 Thank you, Kim, for inviting me to give a talk about immunotherapy. My role within the University of North Carolina is actually melanoma specialty. So you would ask yourselves why melanoma doctor is trying to give a talk in renal cell. And the answer is supposedly we are seeing the melanoma doctors are seen as doctors from the future for what is going on in the field of renal cell cancer. Which lacks approximately one to two years in development in relation to what is going on with renal cell carcinoma. Does anybody there to say what this looks like? Patients wise, not doctors. So I tried to find a picture in the internet about how a cancer cell looks like and how lymphocytes look like. So I want the patients to understand there is a size difference between what is a cancer cell which is usually a big thing and how these tiny things are trying to go against the cancer cells and kill it. So we have a size difference and sometimes number of cells of immune cells and function matters. So the talk point is that since it's Christmas I'm going to give you a couple of recommendations books for Christmas. I'm going to try as simple as I can with respect to describing what is a normal immune system functioning. Because a lot of lessons from the normal immune system functioning you will answer yourselves about what these drugs that are coming out in the renal cell carcinoma mean and how do they work. So an important aspect of what is immune surveillance and immune editing. So and then what are the mechanisms of cancer and immunosuppression. Just to explain the variety of different mechanisms that exist and why immunotherapies is not one side fits all. We also would like these audience to remind the high dose bolusile to it is no longer a sexy drug as this has been out for 20 years but nevertheless should not be overlooked as progress goes by. And then the future for now is immune checkpoint inhibitors and that's what we're going to talk in the end. And then the question is whether the future is for everyone. So these are the books for Christmas. The left side book I read when I was a resident 14 15 years ago. It is written very almost 15 years ago. So there's not going to be any excitement about the recent advances of immunotherapy. But it's going to give you a very nice history of immunology and immunotherapies in cancer. You will see all this drama that has happened over the last 100 years about questions like that a scientist had. Does the immune system work or does not have it all. So we had a lot of ups and downs throughout the 120 years as to whether the immune system plays a role. So there is a nice nice book here pretty big like 300 350 pages. Not an easy book to read but I would therefore recommend. And the one is the one I'm trying to finish when I'm going back and forth to work through an audiobook. This is a generic history of cancer book. There's no talk about a lot of immunotherapy but again you're going to see how doctors and researchers are by all means human beings and they're having their own biases and how progress is are being made. So the purpose is not to explain you how normal immune system works but show you that basically we don't talk about immune system in general. We talk about two different arms of the immune system. The one that is less relevant for cancer less relevant for cancer and the one that is more relevant for cancer. So this is the adaptive immune system. The immune system needs to remember what the cancer cell is because it's a non self so it's not something non specific. And the key to all this the key is the interaction of these cells that are called habits and presenting cells. These are the cells that pick up stuff that is known for that is known for in from the from the environment. This can be viruses because this can be bacteria. But yes it can be cancer cells because cancer cells are known self cells. So these are sample from the micro environment and are being presented in these aunties and presenting cells. And it is this key interaction with this other cells that are called lymphocytes that you saw in the very first slide. That is the key to educating the immune system. Okay so that's a different way of seeing the adaptive immune system. Fancy picture where antigens are being picked up at these aunties and presenting cells. These are called dendritic cells from the Greek word dendros which means tree. So they have these spiny projections and it's again an uninstructed naive T cell that is going to come and encounter the antigen presenting cell. And then it's going to get activated and either it's going to kill the cells or some of them are going to be left behind for memory. So that's a very simplistic approach of what is adaptive immunity. And again the key interaction here is the interaction between the antigen presenting cell and the lymphocytes. So here's your first kind of complex slide but the way I'm going to present it is like it's basically the interaction between the antigen presenting cell that I showed you before. And a lymphocyte, a T cell is actually so complex that over the last 20 years there have been so many molecules that have been identified to play a role in this interaction. And it's no longer a simple interaction of a signal that means that these antigen presenting cells is going to present the antigen and oh, the immune cell is going to get activated. The decision, so it's no longer one what's called first signal. It is a number of other things that the interaction between these two cells have to be taken into account. And whatever is in red, it means that these are actually proteins that are going to say no, I'm not going to get activated. And then those things that are green, these are the cells that say yes, I'm going to be activated. So the net effect of whether an immune cell is going to actually get activated is the net result of the positive and the negative factors. And it's easy to understand that this looks to me like a complex car with multiple brakes and gas pedals. So that's how complex nature is. And all and right away, you're beginning to see things that you may have seen already on the Internet. You're seeing things like C-T-L-A4. So there's already a drug against C-T-L-A4. It has been used for renal cell cancer. It's called Hervo. It has not been approved yet. Also, you see these other negative immune checkpoint protein that's called PD-1 or PD-C-1. That is the target for Nevolumab or pebroluzumab, pebroluzumab that was FDA approved melanoma three months ago. And then whatever you can see in red, it means that there are already drugs in development. So it is no longer just the PD-1 that you see or the C-T-L-A4. There are a bunch of actually targets that are currently in clinical development. So this is a very hot area of interest. So there's going to be more to come over the next five to seven years. Okay, so this is the gas pedal scenario in normal states. So if you have two gas pedals in one break, then it's a go. And that's a nice looking car that's actually makes a turn and does not go upside down. And this usually happens when there is an early stages of an infection. An immune system has to become activated. Very simplistic the way presented, but this is a good way to understand how it goes. And then when the immune system takes care of business in the normal states, then all these several of these negative immune checkpoint proteins are being upregulated. And then basically you have your car nicely parked, ready to be used for something else. So I want people to understand here that cancer and the immune system, there is constantly an interaction. I remember I was a third year medical student in Greece when our pathologist said, our body makes approximately 30,000 cancer cells per day. And the only reason that we don't develop cancer is because we have a constantly working immune system. So there is always this tendency, the Darwinian tendency of our bodies to develop mutations, to become something different, to evolve over time. But there is constantly this system that's called immune system that is trying to seal things off. So therefore any conditions can turn a normal tissue into a cancerous tissue. And by definition, the cancerous tissue is slightly different from the normal tissue. And that is perceived as foreign as a non-selfmade immune system. And in so doing the immune system is trying to eradicate those cancer clones. And then there is this constant interaction between how a cancer becomes genetically unstable, develops new mutations, okay, becomes more different, and how it actually tries to suppress the immune system and how this battle between the immune system and cancer is going on and on. And that has probably been going on for years and years to come. This is not an overnight event. And eventually cancers develop because the immune system has failed. So when somebody has cancer, it's basically a failed immune system. So there's not anything to fix it. It's not like if you increase your exercise, or you increase your activity, or you improve your diet, or you get a supplement, it's going to get better. It is already broken, and therefore there have to be ways to restore in the way of drugs. I believe in alternative medicine, but the effects of it are very well-unknown in a patient with metastatic cancer. So again, will the future be one size fits all? I just talked to you about one way that the immune system is suppressed. And that is by upregulating these breaks. But there are a number of things that are going on. There are many different ways that the family can become dysfunctional. I quote one of the very nice phrases that Alexander Tolstoy has wrote in Anna Karenina. There's one way that the family can be functional. People would be happy and, you know, kids love their parents and vice versa and everybody's happy. But there are many ways that the family can become dysfunctional. That is how cancer is. There are many different ways that your immune system can become suppressed. So here we go. So if the cancer cell does not upregulate these HLA molecules, the ones that require for the first signal, the immune system is not going to see it. And therefore that's how cancer cells evade the immune system. That's one way to do it. The other way to do it is to produce all these molecules that basically suppress not only those cells that are supposed to pick up the Zandigen and instruct those lymphocytes, but suppress pretty much everything, suppress the anti-Zandigen cells, but suppress the immune cells as well. And guess what? Many of these things that are being secreted by the cancer, or when the lymphocytes are coming encoded with the cancer, it can be a toxic effect. So as this nice review article from Tessa Whiteside, who was my neighbor in the neighbor's office in Pittsburgh, she says immune cells in the tumor microenvironment are functionally impaired and I'm adding and are killed. So your lymphocytes are getting killed by the cancer cells. And you all are patients and you understand how to read a complete blood count test. But what I want to emphasize you here is I'm going to show you eight different patients, CBCs, simple as that. The common with these patients is that all of them have metastatic cancer. And the one thing that makes a big, big interest is that the fact that all of these lymphocytes are low. So there is a fundamental problem in most of patients that end-stage cancer, that their lymphocytes are low in the blood. So for people who don't know what is a high dose bolusal to it, it has been FDA approved therapy for 20 years. It's not for everybody. It is a very toxic therapy. Not everybody can do it. It has been given in hospitalizations. This is called a hospitalizations called the cycle. Two cycles include a course and we can evaluate things between every two courses. So this is what IL-2 does. So this is our very first patient that was treated at the University of North Carolina with renal cell cancer. So what you can see here is that before he got into the treatment, his lymphocytes were low. And then when he started to get IL-2, his lymphocytes disappeared. And that's what IL-2 does, makes the lymphocytes disappear from the blood and they're going to different parts of the body, including the cancer cells and they're supposed to eradicate the tumor. And what happens is when the cycle ends, then the patient shows up right before the next dose and his lymphocytes are almost double right before the second course. So what I want to emphasize, again, do not forget drugs like IL-2. So IL-2 is otherwise called T-cell growth factor. I call it the T-cell steroid. If patients, in a way, would mean suppressions, actually, they just don't make a lot of immune cells. IL-2 could be a very good drug to give. So the same thing now, but now I have this thing there, which means that the cancer cell can actually be immunosuppressed because it can also develop properties of antigen-presenting function. And then all of a sudden you see that the lymphocytes can take instructions, wrong instructions from the cancer cell. As you can see, there are more breaks that the cancer cell can induce as opposed to gas pedals. And this is now the scenarios when somebody has cancer. So you may have advanced cancer and your first signal is functioning and you have two breaks and one gas pedal and therefore you're looking like a Formula One car that is on high brakes. But if, for example, your immune system, the cancer does not have expressing those things that makes the cancer cell visible, then you're like a car that is driving in the middle of the night without knowing where things are. And you can have the third situation of immunosuppression where things are functional but the cells are dying because the cancer is suppressing them and this is a car on fire. So what the immune checkpoint inhibitors in the cell cancer, and that seems to happen in 50% of patients with renal cell carcinoma, is that you may actually be able with one of these drugs to eradicate one of the two gas pedals and that could be sufficient for the immune system to get activated. And sometimes if you use two of them at the same time, and this is the PD-1 plus the epilimumab, then this immune system is really revved up to the point of going up in the air. So this is a most updated list of clinical trials using these immune checkpoint inhibitors in various cancers. And I want to show you the renal cell cancer in relation to other cancers. So what I want to show you is that if you use these two drugs, the epilimumab and the involumab in various doses, in combination you can rev up the immune system to such an extent that you can see a response rate of as high as 44. Now if you use only the involumab in renal cell cancer then the responses are less. But nevertheless, much better for responses that you get in other cancers like lung cancer or variant cancer. So what I want to emphasize is that different cancers would respond to these drugs in different percentages and it seems that the renal cell cancer behaves in terms of response rates similar to melanoma. So again, see where the epilimumab and the involumab was given in patients with lung cancer, the response rate was only 16%. So whether the benefits and challenges of this new class of immunotherapy, so definitely the way we see that in melanoma when epilimumab was approved in 2010, we were able to give immunotherapies in a much larger number of patients. We were giving epilimumab in a 90-year-old. We were giving epilimumab in a 70-year-old with congested heart failure. We were giving epilimumab in somebody with coronary artery disease. IL2 cannot be given in those patients. So the application of immunotherapies will be much larger in a larger group of people the same way we saw that in melanoma. What else would be convenient? It's going to be an outpatient therapy. You don't have to be admitted for this horrible five-day course of high dose bolus IL2. In fact, if you come to the MICU, the Medicine Intensive Care Unit at UNC, you're not even going to have a bathroom. So it is definitely less toxic. So that's no questions asked. But again, we have to see the less toxicity in a different perspective. The benefit of IL2 is that you will do it for two months or four months or six months and then you're going to be done. Because of immunogenic point therapies, potentially the side effects can be long-lasting. In particular, if you use the combination of IPL1 and IL2. Will they be more effective? So in our mind, we have linked response rates that I just showed you with clinical benefit, which is progression free or overall survival. The trials are too early right now to say whether this high response rate actually lead to longer survival, but it's very safe to think this way. But unless we do follow these trials over a longer period of time, we will not be able to know the long-term benefit. And the challenge is we're talking about drugs that are, it's $20,000 in infusion here. So we should do better job. We as doctors to really refine which patients actually are candidate for. And I think I predicted that these combination of drugs can be effective in up to 50% of patients, but definitely not 100% of patients. And for how long we're going to give these drugs? So right now the drugs, at least the approval of the peperoluzma from melanoma is basically indefinite. So as long as you have cancer and you respond to that, then you're going to be getting peperoluzma forever. Is that the right thing to do? I mean, this provides a huge burden to the insurance companies and the healthcare system. And again, as I said, as a response rate correlated with longer benefit and what's the cost and how to combine these drugs with other drugs. And I intentionally did not do that because I would wait for you to make your questions in the final discussion. So my summary and conclusions is that future is for some, definitely more than the lucky aisle to candidates. So you shouldn't be privileged because most of you, you will be candidates for both of these drugs. The peperoluzma alone or in combination with epilimumab. But not one side fits all that. I think I showed you that there are many ways that cancer, either family can become dysfunctional and this is one of them. And do not forget that there are also good old drugs. So taros and kinase inhibitors. Can some of them have seen that they have response rates 20, 30, 40% and people have been on that for years and years to come. And there are also high dose bolusile do that you should not forget. But if the patient is in an advanced stage of disease, this cannot beat up a dead horse with any immunotherapy, in which case you have to use other types of treatments. So these treatments are not for everybody. So I thank the six, seven patients and their families who have trusted us to give them high dose bolusile to in the hospital. And I'm sure that they are eager to see something less toxic than IL2 and the GGU program that refers patients to us for this. Thank you.