A Duke Health clinical trial may lead specialists toward improved donor kidney matching for highly sensitized patients who often wait years with little chance of finding an organ because of antibodies to human leukocyte antigens (HLA).
In sensitized patients, HLA antibodies increase the risk for transplant failure as a result of antibody-mediated rejection (AMR), the most common immunological cause of transplant failure. The promising trial, which has concluded its first phase, evaluates a combination drug therapy that may reduce the risk of graft failure by modifying B-cell lymphocyte memory.
For many years before the clinical trial, Duke has been a national leader in identifying organ matches for sensitized patients with HLA antibodies. Stuart J. Knechtle, MD, executive director of the Duke Transplant Program, says the transplant program prioritizes efforts to find matches to help more patients and utilize more donor organs. National transplant organizations have also prioritized matching for sensitized patients.
Knechtle is principal investigator of the ADAPT trial, which concluded its first phase with positive outcomes. His laboratory developed the ADAPT trial premise based on a nonhuman primate study. Those results were published in 2019 in the Journal of the American Society of Nephrology. Knechtle and colleagues have studied HLA sensitization for the past 15 years; Duke researcher Jean Kwun, PhD, has played a key role in the nonhuman primate investigations that led to the clinical trial approval.
Long waits for donors, greater risk
The average wait for a donated kidney may stretch three-to-five years; 85% of patients on national transplant waitlists need a kidney. For those who are sensitized, the wait is much longer — if a match can be identified. Most patients become sensitized as a result of pregnancy (not every pregnancy), an unsuccessful previous transplant, or a blood transfusion. Some other patients become sensitized as well, but the cause is not fully understood, Knechtle says.
“Because of our extra efforts to identify these matches, the organs we evaluate are often considered to be of lesser quality or have abnormal anatomy or injuries that would make them untranslatable by other centers,” Knechtle says.
“Many of these patients who need a transplant are highly sensitized to 99% of potential donors,” Knechtle says. “That means the patient is going to wait an indefinite number of years for transplant. Unfortunately, this means that many such patients will not find a match in their lifetime. It’s an immunological conundrum unrelated to their behaviors or choices.”
To facilitate a solid organ transplant evaluation for your patient, please refer to our transplant referral forms.
Trial design, early results
A key clinical goal of the ADAPT trial is to determine if treatment by two drugs — carfilzomib and belatacept — can help desensitize patients by reducing the number of plasma cells that create antibodies. Four of the five Duke patients enrolled in the initial phase were transplanted successfully and have functioning grafts, Knechtle says. None has had a rejection episode to date.
The trial is being performed in conjunction with a related investigation known as ATTAIN conducted at the University of California-San Francisco Medical Center. Both trials will enroll 15 patients during the three phases.
The trials are funded by the National Institute of Allergy and Infectious Diseases and operate within the Immune Tolerance Network program, an investigative consortium that conducts clinical and associated mechanistic clinical research.
“The trial has been successful to date, but we have only worked with five patients during the first phase,” Knechtle says. “They have all tolerated the treatment well, and we’re thrilled that four out of five have been transplanted. That’s a very high success rate for a group of patients who have clinical challenges related to sensitization that makes the process extremely challenging. It’s especially rewarding to see that none have had rejection so far.”
The leadership of the Duke clinical trial team includes nephrologist Scott L. Sanoff, MD, MPH, sub investigator and patient manager, as well as Kitza Williams, RN, FNP, the clinical trial study coordinator. Another Duke researcher, Shengli Song, PhD, has developed a sensitive assay to detect the number of memory B-cell lymphocytes in patients — a key element of the investigation, Knechtle says. An Emory University researcher, Eun Hyung Lee, PhD, has also advanced the research by measuring HLA-specific plasma cells involved in sensitization and desensitization.
