(Guest Lecture): May 2022 - CAR-T 101 - More Gertz, MD, MACP | MCRT Chicago, Illinois April 30, 2022

No more talking about weed killer. Now we're going to talk about harnessing your immune system in an effort to control the cancer. So what do we know about the immune system in protecting you? Well, the first understanding of the immune system actually goes back to the origin of vaccinations. So that goes back 350 years when Dr. Edward Jenner noticed that milkmaids didn't get smallpox very often and when they did they got a much milder case and tried to understand that and realize that the milkmaids were getting infected with cowpox, which is pretty serious disease for cows but not so serious for people. And what he did is he'd take the cowpox, which were sores on them and scraped it and then took that raw material and then rubbed it into the milkmaids arms and found that they just didn't get smallpox and that was the first vaccination. That's 300 plus years ago and it was a recognition that you could build immunity, you could get your body to kill viruses by exposing them to the virus. Same things happen with influenza, pneumonia, where they take a piece of the protein of the virus or the bacterium and inject it and when you make immunity against that protein, it kills it and you're not at risk of exposure. So there's clear evidence of that and when we talk about a protein, the medical term that we use is antigen and we're going to talk a little bit more about antigens, which is proteins on the surface of something that's unwanted. So what do we know about immunity and cancer? Well, there's some pretty good evidence of that. First of all, if you want to try and grow multiple myeloma in mice to study the disease, you inject myeloma cells into mice to try and see if the mice get myeloma and you can then learn about the disease, you can't do it. If you inject myeloma cells into a mouse, the mouse just destroys those myeloma cells. So actually to study it, you've got to take mice and you've got to destroy their immune system because if they have an intact immune system, the myeloma will not take hold. They kill the myeloma cells. And then now it's coming up on 50 years where it was first demonstrated that patients with leukemia could get bone marrow from a brother or sister and your brother or sister's immune cells would attack the leukemia and could cure the leukemia. So clearly there was something wrong with the patient's immune system that the leukemia is growing and the immune system is just standing there looking at the leukemia doing nothing at all. But when you took the immune system from a brother or sister and gave it to the patient, the brother's immune system or the sister's immune system could recognize the leukemia and destroy it and cure it. So clearly it's possible to manipulate an individual's immunity and in so doing destroy cancer. No question about that. So we have to talk about the immunity cells. It gets a little complicated here, but let's say there is a myeloma cell. That's a beautiful picture actually. And this is a white blood cell. Now there are a lot of different white blood cells. Those of you who get regular blood counts when you're getting treated will get a white blood cell count and they'll see all kinds of other things in there. Granulocytes, lymphocytes, monocytes, eosinophils, and basophils in the blood count, whatever that means. And the granulocytes are the cells that fight infection. They're the ones that your doctors worry mostly about, getting the risk of infection and use that number to adjust doses of chemotherapy so it doesn't get too low. Not the cells I want to talk about. What I want to talk about are lymphocytes. That's a type of white blood cell. That's a type of white blood cell that's not a white blood cell. That's a type of white blood cell that has the ability to destroy virus, fungus, and cancer cells. And there are two different types of lymphocytes. One's called the B cell and one's called T. And you're thinking, well I've never heard of that, T lymphocyte, but here's where you did hear about it. T cells, which are so vital in the prevention of cancer, virus, and fungus, have sites on the surface that bind the AIDS virus. And the AIDS virus destroys these cells. It just eliminates them completely from the circulation. So you actually do know the consequences of getting AIDS. That virus destroys these cells and when those cells are destroyed, all kinds of problems occur with infections and some very exotic cancers. The surface of every cell of the body, every cell, has proteins on it, which I said were antigens. Now there are some antigens that just exist on every cell of your body. They're so important, these proteins, that you find them on every single cell. But there are some proteins, antigens, that identify only one type of cell. It's the only cell that expresses these antigens. So this T stands for T cell. And you're thinking, I never heard of an antigen before. So I'm going to ask you this quiz, Greg, wake up. And I'm going to tell you the antigen and I want you to tell me what cell it's unique to. The first antigen that was ever discovered, 1903, and it's antigen, I'll give you more clues, A. Antigen A identifies one unique cell in the body. Anybody know? Keep moving. The second antigen that was described, 1903, was antigen B. That was the second. Also identifying only one type of cell. Still no one? Okay, the third antigen described was A B. So it identifies blood cells. That antigen, A B, A B, and of course O, identify red blood cells. No other cells of your body have those antigens. In 1903, they didn't talk about antigens. Of course, they talked about blood type. But really what we're really saying is the A proteins on that red cell surface, the B proteins on the red cell surface, the A B protein. And if you want to see an activated immune system, take someone with blood type A and give the blood to blood type B. You're going to see something very impressive happen. The immune system is so sensitive to those differences that it will cause what they used to call a transfusion reaction. But what it really is, is it's a hyperacute rejection. Because when these A cells with the A get into B, that person will destroy every A cell and will do it in about a minute. Will destroy a pint of it in a minute and cause an amazing immune response. Quite catastrophic, actually. So you know A B and A B, those are proteins that are exclusive to the red blood cell. Well, myeloma cells also have exclusive proteins. And I'm going to draw that protein. I'll just represent it by a triangle. And that's all over the myeloma cell, that triangle. And there are three different proteins that are identified only to myeloma cells. Unfortunately, they've got goofy names. CD38, CD138, and BCMA. Which stands for B cell maturation antigen, which is not important to know. Now for most myeloma patients, their T cells are circulating around and their myeloma cells are hanging out. They just kind of walk by each other. Nothing happens. But what it's possible to do is engineer, start To make sure that they do recognize the myeloma cells. So step one is to collect the T cells out of the blood. Now the technique for collecting T cells is exactly the same as the technique that we collect stem cells for transplant. Everyone knows who's had a transplant. There's either a line here or a line here and the blood goes out and the machine is spinning and extracting the stem cells and the rest of the blood goes back. This is a very similar technique. The blood comes out of a tube in your chest or in your neck. The T lymphocytes, these killer white blood cells, are pulled out and your blood is returned. So that's the first step is you have to get the cells for engineering. The second step is the engineering part. What they do is they attach synthetically on to the T cell, something that cartoonishly looks like that. The point here is that what they attach actually can recognize that thing sticking out. Those things are going to bind like a lock and a key. So now we'll pause for a second. More questions. Who can tell me what a chimera is? Can anybody? Oh, Greg, you don't know what a chimera is? That is correct. It's Greek mythology. What is it? Pardon? You're confusing with chameleons, so get out. So a chimera has the head of a lion, right? Now you want to finish? Body of a goat, tail of a serpent. Described by two people, Ovid in Metamorphosis and Homer in the Iliad. So the chimera doesn't really exist. It doesn't occur in nature. It's a construct that's mythical and it doesn't exist. So this is a T cell. It's been equipped with a protein here that's specifically designed to bind here, meaning bringing the T cell and the myeloma cell very, very close together. And this doesn't exist in nature either. You have T cells. People have antibody proteins, but not in the same place. And so that construct is a chimera. And this, that's the protein that's unique to the myeloma cell. For most of these, it's that BCMA thing. And this is the thing that binds to the antigen. So we refer to that as an antigen receptor. And I think they must have worked very hard to figure out the terminology so they could come up with something cute like CAR T. And so the whole point is equipping the T cell so it absolutely will recognize, but only recognize, the myeloma cell. And when these two get close and the job of that cell is to kill, it kills. And that's the way to harness the immune system. But that's what it's like on paper. The reality is fundamentally different. A couple things. First of all, after you get those cells collected, it's taken out like stem cells. The engineering, the manufacture of this takes a month. Well, that raises some problems for some patients, for some patients with multiple myeloma that's very active or very aggressive. A month waiting for the stuff to be engineered is a problem. And how will we control the myeloma for a month to allow that to get engineered? And so some people need some kind of chemotherapy to kind of just keep the lid on while the manufacturing process goes on. So the technical term we use is bridging chemotherapy. Some people don't need it if they have biologically not aggressive disease, but people with aggressive disease, it's like, oh gosh, I've kind of run out of weed killers. What will I do to keep the lid on while I'm waiting for this to be manufactured and returned? Two, the manufacturing process is not that simple. And there are very specific specifications that the FDA says about the quality and the viability, the number alive, of the cells. And that's not guaranteed that every time we send cells that they come back pristine and ready to go. There can be failures. And of course, then what's the patient who's been waiting a month to do? Next, this T cell belongs to you. But this is synthetic. And once you do this, it's different. It's changed. It's not you anymore. So if you had a stem cell transplant, they take out your stem cells and give you back your stem cells and they grow back. They take out your T cells and then start attaching funky stuff like that, antigen receptors. It's not just a question of reinfusing them, because if you just reinfuse these, your body's immune system are going to look at those and say, this does not belong to me and I'm going to kill it. My immune system will get rid of that. And of course, that's bad. You need those cells. They're supposed to kill your myeloma. And so what do you do so that when you give that back, it stays and does the job of killing the myeloma? Well, what you need to do is you need to take and tone down the immune system of the patient, just like we had to tone down the immune system of the mouse for it to grow myeloma. You'd have to tone it down and engineer the mouse. Patients have to get specialized treatment to lower their own immune system. So when that gets in, it stays in. The technical term for that is lympho depleting chemotherapy. Anyone who's gotten CAR T knows that they got probably three days of chemotherapy before they got their engineered white cells back. That wasn't to kill myeloma. That was to lower your body's immunity so that it would get in and stay in. So bridging chemotherapy, lympho depleting chemotherapy, lower the immune system so it'll stay. But once it's in, it gets also can be quite toxic. So first of all, when those get in, they start to kill the myeloma cells instantly. I mean, they really attack the myeloma cells and really they explode them. And when that happens, that can cause a profound inflammatory reaction. I mean, big inflammation. Fever. Chills. Drops in blood pressure. Rapid heart rate. Changes in liver function, changes in kidney function. It can really be quite an insult and quite traumatic to the system when instantaneously we're starting to kill all of those myeloma cells and that can be a dangerous proposition. In our program, one person in five gets this and goes up to the intensive care unit for ongoing supportive care because it can be quite catastrophic. Unfortunately, it's kind of hard to separate. That's in a way a good thing because that whole reaction is your myeloma being killed off by these reconstructed white blood cells. That usually occurs depending on the engineered product can occur a day after five days after eight days after it varies based on the engineering of the product. Secondly, neurologic. Someone asked a question earlier about the neurologic complications where someone didn't know who they were couldn't recognize themselves. That's true. That happens. The neurological complications are really uncommon, but they're dramatic when they occur and it's not just not recognizing who you are. You don't know what day it is. You don't know what time it is. You don't recognize your family. You're lethargic. You're in a coma. Parkinson's disease has been described day 60. Guillain-Barre syndrome, which is where you start to lose feeling and strength in your legs. Serious complications overall. The way we're using it today, far more dangerous than a stem cell transplant mortality with a stem cell transplant is well under one and a half of 1%. With this technique on the population, we're using it. Mortalities 1%. It's more than double. So there are very real risks with CAR T therapy. Albeit it's quite effective. The hard part is so what happens after you recover from those side effects? Well, there are problems because there are a lot of people who have recurrent myeloma even after CAR TY. All the reasons not understood, but there's evidence that once those T cells go in, they're not there permanently. Ideally, you'd want them there for the rest of your life as a surveillance, keeping an eye out for the myeloma and killing it. If it should recur anywhere, it disappears in some patients. It goes away. Number two, the key is that this binds to that. Well, I told you myeloma in evil disease. In some patients, the myeloma figures out how to internalize it. So it's on the inside and not on the outside. And if it's on the inside, these cells can't see it. They bring it in and they can become resistant. And so CAR T has significant risks and it's not a guarantee, even though it's a remarkably effective technique, particularly for those patients who've exhausted all of their weed killers. One of the nice things is that we haven't really scratched the surface of this product. Because people are starting to look, well, what if instead of having one of these things on, we have something like this to bind to another protein on the surface? And so we've got actually two different binding sites, bifunctional CAR Ts are being developed. There are other killer cells in the bloodstream besides T cells. There are what's called natural killer cells that exist and people are looking at CAR NK. And so even though this is just the very beginning, I mean, that's all you can really say. And it's good for what it does. It is not a panacea. It is a toxic procedure, which, of course, is why you have to go to a specialty center. I mean, this is not something you do at the community hospital. You know, if someone gets explosive inflammation, the technical term is CRS. That is not important, but you get this intensive inflammation and then you get this the neurological problem where you get confused on where you are. And that's called ICANN. Also not important what it stands for. And so it's really an exciting new. But I don't think it's fixed our problem completely yet. I still think we have a long way to go on this, but I just kind of wanted to give you some kind of construct about what's going on. So the principles are antigens, proteins specific to the myeloma, just like AB and AB are specific to red blood cells, killer cells found naturally in your bloodstream, and then the ability to engineer those cells so they get new attachments, making it chimeric, not existing in nature. They can seek out and destroy. So there's no weak killer here. Other than what we're using to lower your immune system so it's not rejected. And it's a way to really change the way your immune system interacts with cancer. I think that's good enough.