Morton J. Cowan, MD, Professor of Pediatrics at University of California, San Francisco, Benioff of Children’s Hospital talks about improvements in gene therapy treatment for Severe Combined Immunodeficiency Disease.
Interview Conducted by Ivanhoe Broadcast News in July 2017.
Tell me about Ja’Ceon’s condition and how rare it is?
Dr. Cowan: Ja’Ceon has what we call Severe Combined Immunodeficiency Disease which is also known as the bubble boy disease. He was born without an immune system, without the ability to fight infection. Normally, people have lymphocytes that fight infection, viral infections, bacterial infections, and so forth. This involves what we call T-cells, B-cells, and natural killer cells. Ja’Ceon’s disease affects all three of those types of lymphocytes, so they are all nonfunctional. He does have B-cells present, but they don’t work. He has a pretty severe susceptibility to infection.
Typically back in the day when we first heard about bubble babies it was said that they basically lived in a bubble. Correct?
Dr. Cowan: Well, there was one. When we first started recognizing this disease, the babies would look very good at birth, and even for the first month or two of life. But afterward, they would start to get infections. Eventually, they would develop skin rashes and other problems, and ultimately, would be diagnosed with this disorder. In the 1960’s, there was a boy in Texas identified with this disease whose brother had previously died with SCID. A very sophisticated sterile living quarters or a “bubble” was created for him when he was born. He was kept alive, infection free in this bubble, for many years. Eventually, he wanted to get out because that is not a way to live, nobody can touch you or be with you. They did attempt a bone marrow transplant for that child, but unfortunately, it didn’t work, and he ultimately died. Since then, we’ve obviously learned a lot about this disorder. We know that Severe Combined Immunodeficiency, or what we refer to as SCID, actually represents more than fourteen different genetic defects. The result is this inability to fight infection due to the severe deficiency of T-cells and at least B-cells and sometimes natural killers or NK cells. We’ve learned a lot over the years as to how we can treat this and the standard treatment for this disease has been doing a bone marrow transplant. So taking stem cells from the bone marrow of a healthy donor and getting them to grow inside the patient will then restore at least normal T-cells, and in some cases, normal B-cells and NK cells.
Tell me about this gene therapy treatment?
Dr. Cowan: Ja’Ceon’s specific defect is in a gene called Gamma-C, it’s the one type of SCID that is inherited from mothers or passed on from mothers to sons. Essentially, only males in the family are going to be affected. Gamma-C was one of the first genes that was isolated and cloned many years ago so that people could study it. Maybe about fifteen, or twenty years ago, the technology was developed to insert the normal and healthy gene into what we call a viral vector. We then use that vector to insert this gene into the DNA of the patient’s bone marrow stem cells. There has been a lot of progress made over the years, and it has continuously gotten better and better. We are now using what we call the third generation of these viral vectors. We believe that these vectors are more efficient and safer to use than the previous method of gene therapy for this disorder. The process involves initially taking a sample of bone marrow from the patient. Ja’Ceon underwent this process in January where we took about five to ten percent of his bone marrow in the operating room. The stem cells were then isolated and treated with this viral vector over a four day period to get the gene into the DNA of the stem cells which were then frozen down in liquid nitrogen. Once all the testing was done, which took about a week to make sure that it was safe they could be used for the transplant. When we were ready to do the gene therapy, we treated Ja’Ceon by giving him a low and specific dose of chemotherapy to open and create space in the bone marrow. Whenever we do a transplant, typically, if it’s a kidney transplant, we take out the bad kidney and replace it with the good kidney. With bone marrow, it is in every bone in the body, so you can’t really surgically take it out, you have to use some type of chemotherapy to get rid of some of that bone marrow. What we’ve found over the years is that for most standard bone marrow transplants, you really have to give very high doses of chemotherapy in order to get rid of the bone marrow and open up all the space there for the stem cells to grow. However, for kids with this kind, and maybe other kinds of SCID, is that we don’t have to give a really high dose; we can give very low doses. We’ve also worked out, and a lot of the work was done here at UCSF, the technology for specifically determining the appropriate safe dose of this chemotherapy for the babies. That’s what we did; we basically gave him two doses. After the first dose, we measured how much chemotherapy actually got into his body and we adjusted the second dose so that he got a target-specific amount that was safe for him; what we hoped would be effective enough to open up enough marrow that would allow the stem cells to grow and become normal T-cells, B-cells and NK cells. So he got that chemotherapy over two days and then on the third day, we infused the cells. We thawed the cells that we had corrected and we infused them intravenously through his IV catheter, and that was pretty much it. He had a very nice course; no problems, he didn’t get sick from the chemotherapy, and he didn’t even lose his hair, which is a common thing that you see when you give high dose chemotherapy. We weren’t sure what would happen, but that level of dosing looks pretty safe. He stayed in the hospital for a couple of months to ensure that things were working and that he was getting some immunity, then we were able to discharge him. We now have evidence for him, that we can identify corrected cells in his blood, and in his bone marrow. We can identify cells, not only T-cells, which are so important as you need to have those in order to live, but we’re also finding them in the B-cells and in the NK cells. Ja’Ceon now has normal functioning T-cells in his blood. He’s got normal NK cells in his blood and he has some normal B-cells in his blood as well. After a transplant, any of us, would be extremely happy to see this kind of result. We are now waiting to see how the B-cells function so that we can take him off the supplemental gamma globulin that he gets every month. Once he’s off that, and we hope that will happen this spring, we’ll immunize him just like any other baby who gets immunized and he should be fine. That’s our hope, that’s our expectation.
He’s part of this study?
Dr. Cowan: Yes.
Is the study just for UCSF or does it involve other hospitals?
Dr. Cowan: There are three institutions that are involved. St. Jude’s Hospital is the lead institution. They made the vector, this viral vector, and they designed the protocol. We worked with them on the protocol, but they hold what’s called the IND, the investigational new drug license from the FDA. In fact, the way Ja’Ceon’s transplant occurred was that we collected the cells in the operating room, we packaged the cells, and we then sent them by a carrier to St. Jude Hospital. It was actually in St. Jude Hospital’s laboratory that the transfer and the correction of the cells were done. Cells were frozen down and then sent back to us for the transplant itself. Our hope is that some of this research, funded by the California Institute for Regenerative Medicine, will allow us to develop the gene correction treatment in our own laboratory. Our plan is to hopefully do that for the next kid that comes through so that we won’t have to be sending the cells back to Memphis for correction.
For UCSF are there other patients that are in this study?
Dr. Cowan: Yes we do have another patient; the study is going to enroll up to twenty-seven patients in total. The initial fifteen will determine whether the results look good and then we’ll move on and enroll more. Right now I think the study has enrolled a total of five patients, two from UCSF, three from St. Jude, and then the third institution is Seattle Children’s Hospital. These are the three centers that are participating in the study.
Ja’Ceon he was the first at UCSF?
Dr. Cowan: He was the first at UCSF, he’s patient number three.
It sounds like he’s had great results, maybe better than expected?
Dr. Cowan: There have been maybe fifty kids with his type of SCID who have been treated with gene therapy over the last seventeen to twenty years or so. This is the first time,however, with this particular third generation vector, this trial. Prior to about five years ago, these kids were just treated with the gene therapy. They were infused with corrected cells, their own cells that had been corrected with either a first or second generation vector but without any chemotherapy. However, what people found was that although it tends to correct the T-cell defect; it did not correct the B-cell or NK cell defect. Thus, the large majority of these children had to remain on gamma globulin supplementation. Then, about five years ago a group at NIH, National Institutes of Health, in collaboration with the people from St. Jude, started a protocol where they were treating patients with X-SCID. These patients had received a prior transplant from another person, usually from a mother or father, and who had some correction of their immunity but it wasn’t complete. Many of those patients, in fact, we sent three of our patients to NIH, were sent for this treatment. They were sick, some of them were still going to school but they were having problems and they would miss school and so forth. I think the initial patients were actually in their twenties. They were out a long time but you know still not fully corrected and so they gave them a very similar approach using the same virus vector that we’re using and also a similar type of chemotherapy. The results, after some good follow up, looked very promising. They were the first ones with x-linked SCID treated with the chemotherapy and showed that it looked to be effective in getting the B-cells reconstituted. We decided that for the babies we wanted to do the same thing, although we modified the dosing of the chemotherapy so that the babies are getting even a lower dose than these older kids got and we’re able to specifically target the amount of chemotherapy that these babies are exposed to. It’s about a quarter of what would be the standard kind of dosing.
What is it like for you to have this healthy baby boy in front of you?
Dr. Cowan: It’s pretty amazing. When I started over thirty years ago we weren’t doing transplants yet, or we only did it if the patient happened to have a brother or sister who was a perfect match. I can tell you that the odds of that happening are less than 20 percent. Because many kids, if they’re the first kid in the family, they don’t have a brother or sister, and then the odds of brother or sister being a perfect match is maybe one in four. Overall most of these kids don’t have good matches. And we weren’t looking; we didn’t have the ability to do alternative donor transplants. So if we couldn’t do a transplant, we were giving antibiotics and we would give them gamma globulin and try to keep these kids alive even for a year or two and that’s about as long as we were able to do it. Eventually the technology developed and we worked on some of it, but a lot of it came from other centers to be able to do transplants from parents. The technology, and this again goes back to the 1980’s, developed out of Sloan Kettering in New York; the ability to process bone marrow from parents who are half matched with their children. Thus, we could avoid some of the severe complications that are associated with doing the bone marrow transplant from another person. This really opened up the possibility of treating pretty much any kid as long as they had a parent that could donate. That was a significant advance in the field. But as we learned over a long period of time doing these transplants, it still wasn’t as effective as we would like. The ability to use unrelated donors who were closely matched was a big advance but many patients don’t have a close match and there can be significant problems associated with even matched unrelated donors and when they are used many centers have also administered high doses of chemotherapy. With these alternative donors we were seeing kids who could live long lives, but they weren’t necessarily normal lives. They would still miss school or not be able to do all the things that they wanted to do. We made a big step forward and that was very reassuring. I have gone to weddings, graduations, seen babies born from these patients and it’s worth everything to see that. But I think with gene therapy, being able to take the patient’s own cells, and correct those cells and give them back to the patient, that’s just another quantum step forward because it eliminates, number one, all the reactions that can happen when you’re using another person as a donor, and number two, we have a chance to correct the entire immune system that’s been defective. We think that these kids will no longer develop some of the chronic problems they have, and we’re using a much lower dose of chemotherapy than what people had previously used. We hope that the late effects from chemotherapy will be eliminated or greatly minimized which is pretty exciting. We’re so early in the clinical trial and we’ve got to follow these kids out much longer. We think the data suggest that we’ve significantly reduced the risk of getting this secondary leukemia, which was part of the problem with the first generation viral vectors that were used for this disease. But we’re going to have to treat more patients; we’re going to have to follow them a long enough period of time before we can be more certain of that. The current data looks very promising and we’re all very hopeful that we’re not going to see that as a major problem, this developing leukemia. But you know we have to be careful, we have to be cautious and we’ll have to follow these patients for much longer before we can really be certain.
What’s your hope for Ja’Ceon in the future?
Dr. Cowan: I just hope that he’ll come back to see me year after year, because usually when you correct a kid like this, as they get older they really don’t want to come back to see Dr. Cowan anymore, that’s kind of old hat stuff. He’s not even six months post treatment yet, but my hope would be that we’ve curedd him. Based on the results to date, I’d be hopeful that he’s going to get correction of his immune system and that hopefully, he’ll be able to come off the gamma globulin infusions. I see no reason why he should develop any of the complications that we have seen with other kinds of transplant treatments.
To say you’ve built a brand new immune system for a baby, I mean that’s huge …
Dr. Cowan: I say it is amazing. I think that in the 80’s there were people who were talking about doing this for SCID. I wasn’t involved in this research at the time but I distinctly remember a very smart scientist telling me, don’t worry, by next year we’ll be able to do this. Now that was in like 1986 or 87 so obviously it didn’t happen, it’s taken a long time and that is probably good because it’s something that has risks associated with it and we hopefully have learned a lot about eliminating those risks. It does take time. I actually think that in some respects it’s going to get better, this is just the beginning of this kind of corrective gene therapy. Although I am not very good at predicting things, I think within the next five to ten years, maybe sooner, we won’t have to take cells out of the patient and correct them. We may be able to correct the patient by just giving an infusion of a viral vector or something like that; that will target the stem cells and will insert the gene into the stem cells. Or, we’ll correct the gene; we call this gene editing which people are very excited about. You’ve probably heard about this CRISPR-Cas9 system which is one of the next approaches that people are very excited about to actually correct the defect. Not by inserting a new gene, but by actually correcting the gene that’s defective. It is not quite there yet, but there are a lot of positive advances that are being made and we’ll probably see that in the near future and there will probably be clinical trials of that. I think there will be a lot more progress, and a lot more advances that are going to be made. But this certainly is a great proof of principle that we can do it and, not just proof of principle, we can actually cure these kids. I haven’t used cure for many of the things that we do because we’ve corrected enough that patients could live but we haven’t corrected everything. And if we can do that, then we can start telling parents that we can cure your kid. And that would be pretty amazing to be able to say that.
END OF INTERVIEW
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