All right, well the next presentation is for the Tom Starzl transplant surgery state-of-the-art lecture and it gives me the greatest honor to present this year's lecturer who is the Eldris Eliasson professor of surgery and the director of the Penn Transplant Institute. He's been a past president of the American Society of Transplant Surgery and is a brilliant researcher in liver transplantation especially related to immunosuppression science. It's a great privilege and honor for me to introduce Professor Avi Shaked to give this year's Tom Starzl state-of-the-art lecture. Thank you David for your kind word. Thanks to the SLD and specifically the president Dr. Michael Fried for inviting me. I look at now and I want to tell you something. If my name was Donald Trump just before this talk I take my iPhone go on Twitter account look around and say this is the largest number of people ever attending this talk. Much larger than Julie Heimbach and Jack Leck. So we are not going to do that right? I thought that if we're not going to do that we can go to the talk and where is it? So I thought it's gonna be interesting to talk about immunosuppression. Not many talks like this here talking about immunosuppression and we have to recognize that we exist here because of immunosuppression. We can do liver transplant because of immunosuppression. So it's appropriate to review the current status of immunosuppression management. Think about what kind of opportunities and what kind of studies are done in order to advance the management of immunosuppression on the clinical side and what there is on the scientific side or science side to help us in the management of immunosuppression. So the first thing that we have to recognize that outcome of organ transplantation is simply great. When you are looking at the five-year survival of kidney patients, liver patients, even heart and lung patients it is amazing and over a period of time if you look at the SRTR data for 2010 to today there is continuous improvement with the treatment for hepatitis C, with the better selection of patients, with more appropriate surgical and medical care. There's definite improvement in the outcome of liver of transplantation in general. If you focus on liver transplantation and think about what kind of half-life we get of a graft. If you are starting today and getting your graft, the half-life of a liver graft is 12 years. If you're looking at those who are surviving the first year after the transplant, it's even getting better. It's about almost 16 years and if you are comparing those who are receiving liver transplants from cadaveric donor versus living donor, it's kind of like almost the same with some tendency for better survival for living donor. Maybe we select them better, maybe there's different biology that is existing there. Most of the time the rejection happens in the first year after transplantation, in the first months after transplantation and you can see that after one year from transplantation it's not too bad at all. We see very low rate of rejection and again it appears that there is lower rate of rejection in those who are receiving living donor liver transplantation. So biology maybe or genetics maybe also going into a more favorable outcome in this patient population. And again it is all because we have effective immunosuppression, no doubt about that. Now those of us who are there like from 30 years ago or something like that, remember treating patient with cytosporine, something that almost does not exist nowadays. And think about where we advanced from the time I joined liver transplantation about 1990 till today. We have more and more and more opportunities to target very specific determinant on the cell in order to suppress this cell that is involved in mediating rejection in order to overcome this phenomena and get better survival. So no question that over the years we got better. However, and I like to show this old slide in fact, however, there is a price and big-time price for using immunosuppression. This is a classic study by Ojo, Bob Marion is around here and was participating in this study published in the New England showing the impact of immunosuppression on the kidney and how bad it is. And notice the immunosuppression affects much worse the kidneys in the liver transplant recipient than in the say heart recipient or heart lung recipient. And the reason is very simple. When you think about those who are coming to liver transplant, many of them are coming to begin with with some kidney injury. Maybe because of the diabetes, maybe because of the hepatorenal syndrome. So we are dealing to start with worse kidneys and once you put this immunosuppression on, the kidneys are really taking a hit. So that's one complication of immunosuppression. It's more interesting to think about other immunosuppression malignancies. Think about it. Skin cancer hundred times more in liver transplant recipient when compared to the general population. Solid organ malignancy ten times more. And that's malignancy. Think about the metabolic syndrome that developed because of immunosuppression. The new onset diabetes 11% and I think that we will see it more and more and more with the patient population that we are transplanting today. Hypertension, hyperlipidemia. It's enormous number of patients who are getting a lot of complication because of immunosuppression. And maybe one that kills our patient very early and even later on the infection. It is estimated to occur in about 80% of the patient at some stage are going to get infection. Most of them in the beginning are bacterial infection and later on viral with some fungal infection. And it parallels how much immunosuppression you get over a period of time. In the beginning, a lot. And then as you go away from the transplant event but still on immunosuppression, you still are impacted and affected as a risk exposure for infection. So what's the current management of immunosuppression? It is so standard that it's amazing to me that we don't teach our fellow immunology anymore. We don't teach them what's behind the immunosuppression. They are getting a protocol and everyone is kind of like adhering to a protocol because the results are so to speak so great. In the beginning, the patients are bombarded with immunosuppression. Not many programs are using antibody. And if you are using by one week, it's off. But most of us are using the usual steroids, the tacrolimus, with or without MMF. And then we have the standard approach, the standard protocol. By three months, most of us are discontinuing steroids. In some autoimmune diseases, we continue steroid treatment for quite some time. The cancinoid inhibitor, you start to cut them off because it's written in the protocol. It's not because you adjust it to the patient. And you cut and cut and cut over a period of time. And we know very little about what's going on in terms of immunosuppression 10, 15, 20 years after transplantation. But do we do really much to adjust this immunosuppression to the patient? The answer is no. When we look at the study that was done by many centers in the States who participated in the A to O study, we saw that patients are placed on a medication, and we forget them in this way or another. Many of them are staying in whatever we give them, and that is it. Two medications, okay, we're fine. Go ahead, and that's what you are getting. The level of immunosuppression medication, we forget it. We just kind of like, it's there. It's fine. It's within the range. And if you look at one year, two years, three years, it's changing very, very little. So the first conclusion that we can have is that immunosuppression is very effective, no question about it. That current immunosuppression drugs are associated with significant side effects. And there's really minimal conscious attempt to change either short or long term immunosuppression. Immunosuppression is, rejection is a bad option. No one wants to see rejection, and we are too comfortable with what we are doing. So what can we do? Can we kind of like completely, completely discontinue immunosuppression? It's possible to avoid immunosuppression. We hear a lot about tolerance in the liver transplant setting, and that's a very nice slide that was presented by Josh Levitsky somewhere. We know that the liver is a big organ. As we transfer this big organ to the recipient, we know that we transfer a lot of stuff with this big organ, and not just liver cells. A lot of hematopoietic cells, a lot of T cells, B cells, and so on and so forth, regulatory cells. And these cells are being transferred with the organ and are going all over. They are going to local lymph nodes. They are going to the thymus. You can find them all over the body. They reside there, and maybe in this or another effect or impact, the recipient or the host to develop some kind of a tolerance toward the organ. And this is known for quite some time. In fact, it was known from the day that Tom Stadel was there. There are plenty of patients in Pittsburgh where it was noticed that they are not taking the immunosuppression and they survive. And then there are all these kind of like studies from center here and there, mainly in the deceased donor setting, mainly in adult, in patients who are taking either calcinoid inhibitor, tacrolimus, or cyclosporine, or those who are on monotherapy with some anti-metabolite. And you can see that a very long time after transplantation, you can see the mean years here are from four to eight, nine. A certain percentage of these recipients are going to become tolerant, and you do nothing. Either you kind of like take them off immunosuppression, or they took themselves off immunosuppression. So that's interesting phenomena that was noticed. Are there any very solid prospective study to see why is this phenomena? I'm going to talk about two interesting studies that came out not a long time ago. The first one is by a Spanish group led by Alberto Sanchez, a very dedicated investigator for this subject of tolerance. And look what happened. You take 500 recipients, and you start to kind of like select from them the most appropriate, the best candidate. And you exclude many for reasons, medical issues, all kind of like other issues. And from 500 people, you go down to 100. You start to take, based on certain protocol, the immunosuppression off, off, off, and off. And by the end of the day, you get out of this 100 about 40 tolerant and 50 or 60 non-tolerant. And then it depends how you present it. You can come to the literature, and you can publish it in a great journal, and you say the success rate is 40%, which sounds great. Like, oh, all of us should take our patients off immunosuppression, right? But when you look at where you started, to begin with, it's really about 10%, 12% from the beginning. And then how long time between the transplant and when you really become a candidate for this particular study? It's almost 10 years. So it doesn't happen like, or in this study, it did not happen in the very early patient. Another nice study by Sandy Fang, who really devoted a lot of her time to study tolerance in pediatric population, a very nice study. It's the same kind of pattern. You start with 129 kids four years after transplant, and then you filter it down to how many of them are really candidate because of this reason or the other. You see that from this 120, you have only 20 kids. And these 20 kids are about, again, eight and a half years after transplant, and you start to take them off immunosuppression, and what happened? 60% of them really don't need the drug. So again, you can look at success rate as 60%, publish in JAMA, very, very nice work, or you can look at success rate of 10% out of very selective, very clinically ideal population. So you can see two studies that are showing you very nice success rate and that people can become tolerant. We did this study ourselves, and this was supported by the NIH, the ITN network, and we went crazy. We say we are going to recruit this recipient not five or 10 years after transplant. We are going to start from the day of transplant, and if we start off the day of transplant, if they are stable for one year, after one year, we are going to cut their immunosuppression, and we start cutting and cutting and cutting, and you see we started with about almost 300 patients. After one year, out of these 300 patients, 95 were candidates for this withdrawal protocol, and the nice thing about this one that we were dividing them to maintenance, control, and those who really went through the pathway of withdrawal, and you can see that about 10, 13% of them very early on are becoming tolerant. So if you look at this curve, you can see the tolerance does develop in liver transplant recipient. It is true. It is real. But there are some kind of factors that determine your chances to become tolerant. The time for transplant, as far as you are out for transplant, the better chances for you to be off drug completely, and interestingly, how young or your age at the time of transplant, the older you are, the better you are able to tolerate withdrawal of immunosuppression. So, but don't forget, we want to get rid of the medication in order to have something good done by the end of the day. We don't want just to get rid of the medication, right? So is there any benefit to getting rid of the medication? Well, 10 years after transplant, it's done deal. All the injury is there. So there's really not much benefit at that time to win off your immunosuppression. If you look at those tolerant to non-tolerant patients in the Alberto study, you'll see that there is no difference whatsoever in any complication that is related to immunosuppression. In hypertension, diabetes, cancer, infection, nothing. That means by that time, it's really too late. So why are we doing it? If you look at our own study, which started very early on, about a year after transplantation, and you compare the tolerant to the non-tolerant patient, those who are maintenance or those who underwent a withdrawal of immunosuppression, you can see that if you withdraw immunosuppression early on and you reduce, reduce, reduce, maybe, maybe there is a tendency to less immunosuppression related complication. Maybe there is a tendency for less renal disease. But the problem with this study that we had little numbers. Now, what do you pay for this kind of trial? Trials are not innocent. Taking patients of immunosuppression is not innocent. And in this study, we demonstrated a little bit of the price, a little bit of the misery that patients undergo when he or she agree to enroll in this trial. Number one, there's a lot of liver biopsy that are done in this patient, because once their numbers are going up, you want to know whether it's rejection or not. You put a needle in the liver. There's no other way to do it. That's already some invasive procedure that is done for the patient. That's one thing. If you look down here, you can see that there are other issues associated. You have to increase immunosuppression in many of them, far more than the baseline. Some of them require treatment and real treatment for rejection, such as steroids. And the more interesting thing, by the end of the day, if you look at their liver numbers, some of them are not going back to the same kind of like normal liver function test as they had before. So there is a price for it that the patients are paying. In addition, if you look at another study that we did, what happened to the novel DSA after or during withdrawal of immunosuppression? And we looked at those who are kept on maintenance, those who failed, and those who become tolerant. As you see here, maintenance immunosuppression developed DSA after the transplant. And it's developing, no question about it. But those who failed withdrawal had more DSA after the novel DSA. And even the tolerant patients developed more DSA after. So there is a price for it. But can we find something, some kind of guide, some kind of a way to identify these patients and to say, OK, you are at risk. So we are not discontinuing immunosuppression. But you are not, and we should do that. So yes, if you look at studies from the late 90s to the 205, it was a lot of flow cytometry, identify all kind of different cells, chimerism and so on and so forth in your blood, and saying to you, OK, if you have this, you have better chance to get off immunosuppression. More recent studies are kind of like more fashionable. You use gene expression studies. And these are studies, as you see, from the late 2008 and up to now. You can see that there are all kind of markers that you see in the blood. You do an analysis of, say, in this case, mRNA and PBMC. And you see that there is difference between tolerance and non-tolerance patient, the green and white, for example. And then you come with what we call signature. And the signature is something that identify some patients who may be taken off immunosuppression. Very nice study published in JCI. But when it was applied, when this signature was applied in other centers, in other patient population, the results were not that great. So it's failed in this way or another. One of the problems in this study is selection of patient population. Those days, you had a lot of hepatitis C on board. And this study was definitely contaminated by hepatitis C issues. But again, you have to be careful. You publish a signature. You are so confident in your study. But when you try it in multi-center study, it doesn't work. So instead of looking at the periphery and PBMC, what about looking at the liver itself? And that start to be maybe a little bit more real and a little bit more interesting. You look at the liver itself in patients who became tolerant and those who are not tolerant. And you look at biopsies that were taken before they were taken off immunosuppression. And you start to see, again, the difference between the white and the red here. And you build another signature. And this time, you validate it with other center. And indeed, it may be working. The interesting thing about this kind of signature that it's not what you imagine. You would imagine that it's associated directly with immune cells and so on and so forth. In this case, the signature is associated with iron metabolism. And the authors, they go through hoops to try to explain why it is associated with iron metabolism. It's like taking my genes, 23 and me, and say, I have 2% of Spanish genes. How do I relate to Christopher Columbus? So they go through all kind of explanation to try to show the association. We don't know, really, the association. But the fact is that it's maybe there. The nice thing about this study and about the group there, the Spanish group, and Alberto, who should get a lot of credit for it, is that they dare to take this kind of signature and go forward now with prospective study to take liver biopsy from patients and say, OK, if you have this signature, we are going to try to take you off immunosuppression. And I think that this is what science is helping us to better personalize what we are doing. We are taking certain kind of biomarkers, and we are trying to see whether these biomarkers are going to help us to identify specific patient population in order to see whether they can be taken off immunosuppression or not. This is a great study, actually, and I'm looking forward to see the outcome. So the second conclusion is that spontaneous tolerance in liver transplant patient is observed. And there is a success of clinically guided withdrawal of immunosuppression, and it's a function of time after transplantation. There may be clinical benefit to do it early. To do it late, it does not help whatsoever. And it's too early to determine whether biomarkers are going to be there or not. But they are encouraging data to say that it may be going to be there. So that's tolerance. Can we do something else with immunosuppression that is going to benefit the patient? Can we personalize immunosuppression? And what does it mean to personalize immunosuppression? It's far more difficult to define this. If you talk to our hepatologists, they're interested in personalizing immunosuppression in order to reduce complications such as kidney injury, such as hyperlipidemia. If you talk to our transplant immunologists, they're not interested in that. They're interested in some kind of thermometer that is going to tell you this immune system is activated. This immune system is not activated. So that's a very different approach to think about personalizing immunosuppression. And if you are talking to our coordinator, for them, personalizing immunosuppression is a patient on too many drugs. Just minimize it, minimize it, minimize it. So we have to think about, what do we want in personalizing immunosuppression? And there are a lot of recommendations out there. And again, if you are looking at the hepatologists coming for recommendations for personalizing immunosuppression, they're looking at all kind of combination of drugs that are going to help you to have less complications. For example, this study with all kind of different groups that I'm not going to go over, was aimed to show that maybe you can have a different protocol that will improve the kidney function. That is not personalizing immunosuppression on that, or that is personalizing immunosuppression. It's something to think about. And if you look at late after transplant, conversion to sirolimus in order to, again, save us from the kidney failure, and so on and so forth, these studies are supported by pharma, most of them. And again, they are not aimed to really determine what's ideal immunosuppression to control immune system. They are aimed to reduce complication, and of course, to sell drugs. Personal immunosuppression, not just for kidney issue. We can go over another set of recommendations, management of obesity, get them off steroid, hyperlipidemia, convert them from this to that. Diabetes, don't use steroids, and so on and so forth. That's recommendation for personal immunosuppression when you're talking about the injury, the impact of immunosuppression on other systems. What about immunosuppression management in terms of addressing immune response, improving your immunity, getting you to where you should be? There was some consensus conference about it by the ILTS. I actually found out that I was one of the authors. I did not know it. And here is a set of recommendation what is coming. And the set of recommendation what is coming is really what I showed you in the beginning, the protocolized approach. Give them this and that in the first three months, reduce steroid after that, and use these kind of levels, and so on and so forth. Is this really personalized immunosuppression? That's actually making it standard for everybody. It's actually getting worse. And I was on this paper. It's amazing. It's getting worse because they tell you that you can minimize immunosuppression, and you can play around as long as the liver chemistry tests are fine, are stable. If they are stable, you can do that. And we also emphasize in this manuscript that there is no need for liver biopsy before you do that. So let's think about need for liver biopsy. When you look at histology, molecular profiling of this patient population on liver biopsy that are taken a long time after, see the amount of injury that you have on patients who are with fine liver test, great liver test. There is injury there. They are not kind of like innocent of this patient. And they are maintained, by the way, on very low level of immunosuppression. If you are thinking about this study, which was done in Europe, Sandy Fang just published not long time ago in gastroenterology what's going on in pediatric population long time after transplant. And you see the same kind of injury in liver biopsy. So liver number tests are not enough, for sure, to start to play around with immunosuppression. So the next conclusion is that we need to define what we mean by personalized immunosuppression. And the recommendation are really kind of like the current standard that we are using. That the liver injury panel are not telling you exactly what's going on in the graft in terms of management of immunosuppression. And that low level of immunosuppression during ejection may end up with injury to the allograft. So can we have any kind of thermometer, a $10 Amazon thermometer that you can stick inside this immune system and say, this is where you should be? Do we have this kind of thing? We know that many patients can tolerate much less immunosuppression that they have. But do we have the thermometer? So think about it. And I'm going to present to you several studies that are done in order to find out this thermometer. Probably there is. There is something. So we did study in a kidney patient. And as you see, we kind of like went through our first year of kidney transplant recipient. And we took urine. Very easy to ask patient to donate. And we took urine at different intervals. And whenever there was bad kidney function and there was biopsy, we took urine as well. And you can see, we collected about almost 1,800 samples on about 400 or almost 500 patients. And then what we did, we tried to look at the urine palette and see whether there is anything that tells us that there is activation of the immune system. And indeed, we found in the urine palette T-cells, or T-cell sequences, I should say, that tell us and distinguish when there is rejection and when there is injury and where there is nothing. So we had this kind of, so to speak, signature without poking the kidney, without pushing needles in the kidney. What's going on with this patient? The interesting thing is we had different samples at different intervals, right? So we could go back to before ejection. And we see that days before ejection, 20 days before ejection, we can start to detect molecular rejection before there is organ injury. What does it tell you? It tells you that if you are trying to manage immunosuppression, to tailor it, to reduce it, and so on and so forth, you want to measure something that is starting a start of molecular rejection before there is organ injury. And there you know that you have to stop. More than that, we could see trajectory of when patients or who is going to get eventually rejection. This patient, you should do nothing. You should not reduce their immunosuppression. Whereas if there is a stable patient there, you can start to play around until these curves start to go up on the molecular level. And then you know where to stop. We did the same study, exactly the same study, with liver transplant recipient with collection of serum specimen this time. And each time we had an event, we again went forward and analyzed the signature of that event and analyzed when it happens. It's exactly the same thing like the kidney, this time with microRNA. We could identify the rejection, number one. And number two, it happens again days before there is molecular rejection, before the liver function test going up. And this is pretty accurate. And we validate this kind of thing. I'll show you one site that Josh Levitsky is going to present later on today, I think this morning. They examine in PBMC 39 genes or something like that, or 37 genes that are giving you molecular signature of rejection. And look in all this study what happens. All these studies showing the same, that molecular signature can be identified many days before there is organ injury. What does it tell you? It tells you that we can actually have some kind of thermometer to see whether we can reduce immunosuppression and eventually get to a point where there's, before organ injury, some kind of activation signal that tell you stop. So we start to have some kind of tools today to personalize immunosuppression. So the last conclusion is that noninvasive marker of acute rejection out there are available, can be used today. We don't need to poke organs anymore in order to do that. That omics valve marker diagnostic of molecular rejection are coming on board before there is clinical injury. That makes sense. And we can adjust, as I mentioned before, immunosuppression to the level that the patient is needing it before there is organ injury. So there are many tools that can go together with the clinical practice today to manage immunosuppression. All we have to have is people who are going to try these tools. Now, it's completely inappropriate to finish this talk by not mentioning Tom Stauder. Those of us, they call us the boomers today. Those of us who are there with Tom and knew him very well know that his passion was not really surgery, and not even, I may say, pathology. His passion was immunosuppression. And I remember being called, Avi, you have to come tomorrow to Pittsburgh. It doesn't matter if I have surgery in Philadelphia. It doesn't matter, nothing. You have to go on a plane, go, and pay attention to what Tom Stauder will say. And you sit in his office above this pizzeria with the two dogs going all over, smelly like crazy. And he start to show you charts of how he manages immunosuppression. And it was fascinating. So Tom, wherever you are, still there is work done. Still there is work to do. And one of these days, his love of tolerance and immunology of liver transplantation will be deciphered. So thank you very much. Thank you, David. Thank the organizers for inviting me. Thank you.

liver transplantation

immunosuppression

advancements

challenges

personalized treatment

biomarkers

Tom Starzl