Xenotransplant and the Future of Transplantation

On January 10th, CareDx brought together Dr. Robert Montgomery, Transplant Surgeon at NYU Langone Health and Dr. Chris Larsen, Transplant Surgeon at Emory University to discuss the future of xenotransplantation. Dr. Montgomery and his team recently performed the first investigational transplant of a genetically engineered pig kidney into a brain dead human recipient. During the conversation, the physicians discussed Dr. Montgomery’s work, the recent cardiac xenotransplant at the University of Maryland, the regulatory pathways for xenotransplant, and the role of current and experimental immunosuppressive drugs in making xenotransplant a reality.

What’s Driving the Interest in Xenotransplant?

Dr. Robert Montgomery (RM): The problem we have right now in transplantation is that we just don’t have enough organs available – about half of the people who are waiting die before they get a transplant. Everything that we’ve been doing to try to increase the number of organs available, it’s like trying to improve on a failing paradigm. I sort of think about it as like fossil fuel –  you can make it cleaner, you can improve the efficiency, but it’s never going to be sustainable. So xenotransplantation is like the wind and solar of organ availability. It would provide us with an unlimited source of organs so that anyone who needed one could have one.

How did You Identify the Patient who Ultimately Received the First Genetically Engineered Xenotransplanted Kidney?

RM: There was a donor where the family had consented to donation of organs. But they were unable to place those organs. I explained what we were planning on doing and that this was an unusual thing. They probably hadn’t heard of xenotransplant before. But they immediately felt like it was something that their loved one would’ve wanted because she was a very caring individual.

Why Were Pigs Chosen as the Species to Use for Xenotransplant?

RM: First of all, pigs are relatively easy to genetically modify. Also, their organs are roughly the same size and weight as humans’. In the first case, there wasn’t an immediate hyperacute rejection of the kidney. In fact, in this genetically engineered kidney that we put in, we didn’t see any significant evidence that there was even a microscopic cascade of injury that was happening in the kidney that we might not have seen by looking at the kidney or measuring the urine output.

It tells us that a pig kidney can be transplanted into a human without an immediate rejection and function normally for several days. Those two things give us the confidence that we can move this out of the non-human primate into human trials.

What are the Next Steps for Kidney Xenotransplant?

RM: We did another kidney in a recently deceased recipient and got almost exactly the same outcome, excellent function. We got a doubling of the eGFR after the kidney went in and really no evidence of antibody-mediated rejection on the biopsies that we did. So our paper is out for peer review right now.

Next we want to replicate what we just did, and extend the study for a longer period of time. In order to do that, we’re going to have to get more input from medical ethicists, the legal community, and religious leaders. Based on where we are, I think we’ll probably be ready within the next year or two to move to the first in living human trials.

Were You Surprised by the News Coming Out of the University of Maryland of the First Heart Xenotransplant?

RM: I had said a year or two until we would move into living humans, and it ended up being four months. So I think everybody was stunned by what happened at the University of Maryland [with the first xenotransplant into a living human]. It’s an amazing leap forward and a really extraordinary development.

Moving Forward, are we Going to Start Xenotransplantation in Patients Who are not Transplant Candidates Otherwise? Is That the Most Logical Place to Start?

RM: No, I would say the most logical place to start would be sponsored clinical trials that go through the regulatory process. But again, it’s going to be difficult because there are patients who are going to die for lack of any other options over the next months to years before a clinical trial starts. Because of this, I’m sure people are thinking about following the Maryland approach – they were able to get an emergency use IMD from the FDA to do this work. It involved experimental drug and experimental pump, multiple devices and drugs and tissue transplants that aren’t approved.

In Which Organ do You Think Broad Use of Xenotransplant Will Happen First?

RM: The challenging aspect of xenotransplantation in heart is there’s no backup or bailout if things start to go sideways. Now as a bridge to heart transplant, that’s an interesting concept. But the truth is that the management of heart failure has gotten so good that it’s really hard to identify a population that you couldn’t manage, with an assist device. For kidney, the thing is you can always just take it out. You do have a bailout there. I think livers and lungs we are just not anywhere near where we are with those two organs.

CRISPR has Changed the Game in Xenotransplant. Could You Weigh in on Single Gene Knockouts vs. Combinations?

RM: I think that different organs are probably going to require different levels of intervention in terms of knock-ins and knockouts. There’s good evidence from the primate data that kidneys can do pretty well with fairly minimal changes in the genome. My feeling was always “how is the FDA going to regulate a 10-gene pig that is a triple knockout?”. The knockouts one thing, but the trans genes, the expression of those trans genes is highly variable within the tissue of an individual pig and between pigs. So you can imagine having a drug, which is what the FDA spends most of their time regulating, where every dose that you give is a different dose. Not only that, but it’s 10 drugs in one vial. There’s going to be variability between each vial. It’s a hard thing to regulate.

In kidney, the longest surviving primates with kidney transplants, which is almost out two years, they’re the triple knockout, the three glycan knockout pigs. There’s no trans genes or anything. Alpha gal is the most important barrier at least for preformed antibody. So we’ve thought that that was probably the simplest thing to move forward with. Then the data that was generated at Columbia about adding a thymic transplant to the kidney is very compelling. So that’s the pathway that we’ve been moving in.

The other thing is that the FDA already regulates the gal safe pig because it’s used as a food source for people of hypersensitivities to alpha gal and meat. It is also approved potentially for pharmaceuticals. So again, better pathway from a regulatory standpoint. So that’s how we’re moving forward.

What are Your Thoughts as You’re Planning Out Your Trials as to Whether or Not to Use Standard Immunosuppression?

RM: The amino acid variation between pigs and humans is orders of magnitude greater than between two humans. So there’s a potential for reactivity to a lot of epitopes, but I think that we do have some really powerful ways of managing a human immune system. We have a lot of experience with it. I was in a room recently with all the leading people in this field. Everybody agreed that you needed to have anti-CD40 or anti-CD40 ligand. The problem is there’s no drug that has been approved (of course, we know that there’s a history of failure here). So that is a challenge, but I think the FDA is really open to including that in the first trials without having a label beforehand. I also think we’re going to use belatacept because that seems to help with the nephropathy that has been seen in the primate. It seems to reduce proteinuria.

I think at least in these early trials, it’s going to be a lot of immunosuppression that we’ll be using.

Going Deeper on the Topic of Immunosuppression, What are Your Thoughts on Co-stimulation Blockade, Anti-CD28 and CD40?

Dr. Christian Larsen (CL): CD40, CD28. Boy, we spent a lot of time thinking about this. Our first work in our lab was in the early nineties. So we’ve been at this for a long time. I remember Jim Burdick asked me in Kyoto at the transplant meeting how long I thought it would take to get it to the clinic and in clinical practice. Being completely naive, I kind of thought about five or seven years. That was obviously incredibly wrong.

So I’ll loop back to belatacept in a minute. But the CD40 pathway, I think so much work has been done to de-risk them. I feel quite good about that, the thromboembolic I think is likely just taking off the table by good science and rigor. I do think that both sides of the pathway are potentially good targets. But I have to say that I think the evidence on targeting the ligand is pretty compelling. I think there was a lot of evidence of greater efficacy at different levels. Mandy Ford’s done some nice work suggesting alternative receptors for the CD40 ligand. Now we’re going to bring it to the test, there are a couple of candidates that are about to embark on trials or in trials.

So I would hope that there’s a path to safe approval and there are other targets trying to explore in rheumatoid arthritis. That helped us with the development of belatacept, to have a companion set of trials in autoimmunity, because we leveraged a lot of that. So I feel like we’re pretty well-positioned to explore how to use those drugs. I do think the combinations are good. I do think the CD28 pathway blockade targeting the receptor might have advantages. We’re poised to do a trial that’s taken awhile to get through the FDA and COVID hurdles.

But Lulizumab is one of the domain antibodies that blocks CD28 while they reject, it’s got a trial in it as well. That may spare TRegs. That may have advantages. It’s got to get through the path to approval to be useful. So I think because of the autoimmune work, I think it’s probably reasonable to include them in xeno experiments. I think that it’s quite likely that they will help.

What has Been Your Experience with Belatacept?

RM: Belatacept has made a gigantic difference for us at NYU. Because we import a lot of organs, a lot of kidneys from other parts of the country that have been turned down. Early conversion of some of these kidneys that end up with a creatinine of 2.2, 2.3 after a month to belatacept and then really low calcineurin inhibitor levels has just been revolutionary for us to get those patients through and get additional years out of those kidneys.

CL: I track all my patients annually and have these reminders to look up so-and-so’s labs. So today was 20-year follow up for one of the first patients in the belatacept trials. He’s been on every other month follow-up for 20 years with rock stable function. We’ll hit probably about 2000 patients on belatacept. We’re kind of an outlier. We use it as our standard of care. We use tacrolimus with it. We are on three to five [months] of tacrolimus, and then wean off. I do think that getting those tacrolimus levels really low can be an advantage for recovery of renal function.

Our mindset though is that we’re doing it not to improve anything in the short term. Although I do think it does improve recovery of renal function, not delayed graft function ”DGF), but recovery of GFR over months. But our focus is really on long term outcomes and getting as many people off calcineurin inhibitors (CNI), with the goal of avoiding CNI toxicity and preventing donor-specific antibodies (DSA), which I think it does particularly well. It’s cumbersome, it’s expensive. We’ve done a randomized trial now. Our goal is to get as many patients on every other month belatacept as we can.

We had 80 patients in the first trial, and that’s held up now with follow up. So we’re instituting that selectively as standard of care. I think there are many key pitfalls that happen to get that drug. We know production, we know other things. But I think we found how to use it. We’re pretty happy with it.

Do Pharmacodynamics Support Every Other Month Use of Belatacept?

CL: Well, it depends. There still is some receptor occupancy, So what we don’t know is what receptor occupancy do we need? So I guess at this point, I wouldn’t work toward receptor occupancy. I would work toward clinical effect. But again, the long term follow up from the original trial has been quite stable.

The other that we’re pursuing is abatacept subcutaneous, which I think has potential as well. I think we were part of the pointing toward belatacept with our non-human primate studies. As we pointed out, those are small numbers. Then you make decisions based on small numbers of animals. But because belatacept was unavailable, we converted nine patients to abatacept when it was unavailable and not immediate peri-transplant. But it looks like you can get stability there too, which might get around the logistical issues.