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Dr. Paul Szabolcs trained at Semmelweis University School of Medicine in Budapest. He completed his residency at Bellevue Hospital/NYU Medical Center and was Chief Fellow at Sloan Kettering Cancer Center in New York City. He completed postdoctoral fellowships at Memorial Sloan Kettering in Molecular Biology and at Rockefeller University in Physiology and Cellular Immunology. He has been Chief of the Blood and Marrow Transplantation and Cellular Therapies division at the UPMC Children’s Hospital of Pittsburgh since 2011. Dr. Szabolcs has dedicated his career to developing effective “reduced-intensity” chemotherapy regimens for patients in need of a blood or bone marrow transplant, especially children with rare immune-system defects and degenerative brain diseases.
John Williams: This podcast is for informational and educational purposes only. And it's not to be considered medical advice for any particular patient. Clinicians must rely on their own informed clinical judgements when making recommendations for their patients. Patients in need of medical advice should consult their personal healthcare providers.
Hi, everyone. Welcome to another episode of That's Pediatrics. I'm John Williams, Professor of Pediatrics and Chief of the Division of Pediatric Infectious Diseases here at the UPMC Children's Hospital of Pittsburgh.
Steph Dewar: And I'm Steph Dewar, Vice-Chair of Clinical Affairs and Residency Program Director. And I'm happy that you're back to listen to this episode of That's Pediatrics. Today, we have Dr. Paul Szabolcs who's the Chief of Bone Marrow Transplantation and Cellular Therapies at UPMC Children's and specializes in pediatric hematology-oncology. Dr. Szabolcs also directs National Institutes of Health Supported Research Program focused on developing strategies to help the immune system rebuild itself and reduce patients risks for viral infections after cord-blood transplant.
He has been a leader in the development of a new approach to blood transplantation that has enabled many more patients to benefit from the potentially life-saving therapy. Paul, thank you so much for joining us today and coming to share a little bit about your activities here at Children's. So, I'm very curious, could you just give us a background of what the main efforts that you have going on here?
Paul Szabolcs: Yeah. Thanks, Steph and John for inviting me. It's a absolute pleasure. So, it's been already eight years that I arrived from North Carolina. Time flies. And clearly, it was a very exciting opportunity to start the Division of Blood and Marrow Transplant here in Pittsburgh with already some history as a program. And now, we have really a divisional effort to address many diseases. Obviously, the classic leukemia, lymphoma, malignancy type of diseases, and aplastic anemia, but really, bringing extra breadth and hopefully depth as well, to a advanced array of nonmalignant diseases.
So, really, I think as you eluded, there's a couple of major directives. One is to really bring a suitable graft and transplant option for any child or adult even, who could benefit from the procedure. So, that really has to overcome certain barriers of HLA typing and barriers of lack of perfectly matched donors. And that's where cord-blood transplant comes into place. And I consider myself a cord-blood transplant expert after nearly 20 years of practice.
And we really refined, I think, here in the last few years the technology to take full advantage of the rapid availability. And for many diseases, that really would historically belong to metabolic diseases, neurology such as leukodystrophy's, like Krabbe disease, metachromatic leukodystrophy, adrenoleukodystrophy and other diseases we have a graft basically for everybody. So, just this last seven years since our protocol has been in place, not a single child who came could benefit we had to turn away because we are able to find a suitable donor. And they range from location, Americans to children from overseas, from Malaysia.
And really, having the access and ability to overcome the miss matches, we've been able to perform 50 transplants, where these otherwise, extremely rare diseases is representing nearly 20 different genetic varieties. Some are well known like sickle cell disease thalassemia and the other ones could be as esoteric as bare lymphocyte syndrome or XLT deficiency and the ones I mentioned. So, that's one real strength I believe that we have here at Children's. And that really is paired with a flow of patients from overseas even and other sides of the country.
We do benefit from close collaboration from my wife's program, the Neuro Development for Rare Disorders. That is a major worldwide center for their assessment and natural history and other therapeutic modality explorations. So, that's one area. And then the other that was really attractive to bring me to Pittsburgh is the possibility to explore further the combination of solid organ and bone marrow transplant. Whereby, bone marrow transplant could hopefully, overcome some aspects of rejection and actually lead to some degree of tolerance and freedom from immunosuppression.
So, we have an NIH supported protocol for lung and bone marrow transplant. And as we are doing it in first in-human trial, we are really very carefully focused on select patients who have primary immune deficiencies. And they could be up to age 40 and they are mostly ineligible for either bone marrow transplant alone, that would have been curative 10 years ago had they been referred to. Or, let's say lung transplants since they are only lumped there and nobody would consider lung transplant for someone who's underlying immune deficiency will destroy the healthy new lungs.
So, painstakingly, very slowly, and working closely with a lot of help from regulatory and other key members. We've put together this protocol and have met patients really from a wide variety of states and underlying diseases ranging from chronic granulomatous disease, interlocking seven deficient cell combining in deficiency, stat three gain of functions, stat three loss of functions. So, it's a really esoteric immunological diseases where, again, these unfortunate patients, teenagers, adults miss the opportunity for a curative bone marrow transplant years ago.
So, we are in the midst of a revision of the protocol. And we're very excited to have ourselves as the only referral base in the country. Otherwise, I'm really proud to say that the division has taken off in many, many areas. And this past year, we've started offering Cartesia therapy. And we just treated a really complex 20-some-year-old patient who had all the CLABSI complication one could imagine with cyto cognitive syndrome and neurotoxicity. But, he received wonderful supportive care. And that's pioneered and led here by Randy Windreich, my colleague. So, I think the long answer, in few sentences. But, there's a lot happening in our division.
John Williams: Paul, it's really intriguing. I think a lot of us grew up in an era where stem-cell transplant was really only done for malignancies like you mentioned. So, I'm really curious, it's interesting that you're doing stem-cell, either cord-blood or marrow or stem-cell transplants for so many other diseases. What percentage of your transplants are for these non-malignant diseases? And are the outcomes different, worse, better?
Paul Szabolcs: Yeah, a great question, John. I think we've actually tipped the balance. Probably 60% non-malignant, 40% malignant transplant. Some of it is related to advances in oncology with new Phase 1 Drugs coming where that might be offered to otherwise historically bone marrow transplant eligible leukemia patients. So, they go onto those Phase 1 Drugs. At the same time, our referral has grown in non-malignant diseases and we open new protocols.
So, our new Sickle Cell protocol that is, again, addressing these teenagers and could be younger patients and even adults who would not have a match sibling, who would not have a match unrelated bone marrow. But we are focusing with T-cell depleted peripheral blood stem-cells to offer six of eight match, therefore two antigen mismatch stem-cells. Which again, would raise the probability of finding a donor up to 90-some percent.
So, that protocol will kick in while we've already successfully used cord-blood for sickle cell. So, I think it's somewhat a combination of both the growth of the non-malignant referral and again, a wide array of diseases. Just immune deficiencies, there's close to 300 genes that's been identified, plus all the other diseases. And also, some advances in oncology that might have reduced somewhat the oncology patients coming.
Steph Dewar: So, I would imagine that many of your patients come from local or regional referrals because they're aware of what happens here in Pittsburgh. But you mentioned people coming from, it sounds like, around the world. How do people know of the services that are available here in Pittsburgh?
Paul Szabolcs: Yeah. So, I think the classic oncology referrals are regional, Western Pennsylvania, parts of West Virginia and maybe Ohio. The rare diseases really, when you have 30, 40 patients, babies born a year in the country, obviously, such as Krabbe disease or some types of other leukodystrophy's, then they tend to gravitate to two or three major centers that have established track record and innovative therapies. So, our cord-blood transplant, for instance, has the best outcome anywhere in the world as far as we can tell.
So, that is a positive draw obviously. We have 95% survival at one year, at which point, usually, most transplant-related complications would have already taken their toll. So, in that sense, our transplant-related mortality 5% or so is probably unsurpassed. And in oncology we are striving for similar outcomes, it's a little bit more complicated there as you are pushing the intensity of conditioning to try to eradicate leukemia.
John Williams: So, Paul, you mentioned you've been doing this for a long time, both clinically and your own research. Maybe you could tell us a little bit about your own areas of research and how that ties into what you do as the division chief.
Paul Szabolcs: Yeah, John. So, back when I was at Duke, cord-blood transplantation in '98 when I arrived there was already established as a viable alternative for those who don't have an HLA matched donor. But, as an alternative, it didn't mean they had equivalent outcome. And it was clearly apparent that some of it is related to the fact that the lymphocytes in the graft are completely antigen-experienced. And to some degree, also, "Immature", which might be actually a biased away from certain [inaudible 00:12:19] TH1/TC1 type of phenotypes.
So, it was an opportunity for me to study in the laboratory since I had a laboratory interest and presence before based on dendrite cell hematopoiesis that I conducted at the Rockefeller University to shift then and look at immune reconstitution in the cord-blood setting and identify opportunities and try to better characterize. So, over the years, I really came to understand that even though it's a different graft, it's not immature, it's just a different graft, it takes time to attain antiviral and protective immunity from cord-blood cells. But, actually, in the inflammatory milia of a patient that can be obtained in a few weeks.
So, I think that helped a lot to design subsequently the clinical trials because immune reconstitution is such a key parameter of what we look at post-transplant. And that led to the various cell therapy interventions, immune boost that we then can create from the original graft that just saline and refreezing a tiny fraction to the more advanced viral-specific T-cell generations with viral peptide simulation and so on. So, that's clearly one area. And then, similarly in pediment and barrier for transplant has been graft versus hostess is over-reactivity, which is rejection from the organ transplant perspective.
So, my lab has always had an interest. And 10 years ago we had an interesting technology developed that just didn't take off for alloreactive T-cell depletion. And then, when I got onto the organ transplant, bone marrow transplant world, realized that our organ transplant colleagues talk always about tolerance, which is basically the flip side of alloreactivity.
So, my laboratory has probably now, a more active arm working on understanding how tolerance is actually attainable. And why are we so fortunate in the bone marrow transplant world, as opposed to, our organ transplant colleagues. So, again, with the cord-blood transplant we have so many miss matches and why is it that we can taper off immunosuppression? So, my laboratory is trying to understand the mechanisms for this and then apply it to the organ bone marrow strategies.
Steph Dewar: So, Paul, what got you into this avenue, this aspect of medicine? How did you enter into your interests in hematology, oncology and then transplant?
Paul Szabolcs: Interesting question. I hope I won't be ... Hopefully, I won't be hurtful to others. But, you always, when you choose between opportunities, you have to say no to some and go with one. So, I was always intrigued about the beauty of immunology. And as a resident, way back late '80s, it sounded like that allergy immunology had sort of a more chronic disease lack of approach whereas atopic diseases or asthma or some other ones.
And bone marrow transplant was emerging as a really exciting world where clearly immunology was underpinning for allogeneic transplant. So, just like I like more intensive care rotations than general pediatrics clinic, somehow, I gravitated towards that. And I went into hemo knowing that I would like to do bone marrow transplant.
John Williams: So, you like complex and sick patients? So, that's a population that clearly you've chosen well. What do you think are some of the most exciting changes that you've seen over the last 20 years of doing this?
Paul Szabolcs: Yeah. Well, clearly, outcomes have improved, supportive care is greatly responsible and our collaborator colleagues, like you john, helping overcome fungal diseases and many of the viral diseases just by pharmacological means has been tremendous. Clearly, I still entered the field when cytomegalovirus was maybe the major killer of transplant patients. They didn't live long enough to die of GDH, they died of CMV1-itis. So, day 28 they had exploratory bronchial lavage to see if there is AIP65 in the cytospins or not.
So, a lot, we were just very fortunate I think, in general, that again, supportive care has improved and technology in general. So, also, cell therapy as well can manipulate now the graft, separate the stem-cell component from the various effector, lymphocytes, determine the dose and timing of the infusion. I think this has been a great progress for the field. And last few years, truly, moving into haploidentical transplant whereby really, everybody has a donor, worst-case scenario, it's an uncle, a son, a sister.
So, that's for adults. I think hugely important. For us, pediatricians, cord-blood could be the answer for anything under age 15. And then, once they get to that age and get a little bit bigger and the cord-blood cell dose is limited, that's when you need to look for haplo-transplant. So, I think, really, cellular engineering, haplo-transplantation and supportive care and the laboratory techniques, they all combine together to improve outcomes.
Steph Dewar: Well, Paul, we're so glad that you came by and chatted with us today. It's very interesting and exciting to know what's happening here in Pittsburgh. And we're glad you made the move to come here. So, thanks for joining us.
John Williams: Thanks for being here, Paul.
Paul Szabolcs: Thank you for the invitation. It's my pleasure.
Steph Dewar: Please join us next time for our podcast. And certainly, subscribe so you hear new content and send us messages for other topics you'd be interested in. Thanks for joining us on That's Pediatrics.
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