Gene Therapy in Sickle Cell Disease

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Rabi Hanna, Chair of Pediatric Hematology, Oncology, and Blood and Marrow Transplantation at Cleveland Clinic Children's. Dr. Hanna joined us last year to discuss best practices for pediatric cancer patients with autism spectrum disorder, and a few weeks ago to discuss Cleveland Clinic's Lysosomal Storage Disease Program. He's here today to talk to us about gene therapy for sickle cell disease. So welcome back, Rabi.

Rabi Hanna, MD: I'm so excited to be here.

Dale Shepard, MD, PhD: Glad you're here. And maybe to start, remind us again about your role here at Cleveland Clinic.

Rabi Hanna, MD: Of course. I am a Pediatrics Oncologist, and I lead our Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation.

Dale Shepard, MD, PhD: Excellent. We're going to talk about sickle cell disease and therapies for sickle cell and about gene therapies, and maybe just as a background, we have a diverse group that's listening in, tell us a little bit about traditional therapies for sickle cell disease.

Rabi Hanna, MD: This is really very important disease that it highlights some of the challenges in our healthcare system, and if I may say, even the structural racism in it. It's important to know that this disease, sickle cell, was actually discovered and described back in 1910 by Dr. James Herrick in Chicago. When he noticed a patient who was a dental student come with chest pain, he thought it may be heart attack. He looked into his blood smear with his resident and saw these crescent shape vessels that really was the essence of what this disease is. It was, at that time, noted to be anemia, and for very long called sickle cell anemia. And in 1949, Dr. Linus Pauling, he described that the reason why that happened, it is actually molecular change from glutamine in the hemoglobin B to valine, which really give that rigid shape when you are inside a hypoxic environment. And that will lead to the causes of really clotting in the small vessels that would lead to pain, and that could happen in the bone or many different organs, like in the lungs and many others, that even the brain.

And for a very, very long time, there was really no therapies, and even in children, many kids were dying. They didn't make it even to adulthood, especially because of infection. So many of these patients will lose their spleen due to, in fact from these multiple episodes, and the kids were dying very high until in the sixties, seventies, it was discovered that if you give them penicillin, you could save them until they can start to mount response to vaccines. And then was noted that medicine called hydroxyurea that many of the oncologists are familiar with, in the eighties and early nineties was used to be for patients with sickle cell, because it seemed to help increase the fetal hemoglobin, and that seemed to be protective against some of the manifestation of sickle cell disease.

And for so many decades, until 2019, we had no other therapies that could help until really, has been interest in the last decade from the NIH and providing more grants and support to pharma and to even principal investigators to come up, and there was a medicine called Crizanlizumab, which is an anti P-selectin 2 that helps to really make the cells don't clot together that seemed to decrease the pain crisis. There is also another medicine, Voxelotor, that also seems to really help increase the hemoglobin and decrease the pain. So exciting time that there is interest, and I also want to mention there was another medicine called L-Glutamine that has been also approved two years ago for the help to prevent further episode of pain crisis.

Dale Shepard, MD, PhD: Excellent. So a couple of therapies that came along. Are these widely available? Are they widely used? Have they been adopted in the care of this disease?

Rabi Hanna, MD: I wish that there is more access to these patients. Similar to any new medication, it takes time. One, for awareness of its availability, two, from access of payer for this. I will tell you, as a practicing hematologist, it's been very hard to even prescribe some, and you have to go through a long process of sometimes pre-authorization, despite it is approved medicine. But I think it is not an uncommon issue with any new medicine. It's exciting that there is more data, that it shows that this is really showing, even in the real world, the difference. And just recently last month, the FDA approved the Voxelotor down to the age of four in kids. So we are seeing also in this therapies not only approved for adults, but also for children and teenagers.

Dale Shepard, MD, PhD: Gene therapy. So you mentioned back in the forties, there was the identification of exactly what the defect is. Tell us a little bit about gene therapy and how that exactly works.

Rabi Hanna, MD: I think sickle cell disease has been a prime example for gene therapy, because it is a single nucleotide change and the sixth position of hemoglobin B gene on the chromosome 11. So it's only one, but it is fascinating, Dale, that it have heterogeneous phenotype and we are learning more and more about this disease. But at the essence, if we could correct that gene, hypothetically, that you could correct that disease. And we know by giving a normal hemoglobin through a bone marrow transplant from a healthy donor, that we can actually help prevent any further. So bone marrow transplant has been done for patients with sickle cell since 1984, but one of the challenges is finding appropriate donors for them. As a transplanter, I do consults frequently for patients with sickle cell, but only 17% of them, they can find an HLA match, unrelated donor or even a related, due to different reasons in our society. Among them, it's the lack of minority in our national marrow donor program. So I want to put a plug that I would love to see more representation and target recruitment from minorities in our NMDP.

And in the early 2000, there has been attempt to do gene therapy by fixing the defect, but at that time, the technology was not very accurate or precise. And we are very excited that there is now two big categories of gene therapy. One of them, it's called gene edition. So we recognize this scientific community that if we could insert into the cells, gene DNA or RNA production that could produce a normal hemoglobin or potentially the fetal hemoglobin that has a protective effect, then the patient will have a normal phenotype and able to live normal life, hopefully. And that has been the earlier phases of gene therapy.

It still does require, one, collection of stem cell from the patient, and that's not as easy as it sounds because this patient, truly bone marrow is a little bit environment harder to collect. So we use not only G-CSF that many of our oncologists are familiar, but Plerixafor to help, and we learned not to use G-CSF anymore because it was inducing pain crisis, so we are using Plerixafor and we could collect enough numbers. Then number two is working with pharma companies that are in biotech, that they able to insert with a multiple variation, initially with adeno vector, but now lentiviruses that can insert a normal gene inside the cells. And number three is give chemotherapy to the patient to get rid of that defect. We don't need to use a very high doses, but we need to create enough space for the cells to ingraft and be able, because we have learned also that if we could get 20-30% ingraft with the cells, that's enough to give protection.

The newer technology now in gene therapy, that we are proud to also have a clinical trial for that, it is using more precise way. It is called a CRISPR technology that it can go directly towards the defect or where's the targeted gene, and be able to literally cut that defected gene and replace that with help of the case-based gene, with whatever you wanted to either correct that protein, that gene that produce, or the hemoglobin B or the one called BCL11 that it is, and activate the hemoglobin F production. So there are two different ways to do that, and we are more excited about this because it potentially will be more better for long term because of the concern about sometimes that insertion addition of the gene can target areas randomly and cause potentially cancer. So that's where we are looking into the next generation of the studies of gene therapies.

Dale Shepard, MD, PhD: How widely accepted or things like gene therapies to patients and patients' parents? And one can imagine that if you start talking about editing people's genes, people might be a little bit hesitant. Is this something that is widely accepted by patients?

Rabi Hanna, MD: I will tell you, I'm shocked about how many messages and requests for this came. It is surprising to me last year, there was a 60 Minutes and there was multiple media productions about gene therapy, where it's an example of little bit the public was ahead of where the results were scientifically. And I don't think yet the gene therapy was at that time, or the result were enough to be able to say this is ready for public use and more in clinical trial. However, there's really just at ASH in 2021 in December, great publication that even came in New England Journal of Medicine that the phase three studies that are quite encouraging. And hopefully, some of this biotech companies are going to go to the FDA and ask for approval.

During conversation through our current clinical trial, the families are actually concerned, and sometimes when they learn more about the details and they recognize the chemotherapy and how it is, they do become hesitant appropriately. I think the reason why so many of the families are willing and are taking this, it is really how severe is this disease. This disease affects the patient. We have patients who get six to eight times admitted for different pain crisis. One of them was more than a hundred days in the hospital on average over the last three years. We know also that the life expectancy of them is in the 40s. So that's why I think some of these patients are ready and there has been studies through one of our even medical students and learners. We have done surveys. Patients are agreeing to a mortality rate of 5-10% if they can feel that this will cure their disease. It just speaks to really the suffering that they have and the long term morbidity and mortality associated with this disease.

Dale Shepard, MD, PhD: Something that thinking back that you mentioned, just struck me, was that you see people in your... You do bone marrow transplants and stem cell transplants, and that fewer than 20% of people who may come to you and would otherwise be eligible for a transplant can't find a donor. How do we fix that? How do we get more awareness to get people to get registered to be donors?

Rabi Hanna, MD: So we've been involved with the community. We went actually multiple times to churches, to have drives. There is really growing non-for-profit organization and patient advocacy groups, and also through science. So we worked with John Hopkins and St. Mary in England to develop a Haplo transplant protocol for sickle cell, because it is really the older ways of doing Haplo didn't work so well. There was a high rejection rate. So we have intensified the regimen and we have very good results. So both from increasing awareness to have more donors, but also really recognizing the challenges that many of this society work and work in the science to develop more therapies specific for this disease. So when our Haplo protocol which is now a multicenter study going on called CTN1507, it uses an addition of medicine called Thiotepa to the regular transplant, it seems to decrease the rejection rate by half, and hopefully can offer that patient a donor from, could be his mom dead or half sibling because they don't have a match donor.

Dale Shepard, MD, PhD: Excellent. So this is a tough disease because as you mentioned, it involves oftentimes damage to multiple organs, and there's historically a lot of these patients have started in pediatric hematology, oncology programs and sickle cell programs. And then there's been frequently an issue with, as they get older, transitioning to care as adults. And I guess with that framework, it's really encouraging to see that we have some new therapies that might change that with the gene therapies, but what do you think an ideal sickle cell program for the life span of a patient looks like? How should we be designing sickle cell programs to really provide the right care for these patients?

Rabi Hanna, MD: Dale, that's the $1 million question. It is real, if more, because our society is very different and what it works in Cleveland, it may not work in Alabama or in LA. And there is great work that has been done by the ASH, American Society of Hematology, and there was a paper by Dr. Julie Kanter back in 2020 that actually suggested four different models of care delivery. And we at Cleveland Clinic, we recognize that we truly have a responsibility and we are developing what's called sickle cell medical neighborhood, because it's not enough for a hematologist. There's just not enough hematologist adults that are able to take care of this. So the model that could help potentially is actually working with the primary care physicians and developing a hub model and a consultation where the care could be delivered potentially by the primary care, because this patient, as they grow, they will have nephropathy, they can have hepatopathy, all of them have blood pressure is issues, mental health issues. And it is beyond just the ability of a hematologist, usually.

Sometimes, example of bigger places where there is more urban cities, there could be a comprehensive sickle cell program in the traditional way. That could work there, but I think different societies and demographic can potentially develop their own protocol. There are essential to have a hematologist, a mental health pain specialist. I think it is very important because especially with the opioid pandemic, there has been suffering for this patient, despite that the ASH and the CDC making comment and really clarifying that doesn't apply for sickle cell. They are in the same category as cancer patient. We know from publication that the number of death amongst sickle cell from opioid overuse is actually less than many other chronic diseases. So the labeling that many of this patient is actually hurtful for them.

One of my patients said, "There is nothing hurts more than the pain itself, other than the pain of caregiver not believing you." So I think it's important to work together to learn because many even of adult providers, they didn't see in their career in the last 10 or 20, survival of sickle cell potential or few of them. Now they're going to seem more and more, because 98% of childhood with sickle cell, they are going to make it to adulthood now. So there's more of them coming, and hopefully by having this resource of a program here, that it is available for different providers, it would help to educate them and deliver the best therapy and care for them.

Dale Shepard, MD, PhD: That's excellent. What do you think are some of the other gaps that we need to address in appropriate care for these patients?

Rabi Hanna, MD: I think it is really, as a healthcare system, trying to make sure we provide access for this patient to the different. Many of them, they become government based insurance, either Medicaid or Medicare, and I feel that it is a somewhat limiting factor for them to get more newer therapy sometimes, including the gene therapy that we talked about. It is an exciting time that we have more therapies now, but we do truly need to do that research to demonstrate that these therapies, one, are safe and two, are effective. And having access to the newer medication that they are approved because it is still the uptake for this new medication is challenged, so access to care remains a huge gap. Before we talk about advances, we just need them to get to the system.

Dale Shepard, MD, PhD: Very good. Well, thank you for your insights today and being with us for this really, really important topic.

Rabi Hanna, MD: Thank you so much for really highlighting this disease that I truly feel has been neglected, and I am excited about what the future holds for sickle cell patients.

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