Leslie S. Kean, MD, PhD, Principle Investigator, Associate Director, Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute talks about graft versus host disease and a potential new drug to help patients suffering from GVHD.
Interview conducted by Ivanhoe Broadcast News in October 2017.
So we talked to Noah and his family and graft versus host disease, it is pretty horrific, can you go in to the problem of that?
Dr. Kean: Sure. Graft versus host disease is the most deadly complication of a bone marrow transplant. And this is really a critical problem, I’m a pediatric bone marrow transplanter, but it’s true for pediatrics and adults. The patients that we take to transplant are patients that have deadly diseases that need a transplant in order to survive. So either they have a very resistant or relapsed leukemia or another non-malignant disease but that would take their life. These kids that we treat are going to die without their transplant. The biggest tragedy of transplant is when you cure their underlying disease but they die of the complication of our procedure. And there are numerous complications that they’re at risk for but the greatest risk is graft versus host disease.
How often does that happen?
Dr. Kean: Well in all of its forms it happens more than half the time after transplant. Most of the time we can get a handle on it and treat it effectively but for the worst cases, so for the most severe graft versus host disease and that happens about ten percent of our transplants there’s about half of those patients that will die. It happens a lot, the severe cases happen less commonly but those kids often won’t recover from their disease.
It sounds like Noah had pretty it bad, like he was on the really bad end of that.
Dr. Kean: He was he’s a real miracle story and it’s just amazing how he came through and both he and his parents are amazing and we’re just so thrilled that he’s doing so well.
What would the standard of care be, is there even a standard of care for this for children?
Dr. Kean: What we try to do after the transplant first of all is prevent the disease from ever happening, so all kids are on multiple prevention medicines for their whole transplant. And those medicines are very toxic so they can harm the heart, they can harm the kidneys, probably the most important thing that they do that we worry about is that they can really harm the immune system. So they can make it much harder for the child to fight infection. Even with children that don’t have any GVHD we have to give them multiple medications to try to prevent it. And as I said about half of those kids will have their GVHD prevented so that’s a good news story. The bad story news is that half of them won’t. So there’s standard prevention medicines that we use but like I said they’re not fully effective and then when a patient gets GVHD we’re still treating them with the exact same drugs we’ve been treating them for the past thirty years. All patients will get steroids first although it’s very well know that first of all steroids are incredibly toxic and they don’t work in a lot of our patients so that would be considered the standard. But if you ask the question is there a fully effective standard the answer unfortunately is no.
So then KY- 1005 comes along tell us about how that works and what kind of impact that could have.
Dr. Kean: My lab has focused on studying graft versus host disease for essentially my whole career. I started to study it because I was treating patients that were dying of the disease and I was really motivated and inspired to start studying the disease. What I do in order to try to study the disease is to study the pathways by which the bad cells, the cells that cause GVHD which are called T-cells, how they get activated, why they go in directions that they shouldn’t be going. Why they become sort of pathogenic cells rather than cells that your body needs to fight infection. What we know in the field now is we know a lot about the pathways that cause T-cells to become activated. And one of those pathways is called OX-40, so OX-40 is on the T-cells and it binds to a molecule called OX-40 ligen on the cells that the T-cells have to see to become activated. And so this has been for many years now a really interesting target because it has at least the potential to be sort of a magic bullet. If you block that pathway on what we call conventional or effector T-cells those T-cells calm down, that’s great. But we don’t only have effector T-cells in our body we also have these sort of good T-cells called regulatory T-cells. And one of the problems with many of our treatments for GVHD is that they do a pretty good job of controlling the effector T-cells but they also control the regulatory ones and so you wind up out of balance again. But the way OX-40 and OX-40 ligen happen to work is that we considered it a possibility that if you block that OX-40 ligen you actually sort of magically block the effector T-cells but keep the regulatory T-cells intact. And so that was actually one of the big questions that we were asking with our study. This had been looked at in a test tube, it had been looked at in other models but we have a very translational model for graft versus host disease and we wanted to test that in our model. And so what we did is worked really closely with this company called Kymab which is a company in Cambridge, UK. They contacted us they knew that we were very interested and they were able to supply their new antibody called KY-1005 to see whether it would work. So all of these studies were done in collaboration with this company who supplied the antibody but it really used the model that my lab had created and developed over the last ten years or fifteen years. And so what we were able to do is ask the question if we gave recipients this experimental antibody could we prevent this GVHD and when we prevented it could we achieve that balance. So could we control the effector T-cells?
In animal studies right now?
Dr. Kean: Yes.
What are the results so far if you can tell?
Dr. Kean: It’s been really exciting probably better than anything and I’ve done a lot of experiments over the years trying to find new targeted agents. KY-1005 is clearly superior to everything else that I’ve tested in the laboratory so far in its ability to control those effector T-cells but maintain the regulatory T-cells. So just what we had hoped would happen and the reason you do experiments is to ask the question. You never know but we really saw very interesting results that suggest that blocking this pathway just as we had hoped would control those effector T-cells but keep the regulatory T-cells intact and what that led to is control. So we have a model where we can create very serious GVHD and we were able to control it for the whole length of our analysis. That was a real first. We have never seen something controlled so effectively. Now this was when that antibody KY-1005 was combined with a standard prevention strategy called rapamycin. There’s a lot of interest in rapamycin for a whole host of medical problems. People are studying it cancer, in preventing sort of metabolic disorders. So rapamycin is a drug that’s already approved and it seems like it has a lot of beneficial effects across a variety of diseases. And what we found is that in combination with KY-1005 when we added that to rapamycin we got this really robust control over graft versus host disease.
And rapamycin is what?
Dr. Kean: Rapamycin is small molecule that inhibits a pathway called emtor which is basically a pathway inside the T-cells that controls signaling and metabolism. And so what we found is that when we place those two together we found what we call a centergistic affect. So that rapamycin is partially effective by itself, KY-1005 was partially effective by itself but when we put them together is when we really saw the really amazing activity.
Teamwork.
Dr. Kean: Exactly.
So are you still preclinical or are you ready to take it to patients?
Dr. Kean: Well we are hotly pursuing the first trial. So the company is already in patients which is very exciting they’re just doing their first safety tests.
In England?
Dr: Kean: In England yeah. First they do what you call Phase zero testing which is healthy volunteers, make sure it’s healthy it’s safe and those studies are still ongoing but there’s no indication of any issue at this point. And then they’ll do a Phase I study, a small Phase I in patients with psoriasis and then I am essentially every day working with them on the first trial of KY-1005 for graft versus host disease prevention and that’s a study that we would hope to do right here in Seattle.
Starting in the beginning of the year?
Dr. Kean: Oh it takes a while to do these so I think that hopefully within the next year we will be designing the study and then really there are a lot of complicated decisions that are made. But that’s sort of what we’re working toward.
How would the drug be delivered, is it a pill or IV?
Dr. Kean: It’s IV. So all of our patients already have catheters so you know that the upside of having to have that is that that’s not so much of a problem.
After talking to Noah’s mom something like this can be prevented, the impact for families would be incredible.
Dr. Kean: It would be huge and you’re absolutely right in that this is probably the most impactful thing that we could do for our families is to prevent this from every happening. So you have to make sure that that’s a safe therapy so all of our therapies have risks. What we saw in the preclinical studies was that it was so very safe which is really important. And that’s what the clinical trials are for but if we could use this combination and save kids like Noah from ever having to go through what he went through would be a really big win.
What are your top three pieces of advice to parents who have kids who are diagnosed with cancer?
Dr. Kean: If a family is facing a new diagnosis of cancer the first thing that they absolutely must do is get to a cancer center, the best cancer center that they can get to that is part of what we call The Children’s Oncology Group in the United States. So it’s a national group of cancer centers that all run the state of the art trials. The second thing is to have hope. You know one of the things that we know about childhood cancer and there’s a whole range of childhood cancers but because of the clinical trials that have been done in this country over the last fifty years the survival rates for childhood cancer have gone up every single decade. And that’s because parents and doctors and the kids all collaborate, they all work together to do these really important clinical trials. And as we keep on testing and keep on testing we’ve been able to improve outcomes and improve the lives for the family. So I think that’s really important to know that there’s a lot of hope.
How can parents talk to their kids about cancer?
Dr. Kean: So you know the question of how parents talk to their kids about cancer, there’s probably a different answer for every family. As a mom, I have two kids, my kids are 27 and 24, so they sort of walked with me through medical school and training and through my life as a physician so I really relate to my family as a mom as well as a doctor. First of all I think what is important to remember is that kids usually know that something is going on so the idea that we can totally shield them from the news is usually not so much the case. And that I think that as a mom and as a doctor that you probably do better with your kids by telling them what’s going on in a developmentally appropriate way. So for instance, a three-year-old will not understand cancer but they’ll understand that they’re sick and they’ll have to be in the hospital. A six-year-old will understand a little more. One of the things I think is really important to do as a parent is to be open for those moments of opportunity when a child asks you something and you’re able to have those important conversations with them. Because you know when a child gets a cancer diagnosis unfortunately it’s a long treatment usually. And so the more we can talk to the kids and listen to them as well and reflect and relate what their questions are and try to answer what their questions are and what their worries are that takes courage from the parents to really hear those sometimes difficult questions from the child; I think the better they can come through the experience. We talk about cancer survivorship and there’s a new kind of concept called cancer resiliency. The goal of the parents is really to create those resilient kids. Having conversations with them sort of throughout their growing up years will help make them resilient cancer survivors you know not only in their childhood but also in their adulthood. And that’s what we’re hoping to help create.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Lindsay Kurs
Lindsay.kurs@seattlechildrens.org
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