New Research: Could Organ Recipients Forgo Anti-Rejection Medication? Webcast March 27, 2012 Joseph Leventhal, M.D., Ph.D. Lindsay Porter Please remember the opinions expressed on Patient Power are not necessarily the views of Northwestern Memorial Hospital, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Lindsay s Story Kidney transplant recipients currently must take immune-suppressing medications for the rest of their lives, handfuls of pills to help their bodies prevent rejection, which makes them more vulnerable to infections and over time even cancer. Well, coming up, an expert from Chicago s Northwestern Memorial Hospital explains treatments in development that may make these medications obsolete, and you ll meet a patient who is benefitting. It s all next on Patient Power. Hello and welcome to Patient Power sponsored by Northwestern Memorial Hospital. I m Andrew Schorr. Well, imagine, there are people who need organ transplants, and kidney transplants are not at all uncommon, and people who have diabetes over many years may need them. People who have a genetic condition called polycystic kidney disease, and there are other conditions, they may need them too. Well, typically you re getting a donation from someone who is pretty well matched, as matched as well as they can, but you need to take anti-rejection medications for the rest of your life. And there can be side effects, there often are, and even an effect on the donated organ where you may need a transplant sometime down the road. Wouldn t it be great if there could be a procedure where those medications might be taken for just a short time or maybe it could be worked out not at all, but certainly for a short time, and then you go on with your life and you don t have to swallow that handful of pills and worry about those side effects and the organ being rejected. Well, that has been pioneered now with a collaboration of two universities, Northwestern Memorial Hospital helping lead that, and we re going to talk about that today. Let s start with someone who has benefitted. That s 47-year-old Lindsey Porter, mother of five-year-old CJ, who is in the drama and theater field in Chicago. Lindsey, welcome to the program. Back in the summer of 2010 you participated in a clinical trial and so today now, many, many months later, you really don t take any anti-rejection medicines, do you? Don t take any, no. You ve got to marvel at this. Is this like a miracle for you knowing that for so many other people that s not the way it goes? NMH032712/0709/AS/jf
Well, it sure feels like a miracle, I mean in terms of the results. I know that many, many years of hard work went into it, but in terms of the way I feel and the results, it s pretty amazing, and sometimes I have to remind myself that I had a transplant because it s just a memory. Wow. Now, this is very personal for you. Your mother died when you were still in your teens of complications. Actually 23, but yeah. So, but still at a young adult age, vividly remember that she had this genetic condition, polycystic kidney disease, which was passed on to you, and your sister Sarah, too, right? That s true, yes. And so Sarah is doing well, but your kidneys got to be really big. How big? Well, I was constantly asked when I was pregnant--when I was due because I looked pregnant, and when they were removed they weighed 16 pounds. So that s two full-term twins. In fact, my husband and I nicknamed them the twins because I had to wear maternity clothes, I mean, yeah, they were big. Wow. So a transplant was certainly needed in your case, so you have a dear friend, Kurt, who agreed that he would be a living donor. Yeah. And he was going to donate one of his two kidneys to you, and so there was the whole issue of how would it match and taking pills. And I understand you attended a seminar, I guess it was at Northwestern Memorial, and you were learning about transplant? It was when I first got listed for transplant, about a year and a half before I actually had the transplant. Yeah, I went and heard one of the presenters there talk about a clinical trial they were doing for perfectly matched donors or sibling donor--you know, donor recipient pairs, and they said that they were working on possibly in the 2
future being able to do that with nonrelated donors. And it sounded exciting but it didn t sound to me like it was something that was going to happen in a time frame that would work for me. Right. But, and the idea was, could the procedure be done in a way where you wouldn t have to take all those pills and worry about that rejection, but the timing did work out for you. So in the summer of 2010 you not only had Kurt s kidney put inside you but you also had what might be described as sort of a mini bone marrow transplant, didn t you? Yeah. Yeah, I think that is how they do describe it. Yeah, we re going to learn more about it from your doctor, Dr. Leventhal in just a second, but I just want to ask you about the recovery. So we talked about the happy time now you really don t take any anti-rejection medicines, and I understand you have a lot of energy to chase around with five-year-old CJ, but the recovery from the procedure--now, recovering from a transplant is one thing, but what about this sort of stem cell infusion part of it that you went through as well and the chemo conditioning we re going to learn about. It s not easy. No, it was a rough recovery for a while. I knew that it would be. I think it surprised me a little bit because I had a bilateral nephrectomy, both kidneys out, that s a pretty intense operation, but I kind of really flew through that. I felt bad for probably about three months, I mean slowly I recovered over three months, but normally I know transplant patients often report that they feel great a week later. But the long-term result was well worth feeling bad for a short period of time, well worth it. One more thing before we meet Dr. Leventhal who really led the team that did this for you. Do you feel like you received two gifts? One gift was the kidney donated by your friend Kurt, and the other gift was that you were able to participate in this clinical trial of really groundbreaking significance in that you re living so well now. Absolutely. Yeah, absolutely. And I ve often thought that, you know, you get these sort of gifts that there is no quid pro quo for that kind of thing, and the only thing you can do is live your life as healthy and as happy and as well as you can and sort of honor the people who have given you that by sharing the story and treating your body well. We re going to hear more from you later on, but let s honor somebody who has helped you with this, and that s Dr. Joseph Leventhal. Dr. Leventhal is a transplant 3
surgeon, and he s director of the living donor renal transplant program at Northwestern Memorial Hospital. He s associate professor of surgery at Northwestern s Feinberg School of Medicine. Dr. Leventhal, so here s one of your first patients [who has received treatment] that I know you and your collaborators have been planning for a long time. It must make you feel great that it s working out so well right now. Well, it s extremely gratifying, and I think it represents for us validation of many decades of research initially starting in small animals and ultimately translating into the clinic we think an approach, a treatment that will have long-term benefits for our transplant recipients. Side Effects of Anti-Rejection Medications Let s talk about that. So I kind of alluded to some things, but I want you to put it into perspective. So this anti-rejection issue is a big one for certainly kidney transplant but I imagine other organs, too. It s a big deal. People have to take these powerful medicines, and unfortunately rejection is not at all uncommon, right? And the side effects. Right. The mainstay of treatment for any solid organ transplant patient to prevent rejection is drug-based immunosuppression. That s just been the standard of care for more than half a century. We ve gotten better at developing drugs. We have more drugs to use right now in patients to help tailor the anti-rejection therapy, but these drugs are all toxins to some degree. They can increase your risk of infection or certain types of cancer. They have certain side effects on patients in so far as they can promote hardening of the arteries, aggravate or cause high blood pressure, lead to the development of diabetes or bone disease, and although they are very good at controlling the initial immune response they re not all that good at the long-term control of the immune system in that a process called chronic rejection invariably occurs in organ transplant recipients. That, plus the fact that the drugs themselves can have direct injurious effects on the organs we transplant, particularly kidney transplants, this means that someone who gets a kidney transplant today with our standard of care approach who is in their 20s or 30s can expect that that kidney is not going to last their lifetime and will be facing the need for at least one more transplant. And this is particularly a problem for other organs, like a heart or a liver or a lung, where when that organ is lost it s a huge health emergency because we don t have dialysis for someone whose heart fails or liver fails or lungs fail. So we believe this approach that we are developing here where we trick the recipient s immune system, if you will, by using donor-derived stem cells such that the organ is not seen as different and these drugs are not needed will not only avoid a lot of side effects long term but will lengthen significantly the life 4
expectancy of a transplanted organ, and our hope that it s one and done. You get one transplant, and if you re tolerant that s the only transplant that you re going to need. Chimeric Organ Transplantation Wow. Let me go over this with you, help people understand. So if you have an organ donated to you your body will ordinarily say, This isn t mine, and it will fight it or reject it. I know you ve been perfecting different ways, so this approach is where you re taking from the donor, you re taking some of their cells by kind of almost we think of dialysis, but I know it s something called apheresis, but you re taking some stem cells from them that are induced and floating around in their bloodstream, collecting them, and then you re going to also infuse those into the person who received the kidney, right? That is correct. Okay. And the idea is with the help of these cells they kind of join in the immune system of the patient to say, No, no, no, I m not so foreign, and these cells, say, I m here too, and therefore try to discourage rejection, if you will. That s correct. What we have shown you can achieve is engraftment of these donor stem cells, and this state of affairs is termed chimerism, taken from Greek mythology for a creature that was the combination of a number of different animals. Chimerism means the donor cells peacefully co-exist and survive and set up their own immune system within the recipient, and by virtue of doing this the organ is not seen as foreign and no rejection occurs, and the anti-rejection drugs can be eliminated. Now, some people have heard of bone marrow transplant for various cancers and even some other autoimmune conditions, and I know Northwestern has done pioneering work in that, so this is another major procedure. You re kind of doing one and then another altogether, right? And as Lindsey said, the recovery is significant. Correct. This is essentially adding into the mix a stem cell or bone marrow transplant. Unlike treatment for certain cancers where you have to wipe out the bone marrow of the cancer patient to eliminate the cancer and then come in with the stem cells, we use what s known as a low-intensity regimen where the intent is not to wipe out the person s immune system but just to create enough space, if you will, for those donor stem cells to take hold. 5
And there s no question that the conditioning that we use, the preparation that the recipients go through is an order of magnitude more intense than a vanilla-flavored kidney transplant, but the payoff is in getting off the anti-rejection drugs and not being shackled to the use of these agents in a way that if you miss them or stop taking them for even a short period of time you can develop serious problems with a late rejection. And you of course avoid the side effects of being on these drugs for years and years and years. Ongoing Research Dr. Leventhal, I understand this research is a collaboration between Northwestern, which has been a leading transplant center, and you ve helped launch the living donor renal transplant program there, and another institution, so it s sort of scientists working together, right? Exactly. This is a great collaborative effort. We here at Northwestern have a very strong interest in translating insight from the bench to the bedside and are able to do so because of the infrastructure between the comprehensive transplant center and the fact we have a very busy clinical living donor transplant program. We perform 150 to 160 living donor kidney transplants a year here, and over the last five years we ve been the busiest living donor kidney transplant program in the nation. We ve also been pioneers, if you will, in developing strategies to minimize drugbased immunosuppression. We were one of the first centers to practice the avoidance of corticosteroids starting in the late 90s, which led the way for many more transplant centers to embrace this as we showed that it was safe and effective. And we ve developed strategies for patients with immunologic barriers such as blood-type incompatibility or sensitization, and we re one of the first centers in this region of the country to successfully develop that as well. So we had a long interest in kind of being on the edge and seeing where the field might go, and our collaborators at the University of Louisville had done the heavy lifting in terms of a lot of the early basic science work, and so through this collaborative effort we launched this clinical trial here at Northwestern in 2009. And Lindsay represents one of our first eight patients, five of whom we ve been able to entirely withdraw from anti-rejection medicines, two of whom, the other two, of the remaining three were able to be maintained on much lower doses of a single anti-rejection drug. So even though we didn t necessarily hit a home run in those two patients they still definitely got on base on second or third. So we think that approaches using cells in solid organ transplant recipients is going to have a bright future in helping to minimize the need for anti-rejection drugs. So let s talk about that. Let s just think a little more globally, and we ll talk about where this research goes related to kidneys in a second, but you re alluding to the 6
fact that maybe this approach could have much broader implications as far as preventing rejection of other organs. Yes. We believe that the approach that we ve developed and shown proof for principle can work in living donor transplants can be applied to the much larger population of patients who would be getting a deceased donor organ or may have already received a living donor organ. And what we believe will be possible is something that we ve termed delayed tolerance induction, where someone who has gotten an organ, let s say a kidney from a living donor, who is months or years out from the transplant might be able to be induced to be tolerant by putting them through the conditioning regimen and receiving the specially prepared stem cells from their kidney donor, who if still available can allow us to collect by apheresis their stem cells. I just want to make sure I get this right. So Lindsay and the other seven patients you mentioned, they had stem cells from their donor, same person who donated the organ, and that was infused the following day? Correct. But you re saying that this could be a year or two years or three years later and you re going to investigate whether that could work. Yes, that is one of the next phases of the work that we are conducting to test the principle of being able to do this remote from the time of the transplant. And we think that even as early as three months after having recovered fully from a kidney transplant or another type of transplant it might be possible to perform this delayed tolerance induction. Now, with living donors it would mean that we could collect their stem cells after they have recovered from giving us a kidney. For people who receive a deceased donor organ, whether it s a kidney or a heart or a liver, that would mean that we have collected the bone marrow of the deceased donor at the time that we procured the organs for transplant, and these days we can easily freeze away or as we say, cryo preserve bone marrow cells for later manipulation and use. So we think that this is very possible, but obviously requires careful investigation. All right. I just want to understand. So if I received a kidney from someone else, I mentioned about my body seeing it as foreign, but you do all this matching, I mean, is it ever possible that you just have somebody who is a match that there is no worry about rejection, or is that just an identical twin? 7
Well, that s an interesting question. Spontaneous tolerance, where someone is a happy, I guess, occurrence of nature or gets lucky and just stops their medicines and is able to stay off it without any ill effect, they have been able to identify over the last 20 years with the many thousands of patients who have received kidney transplants a total of 30 individuals who were spontaneously tolerant, and that really is a very, very small number of patients. Right. It clearly is a very rare event, so it stands to reason then that you ve got to take your medicines to avoid rejecting your transplant. Right. If you re depending on stopping your medicines and getting lucky, that is not a path to success. Participating in a Clinical Trial Okay. Well then, that just underscores the significance. So people are listening, Doctor, they say, Well, there are eight patients who participated in this trial, it s big news, you ve alluded to other research, somebody saying, How can I participate? What conversation can I have with whom to see could this be available to me? What happens next? Because people are interested now. Well, the trial which we have recently described and written about is one that is still open and ongoing and enrolling patients, and information about the trial can be obtained from a website that the government supports called clinicaltrials.gov that is a clearing house for all approved, regulated clinical trials throughout the world. And so one can go to that website and look at what are--what we call the inclusion and exclusion criteria as well as what the trial involves to get a sense of whether or not this might be for them. If someone has specific questions they can contact us through our transplant website that we have contact information on website related to research interests or interest about a transplant that serves as an opportunity for people to engage us. With respect to some of the other down-the-road areas that we talked about with delayed tolerance induction, once those protocols are in place, again they ll be posted on the government website, clinicaltrials.gov, for people to get information to see whether or not it might be for them. 8
I just want to mention, and, Lindsay, I think you d underscore this, that timing can be everything, that you, the patient, need to--and maybe with a doctor in the community maybe want to keep your eye on this, because Lindsay when you first thought you were going to be having your transplant the trial wasn t open, right, and then your transplant was delayed a month or so and then, boom, it was, and you were one of the patients. It worked out. Yeah. I think the trial had closed, if I m correct, after the seventh patient briefly, and then after July 1st, which my transplant was initially supposed to be in June and it was pushed back to July, I got a call from Dr. Leventhal maybe July 2nd saying that the trial was opened, and I was like, sign me up. Right. So, yeah, it was sort of a lucky accident for me, and I m just so glad that it happened that way. Well, Lindsay, so people are listening, maybe they re not familiar with clinical trials but they say, I understand this whole rejection issue, I m learning about it, and I want to avoid it, what would you say to them about really asking questions and keeping their eye on what opportunities? I mean, heard it mentioned at a seminar, and it ended up, you know, coming to benefit you. What would you say about getting educated and really seeking out what options there might be? Well, I would say, don t do what I do and expect to get lucky because that s really what happened to me. But now I sort of know more about it, and I realize a patient has a little more patient power than I thought. You know, if I had been a little bit more on top of things I could have figured out that this was going to happen and talked to the doctors about it and seen if I could have timed my transplant so that I would have been able to be involved in the study. So there are things you can do. The website that Dr. Leventhal mentioned is one that I ve actually checked out recently. People that I know have asked me about this trial, and I found it there. So ask your doctor, check that website, and, you know, just do some research. Closing Thoughts Dr. Leventhal, you ve been at this a long time and as you said there s been a lot of work. How big a deal is this? In your career, how big a deal is this? 9
It s kind of a game changer or has the potential to be so in that we ve demonstrated the ability to achieve this state of tolerance in mismatched and unrelated donors and recipients. I think that s very important to underscore, that the very large majority of transplants we do are not between perfectly matched siblings or even partially matched family members. They re between individuals who share very little if any DNA matching. The matching that we do ensure with transplantation as much as we can is that the blood type is compatible and that there isn t an allergy or preformed immunity, what we call sensitization. So the fact that we ve been able to demonstrate this as being a safe and reproducible and effective strategy for the large number of the majority of the patients who are out there getting transplants means that this isn t just going to impact in a small way on the sort of transplants that we do but potentially in a very large way. And it s our hope that as we follow patients like Lindsay out long term that some of the things that we hope for, that we hope to see in avoiding the drugs will be realized, that there will be lots of people, as Lindsay put it, forgetting that they ever got a transplant--or not really feeling like a transplant recipient because they re not tied to the use of medicines that represent a constant reminder that this is something that they have to do. Wow. Well, all I can say is congratulations on your progress so far, and I know everybody in this field is thanking you and pulling for you for more knowledge about how you can perfect it and make it available for more people. Dr. Joseph Leventhal, the director of the living donor renal transplant program at Northwestern Memorial Hospital, thank you for all you do and for being with us today. My pleasure. And, Lindsay, I want to give the last word to you. So Dr. Leventhal, your doctor, was talking about it and I know he s delighted how well you re doing. You go in for those blood tests every couple weeks, so far so good. I read that you ve said that your life is totally transformed. Tell us about how you feel. Like, you know, you and CJ, how you feel, your energy and how you feel about your life now. I feel fantastic. I really feel like I sort of stepped inside a time machine and went back about 10 or 15 years because before I had the transplant I was so tired, exhausted all the time. I ended up having to hire a full-time nanny for my son. I could do about one thing a day, and then that was it. And now I don t just feel better than I did, you know, a year or two before the transplant, but I feel better than I have in many, many years. So it s the energy, it s--you know, yeah, I feel transformed and lucky to have been a part of it. There s one other part, too, and we mentioned along the way your sister Sarah. 10
Yeah. Who also has the inherited genetic condition that affected your mother and you, and while she s doing well, someday, who knows. Yes. So if this can all be perfected, made available more broadly not only will have helped you, but will help your sister. Well, this is the thing. One of the other things that sort of inspired me to want to go forward with the transplant, I mean the stem cell transplant, is that this is a genetic disease and other members of my family are affected by it. Potentially future generations of my family will be affected by it, and this is something that I can do now to hopefully make it a much different experience if any of them go through that. And, you know, to honor the memory of my mom who, you know, didn t have any of these opportunities--you know, she had this brain aneurysm that now I ve been checked for every five years. It s a very simple procedure, but back when she died it was not. So it takes people to step up and be willing to try things out so that they become standard of care. Right. Well, Lindsay, your mom would be proud, and you are honoring her and helping your sister, other family members and thousands of others. And I know clinical trials, and Dr. Leventhal would say this too, they take scientists and research, and they take patients who are willing to go forward with it with the hope it will benefit them but also with the hope it will benefit others. Thank you, Lindsay, for what you ve done. Have a lot of fun with your husband and CJ, and I hope your energy always remains off the charts, okay? Thanks. I hope so too. Thank you very much. All right. This is what we do on Patient Power. What a great story, great medical news, and I know we ll be hearing more from Dr. Leventhal and the team at Northwestern Memorial. I m Andrew Schorr. Thank you for joining us. Remember, knowledge can be the best medicine of all. Please remember the opinions expressed on Patient Power are not necessarily the views of Northwestern Memorial 11
Hospital, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. 12