20 years of Improving Transplant Tolerance with Dr. Stephan Busque

This episode features Stanford Professor and transplant surgeon Dr. Stephan Busque. He discusses his extensive experience in the field of tolerance in transplantation, particularly focusing on advancements over the past 20 years. Dr. Busque highlights the significance of his team's work on translating research into clinical practice and mentions that they have the largest experience globally in this field.

Additionally, Dr. Busque shares exciting news about Stanford's first allogenic islet cell transplantation for a patient with type 1 diabetes, indicating a collaborative effort that brought together a multidisciplinary team to achieve this milestone. He reflects on the journey of making islet cell transplants more accessible and expresses hope for new beginnings in this area.

The episode wraps up with a lightning round where Dr. Busque discusses the qualities he admires in skilled surgeons, emphasizing the importance of being a well-rounded doctor who not only excels in technical skills but also demonstrates a deep understanding of patient care and connection. Going forward he’s excited for the development of protocols for various transplant scenarios, including open liver transplant tolerance, and indicates that patients with less-than-perfect matches are the next target group for improvements in transplantation techniques

Link to American Journal of Transplant article: Induction of immune tolerance in living related human leukocyte antigen–matched kidney transplantation: A phase 3 randomized clinical trial

Link to Amy Silverstein NYT article: My Transplanted Heart and I Will Die Soon

Rachel Baker: [00:00:00] Welcome to Scrubcast, where we take a closer look at the research happening at Stanford University's Department of Surgery. I'm your host, Rachel Baker. Today we're speaking with Dr. Stephan Busque. Welcome to the show.

Stephan Busque: Well, thank you very much for an invitation.

Rachel Baker: Thank you for joining us. It is wonderful to have you here.

Dr. Busque, you are a professor in our division of abdominal transplantation and a Canadian, how did you end up at Stanford?

Stephan Busque: Yeah, you're right. I'm a Canadian, actually, to be more precise French Canadian or Quebecois, if you wish, but I'm an American citizen. Oh, it started born in Montreal then medical school there.

Surgical training and some research in immunology, both on the French side and at University of Montreal and at McGill. And then. I was interested in a transplant and I did my clinical fellowship [00:01:00] in United States, so I'm following a bit what my mentors did in Montreal. So Dr. Dao, Dr. Carma. They trained actually with Starzl in the late sixties and brought transplant to Canada, so I followed their lead, trained at the best center in the United States.

I was interested by the West coast. I ended up interviewing at the California Pacific Medical Center. Where Dr. Carlos Esquivel was leading the liver transplant program, a trainee of Starzl himself and also Oscar Salvatierra and other great pioneers of transplant, Dr. Jeff Collins. And, uh, then I moved back to Montreal after that training.

At the same time, they moved their practice from the California Pacific Medical Center to Stanford. So six years later there was an opportunity and they called me back. And I was very interested to be able to join what I would say, like the be drafted in the major league. And, uh, so that's, uh, [00:02:00] history.

Now, that's 25 years ago.

Rachel Baker: Amazing. Well, why did you choose transplant?

Stephan Busque: So first, to understand this or my track, you have to understand that there's two of us. I have a twin brother. Both interested in medicine and in surgery, and at some point not able to make up our choice between going into direction of a surgical career or a medical specialty career.

So my last rotation as a medical student in surgery was with the team doing transplant and then. After a week, it was like clear, an epiphany. It's like, oh, this is the best of the surgery and still the best of medicine. So it's about clear cut. It was my career's choice, and my twin brother decided to go in direction of hematology and bone marrow transplant.

So, you know, at some point the Busque brothers had to be separated.

Rachel Baker: Very [00:03:00] interesting. Your research centers on immunosuppression after transplant. We know that transplant recipients receive medication to repress their immune system so that they don't reject the new organ. Your immune system knows that it's not, your organ wants to kick it out, uh, even though it's keeping you alive.

These meds, while they let you keep the organ, they create their own host of issues. Is that correct?

Stephan Busque: Yeah, absolutely. So these meds have saved thousands of lives and now that we're better at it and they're improved, so people live longer. So we are able to now have a better assessment of what is the burden of immunosuppression.

What does it do? So we are more successful early on. Actually, I'm giving the example of kidney transplant, but then with time, the diabetes, the effect on the cardiovascular [00:04:00] system, toxicity, kidney takes a toll. Yeah. And then what's gained upfront is not as sustained. And, you know, just to illustrate this, uh, I don't know if you're, uh, aware of the, um, essay that Amy Silverstein wrote in the New York Times, maybe three years ago.

So, Amy Silverstein, uh, was a correspondent for the New York Times, got. Two heart transplants during her life. Wow. But he's a good example of what is still imperfect in our field. So our first transplant, despite all the medication rejected, so she needed a second one. She did very well, and then she developed a complication, a little complication of the immunosuppression years later, which is lung cancer.

So her essay title was “Me and My Heart Will Die Soon,” and she published this like a couple months before her passing. She was very grateful for the life, [00:05:00] extended life that the transplant gave her, but she pointed out that there's not a lot that is done in terms of research to reduce the burden of immunosuppression.

So it's kind of like a cry for help to try to help, you know, stimulate research in that area and for other transplant recipients. Actually, this is what we do at Stanford; we are working in the field of tolerance. Tolerance is a process to try to make your immune system recognize the organ as your own so you don't fight it.

So the first benefit is where it failed the first place. It should protect against all type of rejection. So that's the main deal. The second thing is if you do not need immunosuppressants, then you're not exposed to all the potential complications, which where he had the second in a way. A shortcoming of her immunosuppression, which eventually took her life. So that's [00:06:00] what we are working on at Stanford.

Rachel Baker: And you're doing some pretty cool things. I rewatched your Grand Rounds presentation from a few years back, and you used the word chimera. I know a chimera is a fire-breathing monster with like a lion's head and a goat's body, and a serpent's tail. But I don't think you're actually creating those in your lab, unless I'm wrong. You totally could be. I just don't see the IRB letting you do that.

Stephan Busque: No, I don't do bench work research anymore. So it's interesting. So that emblem, which is a mythological beast, which represents a mixture of things, is actually the emblem of the American Society of Transplant Surgeons, but it represents having things from different people.

So actually, when I approach the patient, you know what example I use? It's not the chimera, it's the, um, tangelo, which is a chimera [00:07:00] between the Tangerine and the Pomello. I think it, it's less scary.

Rachel Baker: Less, yes, definitely less.

Stephan Busque: But immunologically, what it means in the context of tolerance, it's the mixture of two immune systems.

So the only way we have been able to get a patient off drugs or attempt tolerance, it was the mixture of the immune system. So it starts from the early research of Medawar in the fifties, got a Nobel prize, that you have this mixture. So this is all based on basically two immune system to get along, you need a process to do so. But that's basically the principle of the chimera. We are creating a chimeric immune system.

Rachel Baker: Cool. One name kept coming up. Who is Sam Strober?

Stephan Busque: Sam Strober. Very interesting story. So Sam Strober is the founder or the [00:08:00] inventor of the Stanford Tolerance Program.

Rachel Baker: Ah,

Stephan Busque: Yes, it all started with Sam. So Sam, he passed away two years ago at the venerable age of 81 years old.

But what is a bit off is that he was a practicing rheumatologist. So, oh, why did he spend all his research career trying to achieve tolerance and solid organ transplant? and also to reduce the burden of grave disease the hematology patient?

So you have to go back many, many years. And, um, I tracked this back. Sam was actually as a medical student working in the lab of Joseph Murray. So if that doesn't ring a bell, Joseph Murray is the plastic surgeon in Harvard who did the first successful kidney transplant between twin brothers, like mid 1955, and he received a Nobel Prize for this. So I think he planted the [00:09:00] seed in Sam's brain to make transplant better.

So then Sam went to Oxford, actually at the same time as Earl Wiseman at Stanford. So they both came back to Stanford and then they saw sometime's like pure serendipity. So. Sam met with another great Stanford pioneer, Dr. Kaplan, who is probably the father of modern radiotherapy.

He invented a treatment for the treatment of lymphoma, Hodgkin's lymphoma, which was called the total lymphoid irradiation. So instead of having the radiation given to the entire body and then your bone marrow will fail, it's only directed to the lymph node. So Sam work with Dr. Kaplan and eventually discover that this type of radiation was helping to create tolerance. So he developed, like in the mid-sixties, a protocol that combined the total lymphoid irradiation, which we can call [00:10:00] TLI, with some anti lymphocyte preparation that is commonly used in transplant. And those two things together, plus bone marrow cell from the same donor as the donor of the organ in the mouse, in the animal model achieve tolerance without immunosuppression.

Rachel Baker: Wow.

Stephan Busque: So he is the initiator, but he has built a big team. So as we mentioned, my academic interest in transplant is improvement of immunosuppression. So I work on new drugs, but what is better than no drug as a best immunosuppression? I was able to join that team 20 years ago.

So I'm part of a group including, you know, bone marrow transplant specialist, Dr. Lowky, Dr. Meyer and nephrology Dr. Scandling, radiotherapist, Dr. Happe, Dr. Shizuru— Sam would call us, we are the trialists. We are doing the trial. So he's the inventor and we are making it happen. So basically we work on translating [00:11:00] his research to the clinic and we've been in the clinic for 20 years in that field.

Rachel Baker: Awesome.

Stephan Busque: You know, at this point we have the largest experience in the world in that field.

Rachel Baker: Well, speaking of trials, you published a paper in the American Journal of Transplantation this past July. I'll put a link in the show notes for our listeners so they can give it a read. It was a phase three trial antigen matched living siblings. Can you tell me about this?

Stephan Busque: Yes. So I think this is a huge landmark. Now I have to backtrack a little bit to explain where it fits in our evolution of our, uh, research program. So. First you have to know a bit how matching works. So we all different, right? But some are less different. So me and my twin brother, we don't need immunosuppression. We can exchange, but that's quite unique.

Rachel Baker: Helpful in case you need a kidney.

Stephan Busque: Yes, we are each other's [00:12:00] organ bank, but so next is the people who are identical at the level of the genes that are more relevant to transplant. Okay? These are called the HLE, the human leukocyte antigen, because it's how the immune system work.

It was not built for transplant. It's how we find the difference between each other. So between siblings. Because you get these genes for your parent, you have 25% chance that between the brother and the sister, they have the same set of genes. So these are the patient that we are less likely to reject.

And if you do a bone marrow transplant, the less likely to have the opposite of rejection, which is the donor takes over. It's called graft source disease. That would, can also be as difficult or dangerous as a rejection. So we started with this group of patients because they were more like to have success and if something would happen, the likelihood to be salvaged for any complication.[00:13:00]

So we started this in 2005. Completed in 2016. So we used the protocol that we talked about, just translated from the animal to the human, which consist of the spatial radiation and some lymphocyte depletion. So reduction to favored engraftment. And we have done 29 patient and more than 80% of these patients, we were successful to get this mixed chimerism and to take them off drug.

So some now are off drug up to 17 or 18 years. So you get a transplant, you're no drug. In a majority of patient. So we are the developer with the RD developer. So we call these like the early phase, which is like phase one, phase two.

Rachel Baker: Mm-hmm.

Stephan Busque: The next step in progression is to do a randomized study. So is this something that anybody can do? Or it's only the specialist Stanford that can do it because they have been doing this for 20 years?

So a randomized study, [00:14:00] which means that you have people that come in, some get the treatment, some get the regular treatment. So it was conducted in 12 centers in the United States, and patient had the same criteria and they were basically given the Stanford recipe.

So it was done independently of Stanford but was based on our protocol. So exactly what we did at Stanford. And they had similar results.

Rachel Baker: That's great.

Stephan Busque: Yes, it's great because a phase three is the last phase before you can actually commercialize. So if it would be a drug. Then you go to the FDA and then it can be given to a patient at the pharmacy.

So this is more complex because it's a process. But basically the FDA adds some criteria to say, if you do this, this, this is the type of success we're looking for. If you meet this criteria, this can become a therapy for patients outside of research, so that's why it's a landmark. Because it has happened so the study met the criteria. [00:15:00]

So for us at Stanford, it means that we really went the full loop where it's bench to the clinic and now, which we rarely do at universal centers. So we saw our basically innovation going to the hospital near you. Okay. So basically to make it available not to people who can only travel to Stanford, and then we need to have research fund to have it.

It means that if a company would take this forward, it's a program that can be available to all patient in that segment. So, which is still a small number of patients. So this is what we call, we re-written the chapter one. Now we are still in the writing of chapter two, which is to address patient that are not as well matched. So we go from full match to half match and maybe eventually to even less matched than this.

Rachel Baker: Okay. So now I wanna [00:16:00] ask you about a patient that you had a few months ago because I don't think that they were as much of a match. Stanford successfully completed its first allogenic islet cell transplantation in a patient with type one diabetes, and it was a whole team effort.

It was Dr. Everett Meyer, who's, you know, the bone marrow person, uh, that you talked about earlier. It was IR’s, Dr. Avnesh Thakor, just a whole team coming together to do this procedure. The recipient and the donor, were they any kind of a match there?

Stephan Busque: Okay, so let me give you a big picture of this. Okay, so islet transplant, we're talking about pancreatic islet, right?

So this is the, the missing eyelet or the missing cells that the patient with type one diabetes have lost. So if you give the islet back, you should restore the sugar control and cure the diabetes. [00:17:00] So I do also full organ pancreas transplant.

Rachel Baker: Mm-hmm.

Stephan Busque: But we don't need the full organ, but that's very successful. So islet cell transplant is the ultimate more precision medicine approach to the cure of type one diabetes.

It has been not progressing very fast in United States for a couple of reasons. The main one is that in the United States, the FDA. Consider this not as a transplant. So the regulation to be more like, you know, like a kidney transplant. They say, well, you are putting those cells in culture and then it's become a drug. So the bar to be able to do this on a regular basis is very high and very expensive.

Rachel Baker: Oh, I see.

Stephan Busque: So that's kind of slowed down the progress of islet transplant in United States.

The second part is phase three trial, just like we talked about, the ultimate trial in islet cell transplant has been completed more than 10 years ago. [00:18:00] And one of the conclusions besides showing that it is efficacious is that most of the adverse events are related to the immunosuppression. So even the conclusion of the study is this will not become a large-scale therapy unless we have a more tolerogenic approach.

It's like calling us by name.

Rachel Baker: It really is.

Stephan Busque: So actually, we had people in the field saying that Stanford should get into this and see what you can bring to the table. So it's been a long, long process and actually it took us many years. First, you have to know that at Stanford and UCSF, we are a center of excellence in diabetes. There's like fantastic basic research and a lot of people who wanted this to happen.

Rachel Baker: Mm-hmm.

Stephan Busque: But the regulation is very difficult. So we are probably the only new islet cell transplant — and we're talking about allogenic — So allogenic transplant program [00:19:00] that has been approved in the last 15 years.

It was a bit difficult because you have the regulation. Then we got into COVID, so it was a lot of process development. What we wanted to bring is a bit similar to what we are doing with the kidney transplant, is to bring some donor cells along with the islets from our deceased donor.

Okay. So we're not gonna have a great match. Right. And we, we still need to develop a manufacturing process to get those stem cells. Mm-hmm. So, which we did. So basically, you take the bones that have the most bone marrow from the same deceased donor. You have to extract them and purify them. So that took some time.

But we get everything approved, approved by the FDA, the manufacturing until we were ready. We also did not want to reinvent the wheel in terms of islet cell preparation. And we have great colleagues at UCSF who have been doing islet cells transplant [00:20:00] for decades, and we were able to actually have a collaboration with them.

So, you know, the goal was if we go in this together. They provide the islet cells, we provide the bone marrow cells, and we can eventually write the protocol together. So, we still needed to start with the first case at Stanford to show that we are able to do this. So that's where we come, this team approach, where we have Dr. Thakor from IR, so he's pediatric IR, but his research is on RSL transplant.

Rachel Baker: Right.

Stephan Busque: So we had already people lined up to say, we want this, we are interested, we want this to happen. So we eventually identified a first patient. She was on the list for some time, and then one day a suitable donor was available and we were able to proceed.

To do this. So, the islets, the pancreas, was brought to UCSF, they prepared the cells, and we prepared the bone marrow. And then, uh, we all convene on a Sunday afternoon [00:21:00] to proceed with the infusion of the cells, which is relatively straightforward. So instead of a big operation that I can do, which is like, you know, uh, exposing the vessels and connecting the bowel, the artery, the veins. Dr. Thakor with one of his colleagues in radiology intervention, put a small needle in the liver. We push those cells in the liver and um, for them to sit there.

Rachel Baker: Mm-hmm.

Stephan Busque: And then we proceeded with our modified immunosuppression, and two days later, she received the bone marrow cells.

The idea is not to do the full chimera, but to get enough of these cells to tilt the balance into her immune system to accept the cells. The idea here was not to make her completely off drug, but minimize immunosuppression. So we're six months out.

Rachel Baker: Okay. How's the patient doing?

Stephan Busque: She [00:22:00] cannot stop smiling.

Rachel Baker: Oh, good!

Stephan Busque: She's so happy. Never had so much energy in her life. She's not completely off. I think she will probably come off of insulin at some point, but it's minimal dose. But she is 100% under the perfect range of control. Very good result. You have to understand that most of the time islet transplant, you require more than one infusion.

So to even hit the mark with only one infusion, it's less than 30%. So even for our first patient, with the help of our colleagues, I think we were able to be not at the beginning of the learning curve to position us as, uh, with the first successful patient. So this is very exciting. But we'll have to see how we can bring this forward because again, the limitation, so there's a company now that is under this requirement of the BLA that can offer [00:23:00] cells, but the financial ramifications still need to be sorted out.

Rachel Baker: Absolutely.

Stephan Busque: So this is, I hope a new beginning for islet cell transplant in the United States.

Rachel Baker: Very exciting. Well, that sound means that it is time for our lightning round. On each episode of Scrubcast, we ask each of our guests the same two questions, and the first one is, who is a surgeon you admire and why?

Stephan Busque: To me, a great surgeon is not only a great technical surgeon. He's a great doctor. Being a great doctor, I include the knowledge of medicine so well-rounded, good with the patient and the family, but I almost think this is like the standard. We should start with this.

Then the little something else that make the difference between the great surgeon and the one that you may remember and just [00:24:00] maybe because of my inclination on, you know, because of music or whatever is, I would say virtuosity when you see somebody that you say, well, that's another league.

It may be not necessary that we all like this, but if you see that in the OR, you know, it's like the OR used to be called the Operating Theater.

Rachel Baker: Mm-hmm.

Stephan Busque: It's a small audience, but we're still performers. You know, if I compare to sports, you know, as I remember in Montreal seeing a session where you had, uh, Roger Federer and Nadal and Novak at the same time

Rachel Baker: Sounds like a good match.

Stephan Busque: Yes, but the fineness of Roger Federer kind of stands out—that thing of virtuosity or you know, the je ne sais quoa, the Ujah Wang of piano. So to me, that attracts me. So I would put — if you want names — I would put Carlos Esquivel there. Mm-hmm. And I put also my original mentor, who passed away this year, Pierre Daloze.

There are probably others, but this is something that the little on top of [00:25:00] what you expect from a great surgeon.

Rachel Baker: I love that. I, I totally understand what you're saying about the virtuosos of the operating theatre. Yeah. The second question we ask is, what is the best advice you have received in 10 words or fewer?

Stephan Busque: We'll have to count the words. Let me, give me two seconds.

Okay. I think this is the best advice that was given to me. By a surgeon before I moved to the United States. Okay? He said, Stephan — I'm not gonna count that word — Starting at a new place, put money in the bank first. What he meant, and I also give that advice to every finishing fellows, it is build your reputation first. So before you take difficult cases, okay, nobody knows you. You have to build your reputation. You don't take too high risk upfront. This patient [00:26:00] needs to be treated, but you may say, Hey, I'd like your help first. And you build your reputation and then you can expand on the difficulty of cases.

Rachel Baker: I like that. Very nice. A final question of the lightning round. What is your preferred or music

Stephan Busque: To the despair of many, I don't know anything that has been composed after 1940. Okay. Classical music. And it's not a despair because I have a lot of empathy, so I'm not making any, everybody suffer, but music in the OR, there's still some criteria here. One: it is still in the background for safety.

Rachel Baker: Mm-hmm.

Stephan Busque: It cannot be too loud. It cannot be annoying. It cannot be stressful. The idea is to reduce the stress of people can function at their level. You need to be able to hear the bells and the alarm. So we have to [00:27:00] be, so that has to be like it still does not trump safety.

Okay. Then I am passionate as much about classical music and particularly the piano repertoire. Then surgery. So this is me. Okay. So I will not operate well, uh, with music that I'm not passionate about. So I would say classical music, but not to, I mean, very appealing, easy for everybody or nothing. So if I feel that this is gonna annoy anybody, I'd rather have the music in my head.

So I can tell you a little anecdote about this.

Rachel Baker: Hmm.

Stephan Busque: One of my former fellows was Dr. Gallo, who you probably know.

Rachel Baker: Yes!

So her preferred music is rock heavy metal. Okay. So not exactly in line. So what I developed a selection with more like easy music, like, you know, the season of Vivaldi, a few Easy [00:28:00] Mozart, whatever, which I called the Gallo suite.

And then, you know what, after a while, everybody wanted me to put the Gallo suite on

Rachel Baker: Nice. I like that. I like to listen to Bridgerton music. It's classical takes on popular modern songs.

Stephan Busque: Yes. Actually, I like it. Sometimes it comes in the OR. I was like, are we listening to the Bridgerton?

Rachel Baker: Yep.

Stephan Busque: But I kind of like it. You know, I would probably it just because I don't have the time to discover other type of music, but when my son comes home, I would just take his music selection, bring it to the OR and I would be fine.

Rachel Baker: Perfect. Well, it has been such a pleasure chatting to you. Before we go, one last question: What is next for Dr. Busque?

Stephan Busque: So next, I think it's all putting it together, this 20 years of experience in tolerance, and I think we are in an acceleration phase. [00:29:00] So chapter two is almost written with the half match. We are going to do open liver transplant tolerance. We have already protocol for disease donor transplant, so I think in the next five years we should see significant improvement in that field.

Rachel Baker: Awesome. I'm looking forward to every minute of it. Thank you so much for talking to.

Stephan Busque: My greatest pleasure

Rachel Baker: …and thank you to our listeners for tuning into this episode of Scrubcast. Until next time, stay sharp.

If you like Scrubcast, we hope you'll tell your friends and subscribe wherever you get your podcast. Scrubcast is a production of Stanford University's Department of Surgery. Today's episode was produced by Rachel Baker. The music is by Midnight Rounds. And our chair is Dr. Mary [00:30:00] Hawn.