Promising research results from the Duke Pediatric Kidney Transplant Program created the clinical framework for a large national NIH-funded trial of a novel therapeutic immunosuppressive drug combination to improve allograft function and clinical outcomes in children and young adults and to prevent development of donor specific antibodies, a common cause of graft failure among adolescents.

The NIH investigation is based on a proof-of-principle concept developed and piloted by the Duke Pediatric Transplant team led by Eileen Tsai Chambers, MD, medical director of the Duke Pediatric Kidney Transplant Program.  The team includes researchers, nephrologists, and surgeons collaborating to identify new immunosuppressive combinations that target biological processes that contribute to development of de novo donor-specific antibodies (dnDSAs) and related allograft failure.  This team was the first to use belatacept/sirolimus de novo in children.

“This national trial will  build upon these exciting pilot results and will assess the efficacy of infused belatacept-based immunosuppression combined with sirolimus maintenance therapy,” Chambers says. The combination proved effective in the initial Duke study.

The Duke team demonstrated the successful use of the infused belatacept-based immunosuppression therapy in two adolescent patients who underwent kidney transplants. The successful pilot has since expanded to include five children

Several studies have shown that children and adolescent transplant recipients have a higher risk of forming dnDSAs, which are difficult to treat and contribute to allograft failure. Many of those failures are related to the presence of dnDSAs.

Chambers will serve as the lead clinical trial chair; she is also the principal investigator for the Duke site. Since joining Duke in 2016 she has focused her research on innovative ways of improving clinical outcomes for pediatric kidney transplant recipients. These include developing biomarkers, overcoming medication nonadherence, and implementing calcineurin-free treatment regimens.

The treatment is modeled on the regimen used for adult patients undergoing kidney transplant, but drug combinations and delivery systems are customized. The trial is the first to test the use of belatacept-based immunosuppression in eligible children, Chambers says. In order for children to be eligible, they require previous exposure to the Epstein-Barr virus. Otherwise, they are at risk of developing post-transplant lymphoproliferative disorder, one of the highest risk complications following transplant.

A key innovation in the trial is the use of urinary biomarkers yielding precise analyses of the implanted organ’s function. Urinary biomarkers allow specialists to gather data on allograft performance more frequently following transplant without biopsies.

“This is an important differentiator because we want to find new, non-invasive ways to help us know if a pediatric patient might not be compliant, or if the graft is in trouble, or if we can intervene to solve a problem that is developing,” Chambers says.

The randomized control trial comparing the belatacept/sirolimus combination to the standard-of-care (tacrolimus/mycophenolate mofetil) will be conducted by 14 centers over seven years; Boston Children’s Hospital will serve as the administrative center of the trial. “The grant is major coup for this patient population and for our program,” says Chambers, noting that it was the only pediatric trial supported by the NIH during recent funding.

Goals of the trial:

• Determine whether this new combination of belatacept with sirolimus maintenance therapy will prevent the development of dnDSA while maintaining optimal graft function.
• Examine whether longitudinal monitoring of urinary biomarkers can differentiate low and high risk patients at risk for subclinical rejection.
• Assess the impact of belatacept/sirolimus on targeting alloimmunity, enhancing immunoregulation and preserving pathogen-specific immune responses in pediatric recipients.

The NIH trial has the potential, Chambers says, to create changes in the immune systems of pediatric kidney transplant patients. “We see the possibility with this combination of drugs that the therapy allows for immunoregulation, which means that potentially the patient’s immune system could become reprogrammed and less immunoreactive,” she adds.