Will We See the End of Immunosuppression?

Two transplant doctors, Dr. Fox and Dr. Martinez talk in hospital hallway
Dr. Mercedes Martinez and Dr. Alyson Fox

Organ rejection is an ever-present complication in transplant work. Take, for example, the chance of rejection in kidney transplant patients: Even with immunosuppressive therapy, 10 to 20 percent will experience at least one episode of rejection in their course of care. For many patients, the need to take immunosuppressive drugs for the rest of their lives—with the prospect of rejection looming—makes transplant feel like less of a “cure” for their disease and more of a step on a lifelong path.

That’s why immune tolerance is, to put it plainly, “the holy grail” of transplant, says Sumit Mohan, MD, the chair of clinical research for kidney transplant. While eliminating rejection and immunosuppressive drugs may seem a far-off prospect, it would alter the trajectory of the field and, in turn, improve patients’ lives—and that's exactly why such passionate clinicians and researchers chase it.

“We have a very robust clinical research program where we participate in all sorts of multi-centered drug trials,” says Lloyd Ratner, MD, director of the kidney and pancreatic transplant program. “We've done a lot of work with studies with drugs to try and overcome delayed graft function, get the kidney to function earlier. We're also now one of the few centers in the world that's doing a tolerance trial.”

That any of these trials are possible is due to the efforts of researchers at the Columbia Center for Translational Immunology (CCTI), led by Megan Sykes, MD, and David Sachs, MD, who pinpointed a mechanism in the immune system that allowed kidney transplants to be accepted without the need for lifelong immunosuppressive therapy. 

The implications are thrilling: This is one major step towards eliminating costly and potentially toxic lifelong medications and improving transplantation success. Considering that donor kidneys are a precious resource, ensuring the success of each transplant would be revolutionary.

The groundbreaking research focuses on a mechanism involving a set of T-cells that seem to react to donor tissue (appropriately named “donor-reactive T cells”). The number of these T-cells increases in donors who reject the organ and disappears in those who accept the organ without the need for immunosuppression. By tracking and studying the presence of these cells in donors, we can better understand who’s at risk for rejection. 

In further study, it appears that patients who underwent a combined kidney and bone marrow transplant were more likely to accept the transplanted organ without the need for immunosuppression. The addition of bone marrow transplantation seemed to induce tolerance to the transplanted organ, a mechanism now understood to be mediated through the decline of donor-reactive T-cells. 

However, patients who receive bone marrow for tolerance induction could also face very serious immunological side effects, including a condition called chimerism transition syndrome, which can cause loss of the transplanted organ and even death, limiting how widely usable this technique would be. That’s where the promise of the PANORAMA trial comes in. 

“The PANORAMA trial is a tolerance study investigating the use of a new drug (siplizumab) in the induction of tolerance after kidney transplantation,” says Josh Weiner, MD, transplant surgeon and lead investigator of the study. “Our objective is to see if we can reduce and/or completely stop the anti-rejection immunosuppression medications that patients normally take after transplant while avoiding chimerism transition syndrome.”

The first patient was enrolled in the PANORAMA trial in January 2023 and later underwent a successful combined kidney and bone marrow transplant.

“Not only did we successfully achieve transient mixed chimerism, but the patient is the first in the world to do so without experiencing chimerism transition syndrome,” says Dr. Weiner. “My hope is that we can complete the PANORAMA trial here at NewYork-Presbyterian / Columbia and expand it to patients who are even more genetically mismatched from their donor. This would have a huge impact on the field of transplantation in the future.”

Given the exciting success we’ve begun to see in the PANORAMA trial for kidney transplantation, we're working on expanding similar tolerance protocols in other areas, starting with liver transplant

“We have a new collaboration with the liver transplant team where we're going to be exploring aspects of the immune response in the setting of autoimmune liver disease and autoimmune liver disease patients who get liver transplants,” says Dr. Sykes. “And we're going to be collaborating on this new trial for a drug that we think might do better at preventing autoimmune recurrence.”

There’s still a lot of groundwork to be laid for liver transplant tolerance, but Alyson Fox, MD, director of the living donor liver transplant initiative, sees significant potential benefits in developing a living donor liver tolerance protocol, especially given the “lifelong problem” and side effects that anti-rejection immunosuppression meds can cause patients.

“When patients forget to take them, they can have rejection, which can be life-threatening in some cases,” explains Dr. Fox. “I would say that, in some ways, immunosuppression has limited our ability to do our best for people. I think induced tolerance could be the next great frontier of transplantation.”  

This is particularly true of pediatric patients. “When you get your liver transplant at one year of age or less than a year, that means that your life is going to be determined by the immunosuppression and its side effects,” says Mercedes Martinez, MD, medical director of the intestinal transplant program. “Having protocols that allow us to induce tolerance so the patient doesn't have to be on immunosuppression for a long time.”

Elizabeth Verna, MD, MS, who heads up clinical research for liver transplant, notes that Columbia enables this forward-thinking approach to address transplant’s biggest problems by maintaining strength across specialties and research. No one doctor or organ group is the program’s lone hero; each provider is at the forefront of their specialty, and together, we can move the needle on major challenges in transplant. “That's one of the reasons why we can do innovative immunosuppression approaches, because we have the expertise of people in other organ systems that are doing things in a different way,” says Dr. Verna. 

It’s difficult to understate the impact of achieving immune tolerance, and current research into the kidney and, next, the liver is bringing us closer to changing our field forever.  “Innovation grows out of our clinical strength,” adds Dr. Verna. “Across all of the organ systems, we have some of the most well-respected doctors and surgeons in the world thinking, what are the major problems that need to be solved through research? What are the major issues that we're not serving our patients well?” 

 

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