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Author Chat with Fred Appelbaum

• Brad Buchanan and G [Josie] van Londen • Episode 24

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In this episode of Cancer Survivor MD, Josie van Londen and Brad Buchanan interview Dr. Fred Appelbaum of Fred Hutchinson Cancer Center about his book Living Medicine and the history—and humanity—behind bone marrow transplantation, the breakthrough that paved the way for today’s cell and gene therapies. 

Appelbaum explains what transplantation is and how it works, reflects on his path into the field and mentorship under pioneer Don Thomas, and addresses the early ethical dilemmas, medical skepticism, and later legal scrutiny that shaped standards for transparency. 

Brad adds the patient perspective through his own transplant and graft-versus-host disease experience, including discussion of treatments like photopheresis and newer GVHD therapies. 

The conversation closes by looking ahead to the next era.

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Living Medicine Fred Appelbaum
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[00:00:00] 

[00:00:00] G van Londen (2): Hi everyone. I'm Josie Van London. and brad buchanan is here too. This is Cancer Survivor md. Today's episode explores the people risks and quiet courage behind one of the great transformations in modern medicine, bone marrow transplantation, the foundation for today's cell and gene therapies. My guest is Dr. Fred Applebaum. He's a physician, professor and executive vice president at Fred Hutchinson Cancer Center in Seattle.

[00:00:34] G van Londen (2): He's also the author of the book we will be talking about called Living Medicine. Fred was trained under Dr. Thomas, whose pioneering work made bone marrow transplantation possible. And Fred has spent his career carrying his legacy forward.

[00:00:53] G van Londen (2): What I love about his book is that it's not just a story of a medical breakthrough, it's a story of belief, [00:01:00] failure, persistence, and humanity. And today we'll explore how this field began, how it evolved and a lot of other topics. So, Fred, we're so happy you're here.

[00:01:12] G van Londen (2): Welcome to the podcast. 

[00:01:15] Fred Appelbaum: Well, thank you for inviting me, Josie. It's a pleasure to be here.


[00:01:19] Explanation of book title
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[00:01:19] G van Londen (2): I thought maybe Fred, if you're okay with that, maybe we can warm up a little bit and start by asking how did you come up with a title? 

[00:01:29] Fred Appelbaum: Well, the title Living Medicine is sort of a play on words in that, at the outset, marrow transplantation is a procedure where you are transferring living cells from one individual to another. And those cells will continue to live in the recipient for the rest of the recipient's life.

[00:01:51] Fred Appelbaum: and so it really is a living medicine, unlike all medicines in the past, which were small molecules that you gave and then they were excreted or they were [00:02:00] metabolized and you had to give them daily or weekly or monthly. This is a living medicine. It is the really the first example of a living medicine.

[00:02:07] Fred Appelbaum: And so that's really where the title started. I could have called it a living Medicine, but then as I was thinking about it, there was this other subtext about Don Thomas' life, in which he really spent his life living medicine. It was his calling. And I think for all of us that, medicine is a calling.

[00:02:26] Fred Appelbaum: we're sort of living medicine. it consumes us from, morning to night. And so it was that kind of double entendre, the living medicine of marrow transplantation being a living medicine. But then those of us who are. involved in all of medical research, really, in all medical care, we live medicine.

[00:02:42] Fred Appelbaum: it becomes sort of all consuming.


[00:02:45] Dr Appelbaum's career
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[00:02:45] G van Londen (2): Yes. I can relate to that. As you know, Fred, I'm a retired medical oncologist. I would like to ask you, although it's not directly related to the book, how did you come into this field? How did you find your mentor? [00:03:00] some of it is sometimes a little random, 

[00:03:03] Fred Appelbaum: sometimes it's very random.

[00:03:05] Fred Appelbaum: And, I think it's actually one of the real mysteries of life of why something just incredibly appeals to you. I liked everything in college and I sort of chose going to medical school because there was nothing that otherwise stood out so incredibly. I, I, I liked, the law. I liked philosophy, but, you know, medicine in the end just was there.

[00:03:25] Fred Appelbaum: And I, so I started medical school, not at all sure what I wanted to do. and then in my second year of medical school, I was just fortunate enough to have this wonderful, mentor a, a woman by the name of Jane DeForge She was one of the early female pioneers in hematology. And she was, teaching us how to do physical exams.

[00:03:43] Fred Appelbaum: And I was doing a physical exam on a guy who had a large spleen. And while I was doing it, this was in 1970, Dr. DeForge was saying, you know, this unfortunate gentleman is not gonna be cured of his disease, at least with what we have today. But I just read a really interesting article by a guy by the name of [00:04:00] Don Thomas, an attempt to make this new procedure, bone marrow transplantation, a possibility.

[00:04:06] Fred Appelbaum: And so that afternoon after leaving the clinic, I went to the library and just read up on the article that, Dr. DeForge had mentioned. And this is where I just don't, I don't understand why this happens to people, but it just struck me, what a amazing thing. And I just said, that's kind of what I want to do.

[00:04:24] Fred Appelbaum: It's like having your brain tattooed. And so for the rest of medical school, I kept thinking about marrow transplantation and, then when it came time to do a fellowship, I was lucky enough to go to the National Cancer Institute and start to work in a laboratory that was doing very early work in marrow transplantation.

[00:04:42] Fred Appelbaum: and then, I published a few articles while I was a fellow and then researcher at the NCI. And then in 1977, almost 48 years ago, I got a call from Don Thomas asking if I'd like to come out and work with him. Which I, of course, it was like the heavens opening and God looking down [00:05:00] saying, would you like to come here?

[00:05:01] Fred Appelbaum: Uh, and um, so in, in 48 years ago, I moved to, the Hutch to work with Don Thomas and have been here ever since. So that's a very brief, story. Um, and it, like you say, it's very serendipitous sometimes. I, I find it very fascinating that some people will just say, ah, cardiology is what I have to do, or psychiatry, or, and, and, uh, why that happens, why someone has to be a poet, or why someone becomes a musician.

[00:05:26] Fred Appelbaum: I think it's one of the great mysteries of life. I'm sure there's a genetic part of it, and I'm sure there's also just a historic part of it. you know, it's both nurture and nature that does that.


[00:05:36] What is a bone marrow transplantation
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[00:05:36] G van Londen (2): Those are psychoanalytic terms. And thank you. Thank you, Fred. I thought maybe my next question should be very simple. Can you explain to the listener what a bone marrow transplant really entails. What, what is that? 

[00:05:53] Fred Appelbaum: Absolutely. So, you have, In your peripheral blood, you have three kinds of cells. You have red cells, [00:06:00] white cells, and platelets.

[00:06:01] Fred Appelbaum: Red cells carry oxygen, white cells, fight infection, and are responsible for your overall immunity and platelets that keep you from bleeding. And those cells are very short-lived. in fact, every second, you have to make like 3 million or 4 million blood cells, because the cells that are in your peripheral blood don't last all that long.

[00:06:20] Fred Appelbaum: Now. Those new cells are produced within your bone marrow. There are a population of cells in your bone marrow, which are called hematopoietic stem cells. Hematopoietic means blood forming, and those cells are responsible for making all the blood that you'll need for your entire life and also making your immune system.

[00:06:39] Fred Appelbaum: Now, every once in a while, those cells can become abnormal. it can be because they simply fail. That's aplastic anemia. they can be destroyed because of radiation, like happened to victims of the atomic bomb. they can become malignant, that's leukemia or lymphoma, or you might be unfortunate enough to be born with a genetic [00:07:00] abnormality, making, for example, abnormal hemoglobin, and that's sickle cell anemia or thalassemia.

[00:07:06] Fred Appelbaum: And so a bone marrow transplantation, what we do. Is, in most cases, we need to destroy the abnormal bone marrow that's in the patient. And we do that usually, by giving a combination of chemotherapy and radiation therapy. and if we give it at high enough doses, it can destroy the bone marrow because it is the most sensitive organ in the body to chemotherapy and radiation.

[00:07:33] Fred Appelbaum: Generally speaking. Then, after we've destroyed the patient's own bone marrow, we can take bone marrow cells or hematopoietic stem cells from a matched donor. and those cells, we can, obtain them. And in the past we obtained them by actually putting a needle into the bone marrow into that spongy place.

[00:07:52] Fred Appelbaum: And that gelatinous material in the middle of your bone, that's where the bone marrow is. Those are, that's where the hematopoietic stem cells are. [00:08:00] In the past, we would put a needle there, suck that out, and then infuse it into the patient intravenously.

[00:08:07] Fred Appelbaum: Now we can, more easily obtain the stem cells by giving a growth factor that causes the hematopoietic stem cells to leave the bone marrow and go into the peripheral blood, and so we can get those stem cells from the peripheral blood of a donor. After we give the high dose chemotherapy or radiation, then we take the stem cells from the donor, we infuse them intravenously into the patient, and magically, the stem cells know how to home to the marrow space.

[00:08:34] Fred Appelbaum: and they do that very quickly. And then after the transplant, we have to give medicines to prevent the new stem cells. Because it is a new immune system from reacting too hard against the patient, which is its new home. So there are three big areas then of the transplant. Number one is giving the initial therapy, that's the so-called preparative regimen to [00:09:00] wipe out the abnormal bone marrow and also immune suppress the patient sufficiently so that they don't reject the new bone marrow, which generally is coming from someone that might not be an identical twin.

[00:09:10] Fred Appelbaum: Then the second phase is that we. do the actual transplant where we take the stem cells and infuse 'em intravenously. And then the third phase of it is when we allow the new bone marrow to grow and provide support for the patient during that period of time as the new bone marrow grows back up, and reaches normal levels of peripheral blood, of red cells, white cells and platelets.

[00:09:31] Fred Appelbaum: And we also have to give immune suppression during that period of time, usually to keep this new immune system from reacting too vigorously against its new host. So those are the three phases, the preparative regimen, the actual transplant, and then the post-transplant care as the patient recovers.

[00:09:48] G van Londen (2): I really like how simple you explain this. I wish I had your terminology when I was in fellowship. I wanted to switch over to [00:10:00] Brad for a second because Brad Buchanan is with us here. I may have failed to mention that in the introduction. but for the listeners who are not familiar with Brad, Brad has undergone a, transplantation that had developed the plentiful amount of complications.

[00:10:20] G van Londen (2): And I'm going to leave it here and I'm going to switch over to Brad, but I have to mute myself because otherwise we have an echo. So, Brad, do you wanna come on and reflect on that a little bit with Fred, if you're comfortable? 

[00:10:36] Brad Buchanan: Yes, absolutely. thank you Josie. and thank you Fred, for joining us. first of all, I gotta say, the second I heard, Fred, about your book.

[00:10:45] Brad Buchanan: I ordered it, and I got it and read it in about 48 hours, because I was just so fascinated by it. I was born in 1970 and so roughly, my lifetime has been [00:11:00] kind of, filled with steps forward in this process. I got my transplant in 2016. So in a way it was like reading my own biography.

[00:11:11] Brad Buchanan: you know, if I'd gotten my transplant in, 1972, I probably wouldn't have survived, But anyway, so it was absolutely a fascinating book. 


[00:11:20] Ethical Dilemmas and skepticism of transplantation
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[00:11:20] Brad Buchanan: one of the questions I had was, because so many of the early patients died, were there ethical dilemmas that Don Thomas was facing and how did he manage those?

[00:11:35] Brad Buchanan: Also, there was a lot of skepticism in the medical community. what made him so determined to keep going and so convinced that this was gonna work? 

[00:11:43] Fred Appelbaum: Yeah. as far as ethical dilemmas go, Don was, it's hard to describe Don easily. Uh, Don was, very old school. he was [00:12:00] pretty rigid about

[00:12:02] Fred Appelbaum: feeling that there was a right way and a wrong way to do things. he did not have, there wasn't a lot of gray area in Don's view of things. and he thought that there were people who were absolutely going to die. And, he felt that there was a logical reason why marrow transplantation might work.

[00:12:24] Fred Appelbaum: he first tried some transplants very early on in a very small number of patients who were just, you know, days from death. It didn't work. and so he stopped, doing it in patients and went back into the laboratory and spent 15 years in the laboratory, until he could actually make sure that he could get transplants to work, not just in inbred mice, but in outbred species and in canines in dogs.

[00:12:52] Fred Appelbaum: And it's only when he could routinely get a litter mate graft to take without lethal graft versus host disease that [00:13:00] he was willing to go back into trying transplants in patients. And so he tried the very first transplants in the mid 1950s, and it wasn't until 1970 that he went back into the clinic to try transplants in humans.

[00:13:17] Fred Appelbaum: that's when that paper I read where he had a patient who had end stage leukemia, did the transplant, and the patient actually went into remission. now the patient died of an infection and the first year he did six patients. And when he went back into the clinic, and none of them survived, but some of them at least were discharged from a hospital in remission.

[00:13:40] Fred Appelbaum: And as far as the ethics of this is concerned, he was very, very, upfront with the patients about what he was doing, and did they want to try this? and Don would always put himself in the same position. He said, if I were the patient, if I were 40 years old [00:14:00] and I had end stage leukemia and I had one month to live, would I consider trying it?

[00:14:05] Fred Appelbaum: And if I wouldn't, then I wouldn't propose it to the patient. but if I would, then given what I know, I would do this. So yes, I would try. So the first year they went back, none of the six patients survived. And then the next year they did nine more patients and Two of them left the hospital in complete remission and ultimately were cured.

[00:14:28] Fred Appelbaum: And once he got to that point where there were, even though it was a small number of patients, even though it was only 10 to 12% of the patients that were cured, these were otherwise incurable patients. And so Don did not feel that there was really much of an ethical issue here as long as the risks were clearly explained to the patients, and the patients were, willing to undergo the procedure.

[00:14:51] Fred Appelbaum: Now, you know, it is true that you can only explain things to a certain extent and there's nothing [00:15:00] quite that's equivalent to going through it. But you know, you do the best you can. As far as the ethics were concerned. I think the dilemmas actually started to come a little later. and that's when, when do you take transplantation from, a procedure that you use in patients who have no chance for cure?

[00:15:19] Fred Appelbaum: and start to take it earlier in the course of disease when patients are in first remission and may have a 25% chance of cure. And you don't know that transplantation, if you treat them in first, remission is going to be much better than that. You hope it will be. And so you propose the study to the patient.

[00:15:37] Fred Appelbaum: Now we said, okay, we would start to, take a shortcut towards a randomized study. And that is, we said, if you have a donor. We would transplant you in first remission, and if you don't, you would serve as a control. Because at that time we couldn't do unrelated donor transplants.

[00:15:54] Fred Appelbaum: And fortunately it turned out that transplantation was in fact better than standard therapy. [00:16:00] So that was sort of an ethical leap. But is it worthwhile trying this in first remission when patients might all really be cured? Then another ethical problem comes on when you start dealing with diseases like sickle cell anemia or thalassemia where a patient might have 20 years of life, it's not a great life.

[00:16:19] Fred Appelbaum: In fact, it can be quite miserable, but it's 20 years. Do you take a child and transplant them hoping that you'll get a long-term cure? And so those were difficult decisions that were made along the way. and many, many people got together. To discuss this. And it was all done, you know, I think in a reasonably carefully, step by step manner.

[00:16:43] Fred Appelbaum: But there were, some quite difficult questions along the way, usually in most of these cases. for example, in thalassemia, we didn't propose to do it right away. It was actually the families that pushed us to do it [00:17:00] because they had already lost one of their children and said, I know what this is.

[00:17:04] Fred Appelbaum: Like, we would like to try a transplant earlier. of course we would discuss it and go through the usual IRB and sort of stuff to, to make sure that it was done in a fair and ethical manner. 

[00:17:14] Brad Buchanan: Yeah. Thank you. And, you know, I belong to a lot of, graft versus host disease patient groups.

[00:17:20] Brad Buchanan: And you know, a lot of the folks say, well, they kind of told me the graft versus host disease was actually a good thing. Going into the transplant because it would show that my immune system was working. But too much of a good thing is not a good thing as, as you're well aware, but, you know, and, um, yeah, and I too got that sort of like, you know, a little bit of GVHD is actually a sign that the graft is taking and you have at least a chance of surviving.

[00:17:48] Brad Buchanan: and a lot of people have sort of asked me or asked each other knowing how bad GVHD can get, would you still go through with the transplant? And I always say, yes, of course, because I knew darn well I was gonna [00:18:00] die of my original blood cancer. And there's no two ways about it. So I certainly don't regret getting my transplant though I nearly died in the process of acute graft versus host. But you know, we are truly between a rock and a heart place here and.


[00:18:16] Legal Scrutiny of Early Bone Marrow Transplant Research
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[00:18:16] Brad Buchanan: I, the reason I asked that question though also is there's a follow up with which, which has to do with the lawsuit that was filed, I think in, the early two thousands against Don Thomas and some colleagues, in part because of some very shoddy journalism.

[00:18:30] Brad Buchanan: Your book does a great job of giving the background to the lawsuit, and ultimately Thomas and his colleagues were vindicated. But I'm wondering if there were some lessons to be learned from that whole situation where there was suspicions of a conflict of interest between the doctors and who had investment in, in some company that was producing some of the therapies that were being used and, and so on.

[00:18:53] Fred Appelbaum: Yeah. so let me first say that I, I'm sorry that you had to go through that, Brad, that you had [00:19:00] the, graft versus so disease that, that you did. It. It is, it's very difficult to, explain to patients the risks and benefits. We try to do our best. it is true that a small amount of GVHD has an anti leukemic effect.

[00:19:13] Fred Appelbaum: And in fact, and, and the other thing that I'm, I, I'm very pleased to be able to say it doesn't help you at this moment, but we're so much better in preventing graft versus host disease today. I mean, we see now with the use of post-transplant cyclophosphamide, or the use of, t-cell depletion, partial T-cell depletion, we see, severe graft versus host disease almost

[00:19:37] Fred Appelbaum: not at all. wow. And, chronic graft versus host disease in the last, series that we've done with, naive T cell depletion, we treated, on the phase two studies, 130 patients. nine of them had chronic graft versus hosts disease out of 130, and all of them got off of immune suppression subsequently.

[00:19:53] Fred Appelbaum: it has been remarkable how much progress we've been making. just in the past couple years, there have been [00:20:00] four new drugs that have been approved for the treatment of chronic graft versus host disease. Ibrutinib, uh, as you know, uh, Belumosudil, uh, tux, uh, uh, ruxolitinib, and Axatilimab four drugs that have been approved for chronic graft versus so disease and for acute graft versus host disease.

[00:20:18] Fred Appelbaum: We now not only have steroids, but ruxolitinib has also been approved for acute. So we have much better ways of preventing it and much better ways of, Treating it, which I think is all great. Going back to the issue of the lawsuit, you know, in the ethical or the regulatory requirements, they evolve just like medicine evolves.

[00:20:40] Fred Appelbaum: When Don was doing the early T-cell depletion studies in the 1970s, the issue of reporting every possible conflict of interest, even if there wasn't a realistic conflict of interest, wasn't there. So there was no way that there could have been a conflict of interest in [00:21:00] the use of the monoclonal antibodies that Don was using because they had no intellectual property.

[00:21:04] Fred Appelbaum: It wasn't being used in that kind of setting. But it was true that he was receiving some consultation fees from the company that was producing the monoclonal antibodies. And today we would absolutely, Not do that at all or at the very minimum, there would be, you know, the issue of, potential conflict of interest would be, acknowledged right upfront to the patient and in all the informed consents.

[00:21:30] Fred Appelbaum: And so I think the lesson from that is that you just have to be absolutely squeaky clean and avoid every detail about a potential conflict of interest. You know, in that case, there was the accusations made by a individual. it went to the NIH to OHRP.

[00:21:51] Fred Appelbaum: They came out and investigated it and found no problem, but that wasn't enough for them. And so then they went to the state quality insurance. state quality insurance [00:22:00] came out, found no problem still, that wasn't enough So the person went to the press and finally found a journalist who wanted to make a big deal out of it.

[00:22:06] Fred Appelbaum: So you cannot be careful enough, I think is the issue where you're dealing with medicine in patients', lives. you just have to be absolutely squeaky plate about it. 

[00:22:16] Brad Buchanan: Well, it actually, it's, to me, it's remarkable that that was really the only sort of serious. question really that came to a legal, point with all this groundbreaking, medicine that was going on.

[00:22:29] Brad Buchanan: All these discoveries that, Don Thomas and his successors, including yourself, have really, achieved a very high standard of transparency, in order to avoid, getting dragged into the muck more often by patients or, people whose loved ones didn't survive or whatnot.


[00:22:46] Extracorporeal photopheresis
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[00:22:46] Brad Buchanan: I guess I had a further question about, ECP or, extra corporeal photophoresis, this might be a very personalized question where in my acute graft versus host disease, steroids weren't doing the job there were no other [00:23:00] drugs that I know of besides immune suppressant, tacrolimus, that were working.

[00:23:04] Brad Buchanan: so what they tried was Photophoresis, ECP, and that seemed to be, it didn't work very quickly, but it slowly turned the tide of my acute GVHD and I had more than a hundred treatments of ECP, over the next, eight years or so, and finally stopped them, recently when I didn't feel like they were having any effect.

[00:23:25] Brad Buchanan: But they certainly, fished me out of the sewer that I was heading into. And, anyway, so what's your view on ECP? Is it a widely accepted treatment of GVHD?

[00:23:35] Fred Appelbaum: Oh, 

[00:23:35] Fred Appelbaum: Yeah. I mean, We use it. we don't use it very often. there's definitely studies that show it works.

[00:23:41] Fred Appelbaum: It doesn't work all the time. It doesn't work in everybody. it tends to work slowly. it works better in situations where most of the GVHD is cutaneous. it doesn't work as well, for GI gVHD, I think part of the reason [00:24:00] that we don't use it nearly as much is that A, we don't see as much GVHD today.

[00:24:05] Fred Appelbaum: And so there's much less need. B, we have at least three drugs that have been approved for acute GVHD that we tend to use first. And so we use steroids and then Ruxolitinib and then Infliximab, as the. Upfront therapies more often. and for chronic graft versus host disease, as I already mentioned, we have four new drugs that have been approved.

[00:24:25] Fred Appelbaum: And so ECP falls further down on the list. It, it's not that it doesn't work, it just works slowly and it works incompletely in everyone.and it's also quite cumbersome. I mean,

[00:24:35] Fred Appelbaum: it's not something that you just wake up and take a pill in the morning. And so it's not, very user friendly for the patient, therapy.

[00:24:43] Fred Appelbaum: and there's also only a limited number of institutions where you can get it. And so If you're sitting out in rural eastern Washington, it becomes a real problem for that. So it definitely can work. there's a lot of biology about how it works, but, it's not something that is probably the future of graft [00:25:00] versus host disease treatment.

[00:25:02] Brad Buchanan: Right. Yeah, no, that makes sense. you know, I've also been told it's expensive. The machines are kind of difficult and it's a, for me, it was like a two to three hour

[00:25:11] Brad Buchanan: procedure. I had to, you know, be hooked up to this machine with very big needles going into my port line and so forth.

[00:25:19] Brad Buchanan: it was quite an imposition, but since it was my best, treatment option, I stuck with it. And, I do believe that I owed my life to it, and it was pitched to me as an experimental kind of thing where it was sort of a last ditch effort from what I now gather. but anyway, thank you 

[00:25:37] Brad Buchanan: for that. I asked because I talked to quite a few GVHD patients and some of 'em have never even heard of it. 

[00:25:42] Fred Appelbaum: Yeah. now all the four drugs I mentioned that have been approved for chronic graft versus host disease have all been approved just in the last four years. So it wasn't like you had that option so there's been a lot of evolution in both prevention and treatment of GVHD.


[00:25:55] Future of cellular therapies: solid tumors
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[00:25:55] Brad Buchanan: Well, and that kind of gets to my next question is like, since there's been such [00:26:00] progress, what do you think the next 10, 20 years and beyond, what can we expect, you know, to, to be able to say and do, with the stem cell transplant?

[00:26:12] Brad Buchanan: i, I, I, I love thinking about the future, That's how I spend most of my time, when I'm not taking care of patients, is thinking about what should we be doing next and how can we make it happen in the most, exciting way. So, I'll talk about, three large themes, if that's okay.

[00:26:29] Fred Appelbaum: we, do marrow transplantation most often to treat malignancy. and usually it's blood cancers like leukemia or lymphoma or multiple myeloma or myelodysplasia. and, you know, that's a substantial number of patients that, can benefit from it. And transplantation works. for two reasons. It works

[00:26:55] Fred Appelbaum: number one, because we can administer higher doses [00:27:00] of chemotherapy and radiation therapy than would otherwise be possible. Because if you gave those high doses and you didn't do a transplant, the bone marrow wouldn't recover and the patients would die with bleeding or infection. And so the one way that transplantation works is because we can administer these high doses of therapy.

[00:27:17] Fred Appelbaum: But a second way that the transplant can work, and this is really important, is that the new immune system coming from the healthy donor sees the leukemia as being foreign and rejects it. And we know that to be true for two reasons. Number one, if you do transplants between identical twins where there's no difference,

[00:27:39] Fred Appelbaum: there is a much higher chance that the leukemia will come back than if you do transplants between brothers and sisters where there are some genetic differences. And further, as you already cited, if you see some graft versus host disease, which means that the new immune system is seeing more of the patient as being foreign, the relapse rates are even lower.

[00:27:59] Fred Appelbaum: And [00:28:00] so transplantation works both because we can give high doses of therapy and because there's this graft versus leukemia effect. Now we've known about that, for over 30 years. And what has since evolved is we have been able to identify what population of cells from the new immune system are seeing the leukemia as being foreign and rejecting it.

[00:28:24] Fred Appelbaum: And it turns out that those are mostly T cells or they're a kind of lymphocyte that are derived from the thymus, that's the population that sees the leukemia as being foreign. And then secondly. We have been able to identify what is, being seen by these cells, what is the target on the leukemia that the T cells are seeing and rejecting?

[00:28:48] Fred Appelbaum: And with that, we started to find out, well, if we can do that, can we find the T cells from the donor that are seeing the leukemia as being foreign? And just give those. [00:29:00] And we found out ways that that is actually possible. But it was very, very labor, intensive. and there was no easy way to scale it.

[00:29:10] Fred Appelbaum: But then in the mid, two thousands, we figured out ways to genetically engineer T cells so we could take out a patient's own T cells or take out the T-cell from a donor and put in to those cells, the genetic information to form the receptor that sees the leukemia as being foreign and rejecting it.

[00:29:32] Fred Appelbaum: And that is what are called CAR T cells or chimeric antigen receptor T cells. And today there have been 15 different indications for CAR T cells. And so now what we can do is instead of doing a transplant for, for example, acute lymphocytic leukemia, we can take the patient's own t cells out, we can put in the receptor that sees the leukemia, grow those cells into large number and give them to the [00:30:00] patient, and cure their leukemia.

[00:30:01] Fred Appelbaum: And so it's a direct evolution of transplantation to this targeted T cell therapy or CAR T cells. And we have now, as I said, 15 indications that have approved it. And there are a thousand trials going on trying to develop these CAR T cells, not just for leukemia in lymphoma, but for solid tumors like pancreatic cancer, for breast cancer, for prostate cancer, even for some of the worst cancers that you can think of, like glioblastomas.

[00:30:32] Fred Appelbaum: and so that is one area that is really evolving directly from transplantation. 

[00:30:39] Brad Buchanan: So, Are you kind of saying that Don Thomas is also the father of immunotherapy? Absolutely. Wow. Okay. I had not connected those dots, but that is fascinating. 

[00:30:49] Fred Appelbaum: the observation that leukemic relapse was

[00:30:54] Fred Appelbaum: lower after allogeneic transplants than after twin transplants was the first [00:31:00] observation in humans of the power of the human immune system to eradicate a disseminated malignancy. That was the very first time we could actually point. Now people theoretically thought it should be possible, but that was the first time we could actually point to a setting in humans where you could show that the human immune system could eradicate a disseminated cancer.

[00:31:22] Fred Appelbaum: and that all grew from marrow transplantation. 

[00:31:26] Brad Buchanan: Okay. That, that is such a game changer in terms of the way people think about cancer from a layman's perspective, right? That it's not like cancer is this thing out there in the universe that comes and like attacks our bodies from outside.

[00:31:40] Brad Buchanan: It's like, no, our bodies produce cancer. We are cancer producing organisms. However, we have this immune system that's usually smart enough to kill it, before it runs out of, control and so on and so forth. And really, by taking care of our immune systems, we are fighting cancer without necessarily knowing it.[00:32:00] 

[00:32:00] Fred Appelbaum: Absolutely. And there's also another person who deserves a huge amount of credit for this, Jim Allison, who won the Nobel Prize several years ago for developing these checkpoint inhibitors where we can just take the breaks off of your own immune system and allow your immune system to react against the cancer.

[00:32:17] Fred Appelbaum: But that's a very non-specific approach. Don's approach was very targeted against the unique antigen that we're trying to kill with the CAR T cells. And frankly, it may be that we want to use a combination of the two, the CAR T cells and then taking the breaks off of your own immune system.

[00:32:32] Fred Appelbaum: And, uh, you know, when I first started in oncology, we didn't have any immunotherapy. It was just radiation, surgery and very non-specific chemotherapy. And today, probably if you have a metastatic cancer, there's maybe a 30 to 40% chance that you'll get some form of immunotherapy today.

[00:32:51] Fred Appelbaum: So it really has, it has been a major game changer. So the big first theme I mentioned was, CAR T-cell therapy. Well, just the [00:33:00] development of cellular immunotherapies that will be against cancer. 


[00:33:05] Future of cellular therapies: genetic diseases
---

[00:33:05] Fred Appelbaum: a second big area I want to talk about, is the idea that marrow transplantation could cure sickle cell anemia and thalassemia and some other genetic diseases.

[00:33:19] Fred Appelbaum: Now, the very first patient ever cured of sickle cell disease got the transplant not for her sickle cell disease. she was a young girl by the name of Kimberland George back in the 1980s, had terrible childhood with painful sickle crises. it was really, quite difficult for her. But, in 1984, she showed up in an emergency room with what they thought was another sickle crisis.

[00:33:41] Fred Appelbaum: But when they looked at her peripheral blood, they saw not only the sickled red cells, but they also saw leukemia. and so she had a transplant for her leukemia. But in curing her leukemia, they also cured her sickle cell disease because she had a donor who had normal hemoglobin. Uh, [00:34:00] and so with that, as transplantation became safer and safer, people could say, oh, now we can do transplants. And now cure rates for transplantation and sickle cell disease are in the 90 to 95% range. which is really remarkable. But you still have to have a normal donor. There still is risk, there is still is the possibility of graft versus host disease or graft rejection.

[00:34:23] Fred Appelbaum: And so while it's great, it's just, it's not a, an absolute home run. Also, it's very resource intensive. And so what's happened over the last few years is that people have figured out ways of taking out someone's own bone marrow and taking the bone marrow out and fixing the abnormal hemoglobin gene. And then giving the patient high dose chemotherapy to wipe out their own bone marrow and give them an autologous or self transplant.

[00:34:52] Fred Appelbaum: And it turns out that that can cure sickle cell disease as well. There's another similar approach where when you're [00:35:00] in utero, you make fetal hemoglobin so you can steal oxygen from the mother. It's some people have fetal hemoglobin their whole life and they do just fine.

[00:35:11] Fred Appelbaum: And so what people have since figured out a way to do is to take out someone's bone marrow and using CRISPR to knock out the gene that causes the switch. From fetal hemoglobin to adult hemoglobin. And so you'll no longer make the abnormal adult hemoglobin. You'll go back to making fetal hemoglobin and using that as an autologous transplant, and that works as well.

[00:35:32] Fred Appelbaum: And so those have now been the very first patient that ever got that. Got it, just six years ago, 2019, doing just fine in every patient that's gotten in it since it seems to be working incredibly well. And so we have another way of doing all these genetic therapies based on the first work with transplantation.

[00:35:51] Fred Appelbaum: Now there's a problem with all this, though. It's very, very expensive and it's very resource intensive. there are about [00:36:00] 300,000 kids that are born every year with sickle cell disease, 300,000. And if you're born in Sub-Sahara Africa with sickle cell disease, your chance of living five years is only about 50 50.

[00:36:13] Fred Appelbaum: And we're not gonna be doing transplants in Sub-Sahara Africa, and we're not gonna be doing gene therapy, which currently costs over a million dollars. But what we're doing now in the clinic is we have developed, I'm gonna use the term vector, but these are virus-like particles that you can infuse intravenously.

[00:36:34] Fred Appelbaum: You don't have to take the bone marrow out, you just infuse these intravenously and they can fix the hemoglobin in the bone marrow Imagine if all you had to do is give a single shot and you could cure every one of these 300,000 kids of sickle cell disease. And you can also, by the way, with a single shot, turn your T-cells into CAR T cells.

[00:36:56] Fred Appelbaum: And those studies are also ongoing in the lab, in the clinic. And [00:37:00] so it may be that you don't have to go through all this, take blood out, give high dose chemotherapy to do the CAR T-cell therapy as well. So these are gonna be game changers. this is gonna happen. You asked me 10, 20, 50 years, this is stuff that is gonna happen in 10 years for sure.

[00:37:16] Fred Appelbaum: And so we talked about, leukemia, lymphoma and CAR T cells and also applied that to solid tumors. we talked about gene therapy for sickle cell disease and thalassemia.


[00:37:25] Future of cellular therapies: autoimmune diseases
---

[00:37:25] Fred Appelbaum: And I'll just go to one last thing and that is there's millions of people in the United States that have autoimmune diseases.

[00:37:32] Fred Appelbaum: Like SLE, systemic lupus, rheumatoid arthritis, scleroderma. And it turns out that CAR T cells against these, against B cells have in early studies, they're looking like almost a hundred percent response rates in these autoimmune diseases to CAR T cells against CD 19 or CD 20.

[00:37:55] Fred Appelbaum: which will be just a game changer if, if that works. And it, particularly if we can again, [00:38:00] make those CAR T cells with a simple in vivo injection. And so all that is just, it's, it's, it's unbelievable. It's gonna come from all this. And really, you know, of course, as many people said, every, every success has, many, many fathers, and every failure is an orphan.

[00:38:17] Fred Appelbaum: so there's lots of people who've contributed to this. But, you know, I can draw a straight line from Don's early work to all these advances.


[00:38:25] Shortage of transplant physicians 
---

[00:38:25] G van Londen (2): Well, Fred, don't we need many, many, many more transplant physicians? Of which there are very few at the moment, I think, or do you foresee that other specialties such as rheumatologists might be able to do this on their own? And secondly, this is a little bit of a self-interest question 'cause you know, I have a primary mitochondrial disease,

[00:38:51] G van Londen (2): Yeah. You ask two very good questions, there, Josie. the first is, you hit on a really interesting and [00:39:00] challenging part of what we do.

[00:39:03] G van Londen (2): when we wanted to start doing transplants for sickle cell disease, we were, leukemia experts, and transplant experts. But we, didn't know very much about sickle cell disease. the experts in sickle cell disease didn't know very much about transplantation. and so it is the case that.

[00:39:25] G van Londen (2): And it's hard to avoid this, but to be a successful transplanter, there's so much you have to know about transplantation that you can't necessarily know about sickle cell disease and vice versa. Now what we did was we had a series of meetings where we got experts in sickle cell disease and transplantation together and had long discussions about what would be the best way to go forward, and eventually would hammer out protocols that allowed this to happen.

[00:39:52] G van Londen (2): But it doesn't happen on a day-to-day basis. The same thing that happened exactly when we were starting to use [00:40:00] transplantation for autoimmune diseases. We knew about transplantation, but we weren't experts in scleroderma, for example. And so we needed people who were experts in these other modalities to work with us to develop collaborations where we could, start to move the field forward.

[00:40:17] G van Londen (2): There is, a limited, limited number of transplant centers. There's a limited number of transplant physicians, and there are very few people who are sitting on a day-to-day basis, at the crossroads between these two. those people are making great contributions, but we need more of those people who are not just experts in autoimmune disease, not just experts in transplantation, but experts in the application of transplantation to autoimmune disease.

[00:40:44] G van Londen (2): and those are the people that are really, the rarest. but, there are people like that and they're making a huge difference. 


[00:40:50] Role of cellular therapies for primary metabolic and mitochondrial diseases
---

[00:40:50] G van Londen (2): the second question you ask, relates to transplantation, and I'm gonna broaden it up a little bit. not just for mitochondrial diseases, but also to [00:41:00] broader metabolic diseases.

[00:41:01] G van Londen (2): when we do a transplant, we, are putting in bone marrow, but all the cells that derive from the bone marrow, including macrophages, that go everywhere in the body. so once a patient has a transplant, they're walking around with 15% of their donor, in them.

[00:41:18] G van Londen (2): and if the patient has an abnormality in a certain metabolic pathway, like for example, a glycogen storage disease where they lack the enzymes that break down glycogen in the right way. And so you get, too much glycogen stuffing in all the cells. if you do a transplant and you have these 15% of cells, they can produce enough of the enzyme to do the job there. Now, it doesn't work in every metabolic disease, but it does work in a lot of metabolic diseases, in mitochondrial disease. Um, as, and I'm not an expert in this at all, Josie, so I, I could, I, I hate to say something that's incorrect and I apologize.

[00:41:59] G van Londen (2): [00:42:00] I'm really not the expert here. There are two kinds of mitochondrial diseases. There are diseases which are the genetic abnormality that's in the mitochondrial DNA, but there's also the kind where it's in a more broad, enzyme pathway, which affects the mitochondria. And at least in, in one of those, I, I know there, there's a, a MNGIE mitochondrial disease,where you have a, a thymidine phosphoryl, which is, lacking.

[00:42:26] G van Londen (2): And by doing a hematopoietic cell transplant, you can produce in the hematopoietic cells enough thymidine phosphorylase that can secrete and replace the lack of, thymidine phosphorylase in the patient. And so. In certain mitochondrial diseases where it's not within the mitochondrial DNA per se.

[00:42:45] G van Londen (2): it can work whether it can actually work in the mitochondrial DNA deficiencies. I think we have a lot of work to do. and there isn't as clear, straightforward approach that I'm aware of, but I'm sure there [00:43:00] are, terrific scientists who are working on that as well.


[00:43:03] Story time
---

[00:43:03] Brad Buchanan: Thank you, Fred. And, you know, we are talking so much, detailed scientific, information here and it is fascinating. But I do wanna get back to the patient stories that you shared in the book, which, you know, there are a lot of them and not all of 'em end happily, but, I think you do justice to the, the people who

[00:43:24] Brad Buchanan: were part of this therapy. now if you could just share one, maybe one story from the book that has kind of stayed with you more than another, of a patient, who underwent a transplant and, and what that taught you or what they went on to do in their lives or, or something.

[00:43:43] Fred Appelbaum: Well, that's, that's a hard one. 'cause there's so many stories, Brad, um, to, to, to relate that, uh, um, in picking one, I, I hardly do justice to so many. I'll just start by saying that it's such a privilege to be able to be [00:44:00] a physician. Um, in general, uh, you have to be very privileged.

[00:44:05] Fred Appelbaum: You have to be lucky enough to have gone to college and have the support, to go to medical school. and you have to, have certain God-given talents that, not everyone is blessed with. and I do realize how incredibly, fortunate I am to be able to do what I do and to hear patient stories.

[00:44:24] Fred Appelbaum: every patient tells a story and they are so interesting. Fascinating to hear, and nobody's boring. I mean, everyone has an interest story to tell, But I'll tell you one story. I'll just say this because this gentleman just died, 10 days ago.

[00:44:39] Fred Appelbaum: and he was a great friend. his name was Harry Pierce. and Harry, came to me about 28 years ago. He had just been diagnosed with a very tough form of leukemia. Harry, at the time was the vice President of General Motors. and, I had been called about seeing him.

[00:44:58] Fred Appelbaum: this is a VIP at the very [00:45:00] highest level. You know, this is the vice president general Motors is not anyone to, you know, not a small person. and Harry came to see me and, I did the consult. And, he was just a wonderful, wonderful man. I said, Harry, you know, if you come here, you have to understand that you are going to be treated just like every other patient.

[00:45:23] Fred Appelbaum: we don't have a VIP suite. our doctors rotate. You're gonna get whoever's on the rotation. And Harry looked at me and he said, Fred, we produce cars. Do you think I would want a car taken off the assembly line and somebody to hand build it?

[00:45:41] Fred Appelbaum: That's not how you do things. You have to have a standard of care. You have to have a way that everyone knows the job and what their job is, and I would expect nothing else. And if you told me that that wasn't how you're gonna do it, I would have problems. And it was such a breath of fresh air.

[00:45:58] Fred Appelbaum: So Harry got his [00:46:00] transplant, and, fortunately did very well. afterwards, Harry, wanted to give back and he became, the vice chair and then chair of the National Marrow Donor Program. Uh, and, throughout his life made a bunch of other contributions. unfortunately, Harry was, 86 when he passed away, two weeks ago.

[00:46:20] Fred Appelbaum: Not from the transplant, but from other complications at that age. But it was just the fact that he understood, that, you're gonna treat every patient as best you can, but, you don't give more care to one kind of patient than another if you wanna give great care to everyone.

[00:46:37] Fred Appelbaum: and so Harry, that's, I just mentioned him because, he just passed away and, he was a very, wonderful guy and was very good for the transplant community over the years. 

[00:46:46] Brad Buchanan: Well, yeah, that's a remarkable perspective, that he was able to give on that.

[00:46:52] Brad Buchanan: you know, with the cars on the assembly line, one thing I always felt like, and this was my overwhelming feeling, the night before my transplant, [00:47:00] when I was walking around the hospital in a state of high anticipation, excitement. Was just, I was feeling very privileged that so many people were doing so much just to help me survive.

[00:47:11] Brad Buchanan: and, you know, I was not a VIP and nor did I get VIP treatment, nor should I have gotten VIP treatment. But nevertheless, just to be in the position where all of these resources, you know, my brother came and donated his, stem cells and, you know, so many doctors and nurses were working, for my continued existence that night I just, I felt nothing other than just sheer gratitude for, all of the things that were being done.

[00:47:38] Brad Buchanan: And now that I know how many other people set, the stage for that to happen, it is pretty overwhelming. Honestly. Reading your book was, uh, yeah, it was, it was an emotional experience as well as an intellectual adventure. So, again, thank you for taking the time to do that.


[00:47:54] Whats next for Dr Appelbaum
---

[00:47:54] Brad Buchanan: And looking ahead, what's next, for your writing career?

[00:47:59] Brad Buchanan: [00:48:00] or, what's next ahead on your personal research agenda? What would you like to share about? 

[00:48:04] Fred Appelbaum: yeah, I'm getting up there in the years, Brad. I'm just, a few months away from 80. So I don't have a timeline for 30 years, but, right now I'm still seeing some patients.

[00:48:13] Fred Appelbaum: I enjoy the human contact of seeing patients there. As I say, it's so rewarding to be able to contribute. I am, still in charge of the hematologic malignancy program here at The Hutch, but I don't do my own laboratory work anymore. I help think about and shape the clinical research that goes on, but mostly I spend my time, trying to be more of a mentor for the younger, clinicians and scientists and hear their grants and try and improve their grants as they go forward.

[00:48:40] Fred Appelbaum: and I do, have a bit of an administrative role here. And you are correct. I am working on another book. I really am so pleased that you enjoyed the book and that it was meaningful for you. That is why I wrote it. and also wrote it because I didn't want Don's story to evaporate.

[00:48:55] Fred Appelbaum: 'cause when I started to write it, one of my colleagues had just developed pancreatic cancer and [00:49:00] was going to die. And I looked around and realized that. there was only one other guy that had been around as long as I had here. And if I didn't tell the story, it wasn't clear that anyone was going to do it.

[00:49:10] Fred Appelbaum: So, that's why I, in part why I wrote it, and I found that writing was, very addictive. I really enjoyed the process of thinking about how to, not only what to say, but how to say it, and how to say it in a way that, I thought was clear and, you know, putting in a few clever little tidbits into it here and there.

[00:49:31] Fred Appelbaum: so I just found the process of writing. a lot of fun. And fortunately, I've gotten a lot of nice feedback on living medicine. And so it meant a lot, I think, to at least a few other people. so that was good. So, yeah, I'm still seeing some patients.

[00:49:44] Fred Appelbaum: I'm still, doing some, mentoring and clinical research and, then, I am gonna get a second book out there, I hope. 

[00:49:52] Brad Buchanan: Okay. Well, we won't ask for any sneak previews of that, but I will say, this book was such a pleasant surprise in terms of how readable it [00:50:00] was. I have a fairly decent vocabulary, but sometimes, reading stuff that's overly technical, my eyes glaze over.

[00:50:08] Brad Buchanan: But the through line of Don Thomas's and his wife also was a huge part of his, They were kind of a team for much of, his career. the human side of this medical intellectual adventure that you describe is really well, narrated. And yeah, there are lots of fun little touches, jokes in the footnotes, and just the whole thing was really, yeah, it was a wonderfully, you definitely provided plenty of spoonfuls of sugar to help the medicine of the information go down, in this book.

[00:50:41] Brad Buchanan: I look forward to more, of your, books ahead and I too am a big proponent of writing as a form of, wellness enhancement. Writing is one of my pet, pursuits I think writing about something that's meaningful to you, is a great way to.

[00:50:57] Brad Buchanan: manage all kinds of, other [00:51:00] things that may be going on on your life, to relieve stress and to gain a sense of purpose in your intellectual pursuits. Uh, and consolidate the knowledge that you've amassed in the course of your lifetime must've been incredibly satisfying to be able to put it between the covers of a book so kudos to you.


[00:51:18] What would Don Thomas be most proud of
---

[00:51:18] Brad Buchanan: last question. if Don Thomas were alive to see what's going on right now, what would he be the most proud of, do you think? 

[00:51:29] Fred Appelbaum: I have no doubt what he would be most proud of. and that would be just seeing more patients cured. Don was not a scientist.

[00:51:37] Fred Appelbaum: Was not looking for some biologic truth. You know, there are people that are out there that wanna understand how a cell works, uh, how, what decides to divide. Don wasn't looking for a scientific truth. Don was looking for a cure. He's trying to cure people. and that's what he was all about.

[00:51:58] Fred Appelbaum: his dad was [00:52:00] a general practitioner. when there very few effective drugs, Don saw people dying and saw the very first cures with, for example, sulfonamides and said, I wanna find a cure for leukemia. the thing that would make Don, the proudest and the happiest, I have no doubt, would just be to see patients who would otherwise be dead, coming back and, 

[00:52:25] Fred Appelbaum: getting married and having kids and seeing their kids grow up. I know that's what Don would, be the proudest of for sure. Without question. 

[00:52:32] Brad Buchanan: And you know, the word cure is also I think, like, I consider myself to be cured of my cancer, but, you know, cancer landscape, I don't really want to use that word very often 'cause it's so hard.

[00:52:45] Brad Buchanan: You know, most people are just, Hey, I'm in remission and that's good enough, but to actually cure it is quite something. So yeah, that would definitely be lots to be proud of. 


[00:52:56] Closing
---

[00:52:56] Brad Buchanan: but I'll let Josie say the final goodbye. but anyway, thank you so [00:53:00] much for your time. 

[00:53:00] Fred Appelbaum: Thank you Brad. Well thank you for having me.

[00:53:02] Fred Appelbaum: it's great getting to see you and talk to you. Likewise. 

[00:53:07] G van Londen (2): thank you for spending time with us I really appreciate how you try to write and maintain a legacy for Don. That's really, really nice. And please, when you can come back for your second book 

[00:53:24] Fred Appelbaum: book, well, you'll have to invite me.

[00:53:26] G van Londen (2): Yes, yes, yes, yes. And by the way, you look much younger than your biological age. 

[00:53:33] Fred Appelbaum: Well, you know, they say that the three periods of man, that there's youth, middle age, and then you're looking good. but thank you. I'm trying my best. 


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Josie

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Brad Buchanan, PhD, MA

Co-host