Hyperthermia therapy is an example of that. Regional hypothermia therapy, where you heat up tumors – heat up the cancer to a fever range, this causes changes on the cells of the surface of the cells, so the cells have to protect themselves from heat. This is happening to your healthy cells as well that are getting heated, but healthy cells are very good at self-repair. From radiotherapy, for example, healthy cells will start to repair within 20-30 minutes after the radiation beam is switched off.
Cancer cells are very poor at self-repair for various reasons. Part of the reason that they are cancer cells, is generally thought to be that they’re not good at repairing damaged DNA. That’s why they are a cancer.
Hyperthermia therapy has an immunotherapeutic effect, because some of the cancer cells die from the heating (not many, but some). When cancer cells die, the immune system says, that’s because the little bits of cancer cells are grabbed by cells called dendritic cells. They’re taken to the local lymph nodes. The dendritic cells essentially hand them over to the T cells, and then the T cells know what to look for, and they go and find some cancer cells and kill them.
The NK Cell Therapy that I have- that’s a bit different because NK cells are able to kill cancer cells that are not presenting any antigens, that aren’t labeled as cancer cells. So that’s why, at least in Japan, there’s a belief and some evidence that with NK cells, you get a longer treatment response, because NK cells are better able to destroy cancer cells that are not labeled as cancer cells .
The way the immune system works is, we generally think of having an innate immune system that’s built in at birth. A lot of that is inherited by our mother or inherited from our father. The immune system is able to recognize foreign things and attack them. Then we also have the adaptive immune system, which learns what to attack.
I mentioned dendritic cells – they tend to be in the skin a lot, because of course we get attacked by nasty things through our skin, but also in those mucosal membranes, like the lining of your nose and lining in the gut. They guard your body – essentially they find suspicious looking things, they grab hold of them with their many arms, they go over to their local lymph nodes and they present them to the T cells, so the T cells know what to do.
You’ve also got these NK cells. NK cells are able to kill cells that are presenting antigens、 but also cells that aren’t. NK cells can kill bacteria and viruses – they can recognize those as well.
I’ve had NK cell therapy and it was autologous adoptive cell therapy – that means grown from my own blood. I’ve also had a dendritic cancer vaccine.
Cancer vaccines are very promising. They’re one of those cancer treatments that should in theory cure everything, because vaccines have been around for a long time, vaccines work very well. Some of them, I should say that I’m talking about vaccines that are used to treat disease. This is different from the HPV vaccine, which is used to prevent cervical cancer.
Dendritic cell vaccine is a vaccine that would be injected or given by a drip, but seems to work better being injected. Essentially you’re injecting a lot of these dendritic cells – these cells that have been selected for high activity against cancer and they may have been trained.
In my case, they’re trained against my cancer, or they could be trained against a commercial product. My wife who has ovarian cancer, she had dendritic cell therapy that was trained with a commercial peptide.
The immunotherapy clinic looks at your cancer type and they will look in their catalog of immunotherapy training products, and choose one. Those cancer vaccines should be really promising. They do seem to work a bit. With dendritic cell vaccines, it seems that for about six months afterwards, you get a lot more T-cell activity which makes sense, because you’re putting a lot more dendritic cells in, and it does seem that you can have it regularly. There’s not really any kind of bad reaction especially if it’s autologous, so made from your own cells.
I’ve never really had any side effects from the adoptive cell transfer. Occasionally I’d get a skin rash or some swelling at the injection site. I had my dendritic cells by injection – it seems to work a bit better than doing an IV drip. The injections are insanely painful. My clinic has done a lot of research on how to return dendritic cells to the patient, and they found the most effective way seems to be injecting around the ribs, because there’s lots of lymph nodes there. They put the syringe at a very shallow angle, to kind of get as many dendritic cells into the lymph nodes as possible.
Some clinics are getting really good results from putting immunotherapy directly into tumors. The reason that the immunotherapy clinic I go to doesn’t do that, is because you need to do that scanner guided, so they’re going to be doing that with ultrasound or with a special type of CT scanner. But injecting the immunotherapy agent directly into the tumor, should get a lot more response.
Of course that might just not be practical. If tumors are deep within the body, you’re not going to be injecting into there. As I said, the cost is going to be a lot higher with the scanning.
Adoptive cell immunotherapy is one type. There’s the T cells, the NK cells, and the dendritic cells. Most places are focusing on the T cells. I have to say that from my understanding, it seems to be because it’s easier and kind of cheaper to do, although the price still seems astronomical. The longevity of the response seems to be less with T cells.
For NK Cell Therapy, the longevity seems to be much longer. It’s much harder to incubate and filter the NK cells. This cell preparation is not a trivial thing. You can’t do it on your kitchen table in a bunch of test tubes. It’s done in a clean room, almost like those clean rooms they’re used for making microchips. So it’s quite a serious undertaking at the cell preparation lab. It’s not someone standing at a counter with a bunch of test tubes and a pipette. It’s a very serious undertaking to get these cells to this quality.
There are types of immunotherapy where the % of cancer patients who will probably get a response is very low. In the case of the immunotherapies I’ve had, NK cell therapy and dendritic cell therapy, it seems that maybe most patients get some response. For some reason, I seem to be a particularly good responder. There’s not any good evidence or methodology about who gets a good response and who doesn’t. Hopefully it will be discovered in the future, but it doesn’t seem to be based on a specific genetic mutation or anything like that.
You will hear a common situation is that you’ll have a liquid biopsy that checks the level of mutation, and you’re told “Sorry, you can’t have checkpoint inhibitors because your microsatellite stable or MSI low”. You may still get a great result from NK cell and dendritic cell therapy.
I’m MSI low (also known confusingly as MSS – microsatellite stable), so my cancer cells aren’t massively mutated and I still got a good result.
Another kind of similar type of immunotherapy you hear about, is the CAR T-cell. That stands for Chimeric Antigen T cell. Chimeric just means that it is animal derived. With those kinds of immunotherapies, there is a safety issue, that you’re introducing very foreign cells. You can get quite serious, potentially fatal kidney failure for example, so that is an issue to think about.
CAR T-cell therapy at the moment is horrifically expensive, hundreds of thousands of dollars.
Cancer tumors contain a lot of white blood cells. Some cancer tumors can be 50% white blood cells, so the interactions are very complicated. You’re often looking for immunotherapies that are going to make those cancer cells in the tumors visible to the white blood cells that are there, or that are going to introduce lots of white blood cells to overcome that or get some kind of immune response.
As I mentioned, there’s adaptive cell, adoptive cell transfer immunotherapy, there’s CAR T- Cell ones. There are general immune system boosters. Hyperthermia therapy is probably the best version of that.
Another one I’m quite skeptical about, is the metabolic treatments to boost the immune system. You read a lot online about DCA (dichloroacetate). There was so much hype about this. In fact, just at the time I was diagnosed (2016-2017), everyone on the web was going on about dichloroacetate, this miracle treatment that starves the cancer, prevents the cancer doing anaerobic respiration, so it will just die. I want to say it’s nonsense, but there’s a little bit of truth in it. It seems to work slightly for a while. It may be very worth doing if you’re having other immunotherapies.
The same with metformin, which is a diabetes drug that seems to cause increased T-cell activity and also makes it harder for the cancer cells to protect themselves with acid.
Cancer tumors have this layer of lactic acid around, which makes it hard to get the white blood cells in. Metformin and dichloroacetate both seemed to inhibit that a bit, but there will be some cells that are not responsive to those immune system boosters. They will continue to hide from the immune system, and they will continue to divide and reproduce, and after a while they become the majority of your cancer tumors.
These sort of immune system boosting treatments – their effect is probably slight and probably temporary. But we find that with all cancer treatments. I have bowel cancer which is radio resistant. Actually, bowel cancer is good at surviving radiation.Radiotherapy is still very commonly used, but for bowel cancer, you need higher doses, more cycles and you may get less response.
As a patient, it’s a very messy, difficult situation to choose immunotherapy, to access immunotherapy. I must say again, I’m very biased but I think it seems to be the most important thing to do, is find what immunotherapy you can get hold of, that makes sense for your cancer type. Connect with other patients who have immunotherapy, look very carefully at what is offered by your public health system if you have one, your private health system, and these clinics that exist all over the world and offer a wide range of treatments.
Hopefully that has given you a bit of an overview of immunotherapy. I can’t not be biased towards immunotherapy, and I can’t not be biased towards adoptive cell immunotherapy. I’ve had great results from it, with no side effects. Your mileage may vary. With immunotherapies, you’re trying to get an immune system response that is potentially dangerous. Our immune system has to be very good at attacking things, but we don’t want it to attack our own body. There’s a lot of mediator molecules and stuff floating around, there’s different cells to suppress.
Part of our immune system is immune suppression. Just like with cancer, the human cells are very good at dividing, multiplying and growing. That’s how our tissue heals, that’s how we grow so quickly as embryos to babies to toddlers. Growth is a really important thing. There’s a lot of mechanisms to stop the growth, because if the growth is unregulated, then you get tumors and you get cancer. So we’re dealing with subtle things and potentially dangerous things.
You do have to do your homework. It would be nice to say “Follow the data and do what the data suggests”, but you can’t really do that, because a lot of the time we’re looking not at clinical trials, but tiny case studies. In the case of the immunotherapy I have, it works best with other treatments, which means it’s almost impossible to do any kind of trial with it, because you would need a whole bunch of people with the same cancer, who are receiving the same treatments. If you have a hundred breast cancer patients, they’ll be getting slightly different amounts of treatment, maybe even types of treatment. So it’s very difficult to do a good trial on that.
Another big issue is that clinical trials tend to look at disease-free progression, which is how long was it before the disease started growing. You can’t really judge that immunotherapy in that way. Cancer tumors can be 50% white blood cells, so when you have immunotherapy, you can get the tumors growing, and those people are counted as a negative response on a trial, at least in most countries. But that’s called pseudo progression. A lot of those patients go on to live a very long time.
In Europe now, the guidelines for immunotherapy trials are actually being changed to make sure the end point is overall survival – how long did the patients live, or MOS (median overall survival) – how long do the average patients live, because the pseudo progression could lead to people being kicked out of a trial, because they say “Our end point is progression-free survival, your tumors are growing, so goodbye”, and then those patients aren’t tracked anymore as part of that trial. They may go on to live a very long time as a result of the immunotherapy that they received.
This is a massive topic. I’m going to revisit this again as part of this course, talking more about the science of the treatments, from a more scientific point of view. This has really been far more from a patient’s point of view.
I shall wrap up there and thank you for watching.