Advances in immunosuppression research may bring transplant patients closer to “one organ for life”

There has been little innovation in immunosuppression therapy for organ transplant patients over the past 30 years. The standard of care immunosuppressive drugs used post-transplant have been shown to reduce the risk of organ rejection, but they are also associated with potentially toxic side effects. While healthcare professionals accept this risk-benefit profile because there are no alternatives, most agree that there is a critical need to improve strategies to reduce the risks associated with immunosuppressive regimens following transplantation.

A new option that could address the limitations of existing therapies would represent a major advance in care for thousands of patients and potentially increase the functional life of transplanted organs, bringing the field closer to the ultimate goal of “one organ for life.”

The history of organ transplantation

Since the first human organ was transplanted successfully in 1954,¹ advances in surgical techniques, organ procurement, donor matching, therapeutic strategies, and other key areas have helped to improve outcomes related to transplanted organ longevity and, most importantly, patient survival. The risk of organ rejection and mortality was very high until 1983 when cyclosporine, a calcineurin inhibitor (CNI), was introduced and when used as the cornerstone of a daily immunosuppression regimen following transplantation, resulted in a dramatic improvement in graft survival.²

The next significant advance in immunosuppression came in 1994 with the introduction of tacrolimus,² another CNI, which today remains the first line therapeutic to reduce the risk of organ rejection. Tacrolimus, while effective, has been shown to be toxic to kidney cells and is associated with side effects including risk of diabetes and hypertension – ironically, the very conditions that lead most patients to require a kidney transplant in the first place.^3,4

An ongoing challenge in kidney transplantation, which is the most common type of transplant procedure performed globally, is that an implanted kidney will typically fail within about 10-15 years using currently available options in immunosuppression.⁵ The fact that transplant patients are on average in their 50s means that most of them will ultimately need a second or even third transplant procedure during their lifetime. Moreover, with the limited number of organs available, many people die across the globe on their national transplant waitlists. In the United States, for example, about 5,000 people in need of a kidney transplant die each year while waiting for a kidney that never comes.⁶

Efforts to encourage more people to become organ donors continue simultaneously, as immunosuppression research advances with the goal of helping donated organs remain healthy and viable for much longer post-transplant and reducing or eliminating the need for repeat procedures. As a result, innovation in immunosuppression therapy is positioned to both improve care for transplant recipients and help expand the existing organ supply to make this option available to more patients.

The next wave of innovation: Targeting the CD40L pathway

In recent years, important advances in immunotherapy research have targeted a pathway known as CD40 ligand, or CD40L (also known as CD154), a protein shown to play a central role in immune system activation and controlling inflammation. Research has shown that, by blocking CD40L, we may be able to inhibit or “turn off” multiple co-stimulatory receptors, including CD40 and CD11, key components of how immune cells communicate with one another. Inhibiting CD40L is also shown to increase polarisation (i.e., activation) of lymphocytes into regulatory T-cells (or “T-regs”), a specialised subpopulation of T cells that act to suppress the body’s immune response.⁷ The central role of CD40L signalling in generating pro-inflammatory responses makes it a highly attractive candidate for therapeutic intervention in the protection of transplanted organs and prevention of transplant rejection. Results from prior studies demonstrate that targeting and blocking CD40L has the potential for better efficacy and improved safety, including reduced risk of diabetes, hypertension, tremors, and other side effects associated with standard-of-care CNIs, such as tacrolimus.^3,4

A novel IgG1 anti-CD40L antibody, called tegoprubart, is the first such antibody with high affinity for CD40L to enter clinical trials for patients who receive solid organ transplants, including kidney transplant, and has yielded promising data thus far. In a Phase 1b trial, results from 11 participants who underwent kidney transplantation showed that treatment was generally safe and well tolerated. There were no cases of hyperglycaemia, new onset diabetes, or tremor commonly seen with CNI treatment and no cases of graft loss or death. Results also showed that after 90 days treated patients had kidney function, measured by mean estimated glomerular filtration rate (eGFR), at levels approximately 40% above the historical averages seen with tacrolimus.

While inhibition of CD40L has shown it may play an important role in immunosuppression in kidney transplantation, it may also have applications in other types of allograft (i.e., transplanting an organ from one human to another) transplant procedures. More recently, this mechanism of action has also demonstrated that it may be a promising option in xenotransplantation (i.e., transplanting an organ from an animal to a human). In September 2023, for example, surgeons at the University of Maryland Medical Center performed the second-ever transplant of a genetically modified pig heart into a human, using a novel immunosuppression regimen of an anti-CD40L antibody (tegoprubart) combined with conventional anti-rejection drugs.⁸ More recently, in March 2024, a team at Massachusetts General Hospital performed the first-ever xenotransplant of a genetically modified pig kidney into a human, which also included tegoprubart as a component of the patient's immunosuppression regimen to prevent transplant rejection.⁹ Xenotransplantation is an exciting area of research that is still in nascent stages, but support for these types of procedures, which could play a major role in helping to address the donor organ shortage, must also involve improved strategies in immunosuppression that are able to extend organ viability and longevity.

A comprehensive approach to address the organ shortage

While there has been an increased focus on immunosuppression research in organ transplantation in recent years, efforts to encourage more people to become organ donors should continue. However, results in recent years indicate that other strategies will also be essential to make enough organs available for all patients who need them and to reduce the risk that patients will need a repeat transplant when organs fail. By identifying and advancing novel strategies in immunosuppression, including targeting the CD40L pathway, we may be able to help organs remain functional for longer – perhaps throughout the natural lifespan of each recipient. Concurrently, options in xenotransplantation could help us develop new potentially viable sources of organs. With a more holistic approach that embraces the full range of opportunities to increase the global organ supply and to improve outcomes, we can deliver a long-term solution to the critical shortage of available organs in the years ahead.