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Dr. Mapara: One of our patients was patient number three in the world who got a gene edited treatment. And so, that's when I think we initially started to talk about, that it really requires some guts on the patient side to really participate in that. That's something which is always awe inspiring that you wanted to be a patient who took on this risk. But I mean, this patient is doing very well now. I think he's now four years out, I believe, and is doing amazingly well.

Erin:  

Up until last year, the only cure for sickle cell disease was a bone marrow transplant. But donors can be difficult to find. Patients usually rely on siblings to donate. But if they have no siblings, or if their siblings aren’t a good match, they may wait years to find a donor. And then, there’s always the possibility that a recipient rejects a donor’s cells altogether. Too often, Sickle Cell patients are left with an extremely painful disease, which can be debilitating, and  prematurely end their lives.  

Until now. [01:00]

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Dr. Markus Mapara alongside his colleagues at NewYork-Presbyterian and Columbia have participated in developing the first ever cell-based gene therapies for sickle cell disease. These groundbreaking therapies take the patient's own stem cells, edit them, and then reintroduce them into the body to prevent red blood cells from sickling.The treatments gained FDA approval in 2023, and they are a significant step toward removing the need for donors entirely in the treatment of Sickle Cell Disease.

BEAT

I'm Erin Welsh and this is Advances in Care, a podcast about groundbreaking developments in modern medicine.

In this episode I speak with Dr. Mapara, Director of the Blood and Marrow Transplantation and Cell Therapy Program at NewYork-Presbyterian and Columbia. He explains why these new therapies are so ground breaking, how they function inside the body and what other advances he sees on the horizon.

[02:00]

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Erin Welsh: Hi, Dr. Mapara. Thank you so much for joining me today. I really can't tell you just how excited I am to discuss some of your research.

Dr. Mapara: Yeah. And it's a pleasure to talk to you.

Erin Welsh: So I want to talk about gene therapy and sickle cell, in a bit, but first I want to kind of zoom out and ask you about the blood and marrow transplantation cell therapy program at NewYork-Presbyterian and Columbia. So you joined 12 years ago. What interested you about this program? What made you think, yes, I want to be there?

Dr. Mapara: Yeah, so I think the unique opportunity really was that NYP, Columbia are obviously worldwide known institutions. And to my surprise, they didn't have an adult bone marrow transplant program. And so when, they reached out to recruit me, whether I would be interested in building that, I obviously, thought this is, of course, to some extent a risk building something and really starting it from scratch, [03:00] but at the same time, given, let's say, really the breadth of research going on here and the breadth of patient care I was very confident that building a program here, despite the fact that New York, obviously is highly competitive and has lots of  great institutions that we would be able to pull this off.  

The initial spark which really interested me was that at that time when I came the idea of combining bone marrow transplant with organ transplant would be one of the major focuses here at the Columbia campus and at NYP. And so that was really together with obviously the excitement of building something is what drove me to come here to New York.

Erin Welsh: Yeah. That's amazing to have also these opportunities to build and say, these are the directions that I want to take this. And so now what are the broad aims of this program?

Dr. Mapara: So at the end of the day we are, we are able to offer all types of  cell therapy or bone marrow transplant Treatment modalities and now, of course, are also participating, and are able to offer all types [04:00] of what is called immune effector cell therapies. So CAR-T is the word here. So where you're more or less, engineer immune cells of the patients, to express what is called a chimeric antigen receptor targeting specific types of malignancies.  

And what is really exciting now is that those CAR-T cells can be also used not uh, malignancies, but can also be used to treat nonmalignant conditions. So really, I think the knowledge of reprogramming the immune cells to achieve certain results, I think is fascinating.

And in that context, of course,  it was enormously important and a huge boost that Columbia was able to recruit Dr. Misha Sadula, to join here and build this Columbia initiative for cell engineering and therapy. which I think really will take us to the next level here of really being able to  offer, in house made novel first in human products so I'm really excited about the future here at Columbia NYP.  

Erin Welsh: Yeah I mean that sounds amazing. [05:00] And it also sounds like we could do a whole other episode on CAR-T cells alone! But I’m especially excited to talk to you today about some of your work on sickle cell disease. Before we dive into the incredible advancements you and your team are working on with gene therapies, can you lay out what some of the current challenges are with treating sickle cell disease?

Dr. Mapara: Overall, the median life expectancy of patients with sickle cell disease is fairly short, right? It's basically in the mid forties. And that is, one of the major challenges in the United States. There are about  100, 000 patients affected by sickle cell disease. And it is expected or calculated that about 20,000 really have a very severe manifestation, which would require a stem cell transplant or gene therapy potentially.

And so, the only, curative option so far really have been doing a bone marrow transplant from a donor. And one of the, I think, exciting clinical observations early on was that, the symptoms really become, very prevalent [06:00] at the time point when, during childhood or during basically early infancy when the fetal hemoglobin gets turned off, within the first six months of life and normal hemoglobin gets produced.

That's when the symptoms really start to be seen. And that more or less led to the thought process that you know if there are approaches of inducing fetal hemoglobin that you may be able to overcome some of the symptoms, right?  

And  um so, you know that more or less presented the starting strategy of how can we potentially genetically engineer cells in a way that they either really start to produce more fetal hemoglobin or produce a protein which is similar because we know what fetal hemoglobin does. It basically, more or less prevents the polymerization of the sickle cell chains, right? And so therefore, if you really have expression of fetal hemoglobin in the red blood cell, it prevents more or less, this this deformation and this creation of those typical sickle cells.

Erin Welsh: It’s incredible. So, let's switch to chatting a little bit more about gene therapy. I wanted [07:00] to circle back to the bone marrow transplant as the only curative current treatment for sickle cell disease, what are some of the limitations of that treatment?  

Dr. Mapara: So the problem really is that we know that bone marrow or stem cell transplants really work the best and have the least side effects if you have a perfect  match. And, when you have siblings,  there's usually a 20 percent chance that there is a full match. You have a 50 percent chance of the half match in the family, and then there's a 25 percent chance again of having no match at all.  

So, it's now also possible to use half matched siblings. And, that has been shown to, to be effective. However, it is more toxic than using a fully matched sibling, but at least that was able to address one of the major problems which we face in the field was that there were not enough donors out there, right? And the reason being that, minorities are underrepresented in the donor bank. So it's much more difficult to find a perfectly matched, [08:00] let's say, donor for an African American patient than, let's say, for a Caucasian patient.  

And so we know from our experience that, Match sibling transplants usually have the best outcomes. And in transplant we really are dealing with two type of what is called rejection vectors since  we're putting in the immune system of the donor, that immune system can recognize  the recipient as foreign and attack the recipient, something which is called graft versus host disease.

At the same time, the recipient has the ability of rejecting the cells from the donor. And the beautiful thing about bone marrow transplant is that usually because you're transferring or transplanting this, this active immune system, that this system has the ability to adapt and, and, truly develop tolerance. So, rejection of the graft, or this graft versus host disease, are really big issues in the context of, of, benign conditions like sickle cell disease.

Erin Welsh: And so as I understand it, there are two basic approaches that you are currently working on, one that involves [09:00] a lentivirus vector that delivers then this new genetic material and the other that uses CRISPR  technology. So I want to dig into each of these. But first, let's start with the lentivirus vector approach. How does this work?

Dr. Mapara: Right. So, so that is a strategy called gene addition. So there really the idea is to put in a gene which is somewhat similar to fetal hemoglobin, and thereby having the stem cells express this, this more or less synthetic hemo globin, which has, you know, fetal hemoglobin like properties, you achieve the same thing as if you would be having higher levels of fetal hemoglobin, meaning that you prevent the polymerization of the sickle cell hemoglobin, and thereby, prevent the development of vasoocclusive crisis.  

Erin Welsh: Ok so that’s the lentiviral approach.What about the gene editing approach that uses CRISPR… how does that one work?

Dr. Mapara: Using the gene editing approach you really focus on more or less reprogramming [10:00] the stem cells to start to produce actually fetal hemoglobin, and the strategies which are out there at the moment and the one which is currently approved. That's for this drug called CASGEVY is where you more or less eliminate this transcription factor called BC11A, which if you eliminate that, you take the break off the production of fetal hemoglobin and you start producing fetal hemoglobin again.

So those are at the end of the day, two competing  approaches, both results have been truly encouraging, which obviously led to the approval in December of 23. And that, therefore I think now is, offers two very nice options, which I think in my eyes are so far equipotent in terms of the benefit they provide to the patient.

Erin Welsh: And how did these two approaches perform throughout the clinical trials? Were there any important issues or lessons that came up?

Dr. Mapara: Issues which, you know, which have come up is that the gene addition approach, has been shown to be, had in the first, let's say, [11:00] part of the initial, clinical trials. They saw two patients who developed, in fact, acute leukemias. And so that's why they received the black box warning. However, It has to be noticed that this happened in the first group of seven patients where they still used bone marrow. And during that early trial, it was seen that the bone marrow is of inferior quality, and therefore they switched the production or the generation from bone marrow harvest to actually stem cell, from the patient.

Erin Welsh: Okay Right. So it was a pretty significant finding that stem cells are the preferred option for these approaches. I also wanted to chat a bit about the patient population. Who are the candidates that are eligible to receive these treatments?

Dr. Mapara: Right, so I mean the, the, as I mentioned, there are about, a hundred thousand patients over in the US who have  sickle cell disease and about 20,000  of those basically would more or less, meet the criteria to have really severe sickle cell.

And that was more or less defined by having frequent crises, [12:00] like, two crises per year for let's say, at least two years. And I think the challenge obviously is that, First of all, there needs to be awareness, both on the patient side and also the referring physician side, that treatment options are available. This may kind of delay patients getting, and that's something we're already seeing, right, is that, I mean, you look at the approval, which happened in, in December of 23, still the number of patients who have received, an FDA approved product, they are still on the lower  side, right, and so there has been a very slow adoption of this FDA approved product.

And then, of course, it requires that the patients do actually, really strongly adhere  to that whole process. So let's say even if we have identified a patient, usually what happens is patients have to undergo two months of what is called exchange transfusions, which helps to somewhat reduce inflammatory milieu in the marrow and is shown to improve the ability to mobilize stem cells. [13:00]

And once you have done those two months of exchanges, then you do the, the stem cell mobilization. And then obviously it depends on how quickly can the genetic engineering happen. And then, once it has happened, you also need to make sure that the cells meet the certain quality and release criteria.

So this can take another six months. And on top of that, the stem cell mobilization average, you need to do two cycles in order to get enough stem cells. So you could  argue that the whole process may take about, up to a year, from start to infusion of the cells. And so that obviously requires that the patient is able, for this one year to fully commit of coming to the program, to get the exchanges done.

Erin Welsh: Yeah: It seems like there are still some hurdles to turn this from a solely scientific solution to a social solution, and that can be more broadly accessed, but it's really encouraging to know that there are people working hard to make this happen. Were the clinical trials for these gene therapies [14:00] conducted at Columbia and NewYork-Presbyterian?

Dr. Mapara: Yes. Yes. So from the starting point both with what is called the HDB 206 trial, which was the Bluebird trial and the, the CTX trials from CRISPR vertex. So we more or less participated in those trials, from the starting point. And I think one of our patients was patient number three in the world, who got the, who got a gene edited. Product.

Erin Welsh: Wow.

Dr. Mapara: And, so, that's when I think we initially started to talk about, that it really requires some guts on the patient side to really participate in that.

That's something which is always awe inspiring, that you kind of, that you really wanted to be a patient, who took on this risk. But I mean, this patient is doing very well now. I think he's now four years out, I believe, and is doing amazingly well.

Erin Welsh: That's incredible. For something like sickle cell disease, which is an every day of your life, chronic condition …for this to completely change the way you go about the world is so impactful. What has it been like to work on these new treatments? [15:00]

Dr. Mapara: So this is something which obviously is enormously, I think, gratifying for a physician, right? To really  see that you really are able to have a, really transformative effect with a therapy on the life of a patient. And, so when you talk with those patients, who have undergone the procedure, I mean, this definitely has changed their life. In terms of being really able to function, continuing now with, for example, school and education. And so, the vast experience is really enormously positive.  

Erin Welsh: Yeah, I mean, it seems like it's about so much more than the pathophysiology of the disease and what it's doing to this organ system and that organ system. It's really about what it's doing to the entire lives of patients who have sickle cell disease, and being able to treat them as a whole is so crucial for just quality of life.  Can you talk a bit more about how NewYork-Presbyterian has made that sort of whole patient approach possible?

Dr. Mapara: At the end of the day the whole life of the patients has somewhat circled around the disease. And now that [16:00] center is lost, and so that creates new problems, and so, we at Columbia NYP, we have been one of the few centers in the country who also have an embedded psychiatrist, who is really able to help patients through the process.

And that has been enormously helpful to be honest. Just fixing the vasoocclusive crisis is not the end of all, right? So you need to be able to really look at the whole patient and offer this kind of holistic approach of navigating them through this process.

Erin Welsh: I mean, it's such an important part of  any chronic disease. So it's really incredible that the whole person is considered. It's, it's been just so fascinating to chat with you about some of this research that is truly groundbreaking and really quite inspiring that's been done at the blood and marrow transplantation cell therapy program over the last 12 years of, of your time there at, at NYP and Columbia. So, how do you feel that the culture at these institutions has really paved the way for this program's growth [17:00] and success?

Dr. Mapara: So I think building a program you really need a strong support, from the university and the hospital system, right? And that's something which really, I think in my eyes is pretty much exemplary here at, at, Columbia NYP that you really have, this, this premier, research institution with Columbia which really  offers access and interaction and collaboration with, world leading scientists.

At the same time, also really having an amazing health care system and hospital system.  Which provides the best care available. I mean in bone marrow transplant you frequently tend to really think in silos because you know you're BMT person, for leukemia or for myeloma or whatnot.  

And so on the other hand, of course, BMT really offers you to somewhat transcend all of those silos because you really are able to offer a treatment approach, which now can really be used, as I mentioned, ranging from using classical bone marrow transplant, using CAR-T's to use, to reprogram the immune system to treat cancers, but also treat autoimmune diseases, right?  And manipulating the hematopoietic cells to then [18:00] cure sickle cell disease. So in my eyes, cell therapy really is one of the most exciting areas to work in at the moment.

Erin Welsh: Yeah absolutely. I completely agree - I always find the immense opportunities that could come out of cell-therapies just so exciting.  This has been so much fun chatting with you. I really appreciate you taking the time.  

Dr. Mapara: Thanks  so much. It was a pleasure

Huge thanks to Dr. Markus Mapara for taking the time to speak with me about the significant advancements he and his colleagues have made in treating Sickle Cell Disease at the Blood and Marrow Transplantation Program at NewYork-Presbyterian and Columbia.

I’m Erin Welsh.

Advances in Care is a production of NewYork-Presbyterian Hospital. As a reminder, the views shared on this podcast solely reflect the expertise and experience of our guests. To listen to more episodes of Advances in Care, be sure to follow and subscribe on Apple Podcasts, Spotify, or wherever you get your podcasts. [19:00] And to learn more about the latest medical innovations from the pioneering physicians at New York Presbyterian, go to  nyp.org/advances.

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