ETC Investigators Work Towards Broader Application of Costimulation Blockade-Based Immunosuppression
In the biochemistry of transplant immunosuppression, costimulation blockade works to obstruct the second signal T cells need to trigger the immune response that can ultimately reject the transplanted organ. Emory Transplant Center (ETC) surgeons and immunologists Christian Larsen, MD, DPhil, and Thomas Pearson, MD, DPhil, played a pivotal role in advancing the therapeutic potential of costimulation blockade when they participated in the development of belatacept, a second-generation costimulation blocker that is a less-toxic alternative to calcineurin inhibitors (CNIs), the current standard of immunosuppression.
After belatacept was approved by the FDA for kidney transplant recipients in 2011, it was shown to cause significant reductions in mortality and kidney allograft loss in a worldwide Phase III clinical trial published in the New England Journal of Medicine in 2016 — Dr. Larsen and UCSF transplant specialist Flavio Vincenti, MD, were lead authors of the study. However, the investigators also reported that belatacept-treated patients had a higher rate of acute rejection immediately after transplant (in most cases, the rejection was successfully treated with drugs and did not lead to graft failure).
"Despite belatacept's proven benefits, its widespread use has been limited due to these higher acute rejection rates, as well as recent unavailability due to production shortages because of changes to its manufacturing process, and logistical challenges as a result of intravenous infusion requirements," says ETC kidney/pancreas transplant surgeon and immunology investigator I. Raul Badell, MD. "But my ETC colleagues and I are continuing to pursue optimization of the clinical use of belatacept to extend the benefits of less-toxic immunosuppression to more transplant recipients and improve long-term kidney transplant outcomes."
Most recently, Dr. Badell is the lead investigator of a prospective, randomized clinical trial at the ETC that is comparing eight-week dosing intervals of belatacept to the standard monthly dosing schedule in stable kidney transplant recipients, 166 of whom are enrolled into the study. After 12 months of administering the dosages, Dr. Badell and his team will analyze and publish the results.
"We anticipate that the data will show that decreasing the dosage of belatacept provides the same protection to the kidney transplant from rejection and improves patient and provider convenience, minimizes the cost of long-term immunosuppression, and reduces the risk of infectious complications by safely transitioning patients to half the immunosuppressive burden over the lifetime of their allografts," says Dr. Badell. "Studies like these could help to reemphasize the efficacy of belatacept."
ETC investigators are also interested in developing alternatives to belatacept that offer similar levels of lowered toxicity compared to CNIs. Dr. Badell was first author of an ETC study published February 15 in the American Journal of Transplantation that documented the successful use of the first generation costimulation blocker abatacept, the predecessor to belatacept, in kidney transplant recipients. Abatacept is commonly prescribed to treat autoimmune disorders such as rheumatoid arthritis and psoriasis, but has not been used in the clinical setting to prevent transplant rejection. While abatacept and belatacept have many similarities, abatacept has the potentially significant advantage of being administrable as a subcutaneous injection, removing the logistical barrier that can be caused by the required IV infusion of belatacept.
For the study, Dr. Badell, senior author Dr. Larsen, and their ETC colleagues reported on nine patients that were converted to subcutaneous injection of abatacept as a rescue immunosuppressant shortly after transplant due to CNI intolerance and the coinciding unavailability of belatacept. After receiving the drug for a median duration of 82 months, the patients experienced successful allograft salvage and 100% patient and graft survival (median 115 months).
"We observed stable, long-term renal allograft function, only one cellular rejection episode, and no clinically apparent protective immunity concerns," says Dr. Badell. "These findings suggest that future clinical studies using abatacept either de novo or as conversion therapy in transplant recipients should be considered."