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Scott Webb: Can you imagine if kidney transplant patients never needed a second transplant, I'll give you a second. That's not a hypothetical. It's a reality. And joining me today to tell us about the groundbreaking and undeniably cool benefits of combining solid organ and stem cell transplants are Dr. Paul Grimm.

He's a professor of pediatrics and medical director of the pediatric kidney transplant program at Stanford university school of medicine and Stanford children's health. And Dr. Lee J Bertina. She's the section chief stem cell transplantation. And regenerative medicine and co-director of the bath center for childhood cancer and blood diseases.

Scott Webb: This is Peds Talks from Stanford Children's Health. I'm Scott Webb. So doctors, thanks so much for your time today. This is a fascinating topic and I can't wait to dig in and hear what you all have to say. get rolling here, Dr. Grimm, what's the benefit of combining solid organ and stem cell transplant?

Dr. Paul Grimm: First of all, thank you very much for giving us the time to talk about this because it's so cool. This is something which, you know, I've been looking after children with kidney disease for more than 30 years and this has the potential to cure people, which, you know, in kidney disease, normally we never can cure anybody.

So if you have kidney failure, you are always a kidney patient. Whether you're on dialysis, have a kidney transplant, you still have to go to doctors, take medicines and always worry that something's going to go wrong. So with a kidney transplant, which is the best treatment for kidney failure, the average kidney transplant from someone who's signed the organ donor card lasts about 15 years. So if you're an adult patient, you know, you're on dialysis, you're age 55, and you get a kidney transplant, that kidney is going to last you almost for sure the rest of your life. Most adults who are living with a kidney transplant when they pass away of natural causes or whatever, that kidney is still working. That's not the way it is in children. When a child gets a kidney transplant, if those things last on average 15 years, they are destined to need more than one kidney transplant in their lifetime.

So why do kidney transplants burnout or rundown or just wear out? Well, part of it is because we can never completely prevent rejection. You know, rejection is a normal immune response that the body produces using the same cells, the same immune circuits that the body uses to protect itself from viruses and cancer. So when we use immunosuppression to protect the kidney from rejection, we are reducing and inhibiting those body defenses. So every patient has a balance and each patient it's different. And so the doctors and coordinators have to figure out what's the right balance of immunosuppression to give the kidney as long as possible, a chance to not be rejected, but not overwhelm the patient with viruses and cancers.

So we do a pretty good job, but it's not perfect. If you look at long-term data like 20-year followup, kids who've had a solid organ transplant 20 years later, if they're still alive, there's a 20% incidence of severe cancers, leukemias, post-transplant lymphoproliferative disease, sarcomas, and things like that because we are continually suppressing the body's immune surveillance for cancers. Children unfortunately pass away of infection. And on the other side, the drugs that we use to protect from rejection are themselves toxic to the kidney. So for all these reasons, the kidneys don't last a lifetime and they present a risk of infection and cancer to people that are living with a kidney transplant.

Look, don't get me wrong. A kidney transplant is way better than living on dialysis. No question. It's safer and it's much better quality of life, but it's not perfect. So just imagine if you could do a stem cell transplant from the donor of the kidney transplant. If you could do a stem cell transplant, you exchange the immune system of the child for the immune system of the donor and then you do a kidney transplant from that same donor, you would not need immunosuppression. You would not have the daily requirement of drugs to protect from rejection because it's the same immune system. The kidney is welcomed by that immune system, so the risk of future cancers go down, their risk of future infections go down and, hopefully, the wearing out of the kidneys stops because it's not being nibbled away by little bits of rejection every day and it's not being damaged a little bit by bit every day by the nephrotoxic drugs. And hopefully, it will last a lifetime.

And the final thing is, you know, anybody who's had a teenager or two knows how difficult it is to get them to take their medicines. The most common cause for kidney transplant rejection or heart transplant rejection or liver transplant rejection in teenagers is they're just teenagers. You know, they try their hardest, they want to be good kids, but life is chaotic and their brains aren't fully formed and so they forget or they get confused or they get so focused on, you know, the problem with their girlfriend or the exam that they're taking or their soccer game that they're at and they just forget that their meds are in their pocket and they don't take them. And so non-adherence is one of our most difficult challenges and all that would go away with a stem cell and kidney transplant. So that's what makes me really excited about this whole area.

There's another benefit, which is some patients have genetic diseases where a kidney transplant alone isn't enough. Like these children who have multiorgan diseases where the disease manifests like SIOD. SIOD is a disease of DNA repair. So there's a genetic defect which damages your ability to repair DNA. So these children are at risk for infection because they have an immune defect. They're at risk for cancers. Children who've gotten kidney transplants with this disease the regular way have a lot of cancers and a lot of infections. And as these children grow up, they have trouble with their blood vessels that can lead to strokes and severe migraines in their 20s. So this is a whole body disease, which potentially could be cured with a stem cell transplant. So you get a twofer, the stem cell transplant fixes the underlying disease hopefully or improves it and it allows you to have a one and done kidney that can last your whole life, no need for medications, no risk for projection, no risk of complications. So if that can happen, that'd be awesome. But I'm just a lowly kidney doctor. So I'm going to let Dr. Bertaina talk because she's the smart one in the room.

Scott Webb: Well, I think you're both smart and I'm probably the less smart of the three involved in this conversation. And you're so right, Dr. Grimm. I have two teenagers and I can barely get them to take their vitamins.

Dr. Paul Grimm: Exactly.

Scott Webb: I feel your pain and as I'm sure most parents listening would as well. Dr. Bertaina, no pressure here. Dr. Grimm says you're the smart one in the room, so why haven't doctors been able to do this successfully before?

Dr. Alice Bertaina: Well, definitely I'm not the smartest one here. It's just the team work as usual. And the reason why this approach is working is because we are working on a team basis and putting together all our smart ideas, experience so on.

Why haven't doctors been able to do this successfully before? first of all, because here we are talking about performing an allogeneic stem cell transplantation patients that or might not need an allogeneic stem cell transplantation for their own disease. And historically, this approach carried a lot of complications, mostly related to transplant-related mortality.

when we talk about transplant-related mortality, we talk about risk of severe infections that can be life-threatening. And we talk about immune-mediated complications, the most one being graft-versus-host disease. And we all know in this field that when we do an unmanipulated allogeneic stem cell transplantation, we can have a rate of graft-versus-host disease up to 60%, and this can lead really to a higher risk of mortality. the first reason was really not having a stem cell transplant approach that could be safely offered to patients who otherwise wouldn't need this type of treatment.

And second of all, there is the toxicity of the conditioning regimen. And this is another big chapter because to make sure that we can really obtain an engraftment with the stem cell transplant, we need to prepare the patient with chemotherapy or a combination of chemotherapy and radiotherapy. of course, this is a very toxic that we are going to do in our patients can lead to acute, but also long-term toxicity and so this was another struggle for the investigators previously attempted that.

And so to get to the point, first of all, you know, in pediatric patients, the programmatic stem cell transplant and kidney transplantation have not been done so far. We are the first one of who really intentionally decided this combined approach. Before, mostly groups on the adult side really tried to use this disease approach. But when they did it in setting, so when the parent of the recipient and the donor were not fully matched, approaches have failed and have failed mostly because either use a reduced intensity conditioning regimen, which didn't in a full engraftment or, in those patients in which the full engraftment actually happened, were not able to discontinue the pharmacological immunosuppression, which is our ultimate goal.

So, what we are doing really different is that we are using a new strategy of transplantation. are using a new strategy of graft manipulation, which is called the alpha-beta T-cell CD 19 B-cell depletion, allow, first of all, mismatched donors and, specifically, we are talking about haploidentical donors, because we are using one of the two parents, but because of the strategy of ex vivo graft manipulation, we are able to assure a really low risk of both severe acute and chronic graft-versus-host disease. this is really the main goal. When we talk about starting this approach, safety was our first concern. to these patients a treatment plan, which was safe enough to really the chance of evaluating, investigating the possibility that using the sequential approach we can remove forever the need of pharmacological immunosuppression .

And second, we are ad hoc conditioning regimen, which are yes, myeloablative, we want to completely make the marrow of the recipient able to fully engraft the donor's marrow, but with a low profile of toxicity, such as either short-term and long-term, we don't have the complications that previously have been reported.

Scott Webb: May I say that my mind is blown when I speak with the experts and the doctors and the scientists at Stanford. But you both have just blown my mind this morning. I'm just trying to get my mind around this. Grimm started answer by saying it's just so cool. And I just think that's just such an easy way to say it. It's just so cool. And when we think about the approach at Stanford, what makes it so unique? What makes it special?

Dr. Alice Bertaina: Well, let me start from what I mentioned my answer before. So the prior attempt to really use allogeneic stem cell transplantation to eliminate the risk of immunosuppression had the goal of establishing a mixed chimerism in the recipient. And so the hypothesis was that establishing this mixed with the time, the recipient's immune system would become tolerant to the one of the donor and, therefore, eliminating the immunosuppression would have been possible. However, that didn't happen. And in fact, in the studies that showed establishment of mixed lymphoid they had a reduction in the number of the immunosuppressive drugs needed, but never completed discontinuation. And in few cases in which they were able to a complete donor engraftment after transplantation, had of fatal graft-versus-host disease, which of course is the first thing we want to avoid. So here, what we are doing differently is really utilizing a new strategy of graft manipulation, the alpha-beta T-cell depletion, with the goal of obtaining, first of all, a full chimerism, is going to allow us withdraw pharmacological immunosuppression within 30 days after the kidney transplant. And this is what happened in the three patients that we treated so far. The establishment of 100% on donor chimerism specifically on the subset of the T-cells really the key ingredient be able to discontinue the immunosuppression. And that discontinuation of the immunosuppression in the presence of full donor lymphoid chimerism going to avoid the possibility that kidney is going to be rejected from the immune system of the patient.

This is exactly what we are creating. We are creating an immune system, which is unable to reject the transplanted graft the immune system is the same. in fact, in the three patients that we treated already with this approach, one year after the kidney transplant, we performed a mixed lymphocyte culture to really demonstrate that we created what we call is functional tolerance. that happened because we tested T-cells isolated from patients. But that at that point, they were T-cells with the DNA of the donor because these patients are 100% donor chimeric. And we tested them against the cells of donor and the cells of the other parent. And it was really exciting to see how the T-cells of the patients did not respond at all when stimulated with the cells the parent who was the stem cell and the kidney donor, while they maintain a normal response against the other parent.

Dr. Paul Grimm: If I could interrupt here, I just really want to emphasize this the most amazing personalized medicine. So Dr. Bertaina's engineered an immune system that leaves the transplanted kidney alone, leaves the child alone, but defends that child and that kidney against anything else. So the rest of the immune system is intact and so it'll defend against some other parent or some other cancer or some other infections. So this is as personalized as you can get. Sorry, Alice, I just had to emphasize that.

Dr. Alice Bertaina: No, please. Absolutely. That's crucial. I think that, you know, for us, seeing those patients who are, first of all, independent from the dialysis; independent from any drug, these are home without the need of any immunosuppression, also other medications that are usually employed to treat the complication of theimmunosuppressionn, like blood pressure medication, for example, or electrolytes because there is a deficiency of magnesium related to the cyclosporine or the tacrolimus, to say something.

Patients who have a total normal immune system, as Dr. Grimm was saying, and so, if they contract COVID, they can respond the COVID as a normal immune system. But still they are not able to affect that kidney. And of course, our longest followup right now is 27 months. But we anticipate that these kidney will never be rejected. And so, here we are going to achieve another goal, which is a unique At Stanford. We are going to eliminate need of the second transplant because that kidney can stay in that body forever without chronic rejection.

Scott Webb: Amazing. You know, and maybe when I produce this, I'll put a little bit of echo on your voice, doctor, when you said the kidney will never be rejected. mean, it really is just absolutely mind-blowing. Dr. Grimm, you know, I know some of the first patients who've benefited and you mentioned this earlier, you touched on SIOD, they've benefited from this approach. Maybe you could break down. I'll let you do the hard work here, carry the heavy load here and spell out, you know, what is SIOD? And has it been treated historically?

Dr. Paul Grimm: Sure. So, SIOD, which is Schimke's immuno-osseous dysplasia, is a very rare condition. It's genetic or hereditary. So it's the kind of thing where you are a carrier of it and you have no knowledge and no one else in your family ever has had it and you happen to have a baby with someone else who's a carrier and has no knowledge of it and nobody in their family have it, but two carriers get together, have a baby and there's a one in four chance the child is affected. And so that's a typical autosomal recessive disease, just like cystic fibrosis or things like that, but it's much more rare than cystic fibrosis.

Anyway, so a child is born, looks pretty normal. But as they grow, they are very short and especially their spine is short and they look a little dysmorphic. But then what happens is their kidney starts leaking protein and the proteinuria gets worse and it doesn't respond to any treatments. And by the time they're five or six, often they're in kidney failure and need dialysis to stay alive.

Well, if they can live into their teens, what happens is they start having little strokes and severe migraines because there's abnormalities of the vessels of the brain. All through their life, their immune system is not normal and so they are at risk for all sorts of infections of various kinds. So say they get a kidney transplant, the normal therapy that we use to reduce rejection, the normal doses would be enough to completely wipe out their immune system and leave them at risk for all sorts of infections. But if you don't immunosuppress them enough, they can reject. But in addition, because their immune system is abnormal or deficient, there are children where they get a kidney transplant and the lymphocytes, the white blood cells that are in the kidney, you can't get rid of all the cells in the kidney, they actually invade the child and try and kill the child. So this life-saving kidney transplant, the white blood cells are sort of like a Trojan horse. They'd jump out of the kidney, they circulate in the child and they can actually kill the child from something called graft-versus-host.

Unfortunately, if a child survives that and lives with a kidney transplant for a few years, the drugs that are immunosuppressive lead to really increased risks of cancers. And in the old days, we have looked after children even here who were transplanted in the old way who developed cancers. And so these children have just a really hard life.

So because of all these issues, we felt that ethically it was the right balance of risk and benefit to try this new approach. So I have to emphasize nowhere in the world are children being treated like this, to purposely do a stem cell transplant followed by kidney transplant. Now, there's some research being done on adult patients in the US and Canada, all these studies are trying to get what Dr. Bertaina was saying, mixed chimerism or partial chimerism where they put in a bit of an immune system of the donor and a bit of the recipient and hopefully they get along. But it's unstable and it really hasn't been a clear solution. There are some adults that have been able to be down to one medicine or sometimes no medicine for a while, but most of the adults they tried this on need medications, because the balance fails. There are some protocols being done where they try and engineer special cells to inject into the patient that would help control the rejection. But it's still very experimental and that hasn't worked.

So really this approach where with Dr. Bertaina's ability to manipulate stem cells to get rid of the cells that are likely to cause the severe complications like graft-versus-host disease or EBV, and then do a full stem cell replacement, that's unique and very novel in this situation because it really allows the stem cell transplant to be done much more safely. So we can take this risk. And these three children that we've done this for are proof of the concept that they are all back home, being normal kids without all these medicines. And it's really delightful to get messages from their parents and updates on Facebook to see how they're thriving. It's just really wonderful.

Scott Webb: Yeah, it really is. And as if this groundbreaking work focused just today on the kidneys and children never needing a kidney transplant, as if that wasn't enough, I may be wrong, but I'm pretty sure there are other solid organs, Dr. Grimm. as we wrap up here, what other conditions may be treatable using this combined approach that you're doing at Standford?

Dr. Paul Grimm: We have all sorts of patients who have diseases that come back in the transplanted kidney. Autoimmune diseases and autoimmune diseases that damage other parts of the body. So there are dozens of diseases where this might benefit. Things like lupus, things like focal segmental glomerulosclerosis. There's a hereditary disease, which is not quite as rare as SIOD called cystinosis. There's about maybe 600 people in the United States with cystinosis and this disease could really benefit from a combined stem cell kidney transplant approach.

And as you mentioned, I hear that there's other organs besides the kidney, although the kidney is my life. Theoretically, this could be used in some situations once we get the bugs worked out. You know, for liver transplants, because a parent can give a part of a liver to a child and we have a really robust program to do that. So this is just to start. Hey, what do you think, Alice?

Dr. Alice Bertaina: Yeah, Okay. think that this is exciting. And I just want to say when I first came at Stanford in 2017, and I got so lucky to be asked about the first two SIOD siblings that we transplanted. And, you know, proposed this treatment. For me, it was like a dream coming true. And now, you know, four years later having treated these three children, really give us the confidence to say that that's going to work and we can expand that to other indications as Dr. Grimm said on the kidney transplantation, but also to build a more robust data that are going to be useful for the liver transplant as Dr. Grimm just mentioned.

And also, I want to say the intestine transplant. know that patients who need an intestine transplant are those probably more at risk of developing rejection even years after the organ transplant. And we believe that from really an immunological perspective, this approach would be perfect for optimizing that. But there is a lot that we have to learn and understand before. So we are going to use all we are learning from these patients that we establish really the preliminary data to delve into the liver first and then, hopefully if this other dream comes true, to the intestine as well..

Scott Webb: I mean, I can hear the excitement in your voices. You know, you're really just at the beginning of this, right? Three patients, and the sky's the limit, perhaps, right, dr. Grimm? We're talking about, "Well, if this works out well, how about the liver? How about the intestines?" I mean, there's just endless possibilities. My mind is just racing of all the benefits in all the children who would benefit from the work you're doing. It's really amazing.

Dr. Paul Grimm: we're starting out with children that clearly there's an ethical balance to doing this because of all their needs. But if we can prove that this is a safe as we believe it will be, we can then expand the indications maybe one day to children who just have just a need for a kidney transplant, you know, for the more common causes. And it's something which could be extended.

You know, it actually would probably be cheaper than a lifetime of immunosuppression and doctor's visits and just think of the quality of life we could improve, where children didn't have to come to the doctor every couple of weeks and have blood tests. And the parents worrying about having that sword hanging over their head. "Is this the day we're going to get the call from the doctor's office that the creatinine's up, and we're going to lose this precious organ?"

You know, it's such a life to be living with an organ transplant. And if we can make it better, gosh, that'd be just fantastic.

Scott Webb: Absolutely. Well, I want to thank you both for your time today. I hope we get to speak again when we move on to livers and other things and check back in on these patients and see how big the study has gotten. This is just work as always. Thank you both. And you both stay well.

Dr. Alice Bertaina: Enjoyable talking to you. Thank you.

Dr. Paul Grimm: Thank you. Thank you so much.

Scott Webb: That's Dr. Paul Grimm, he's a Professor of Pediatrics and Medical Director of the Pediatric Kidney Transplant Program at Stanford University School of Medicine and Stanford Children's Health; and Dr. Alice Bertaina,

She's the section chief stem cell transplantation. And regenerative medicine and co-director of the bath center for childhood cancer and blood diseases.

And to learn more, go to stanfordchildrens.org/en/service/kidney-transplant/SIOD.

This is Peds Talks from Stanford Children's Health. I'm Scott Webb. Stay well, and we'll talk again next time.