New CAR T-Cell Therapy Enables Transplants in Hard-to-Match Kidney Patients

Highly sensitized kidney transplant candidates have extremely high levels of anti-donor antibodies that block matching and prolong dialysis. These patients face long wait times and increased morbidity because compatible organs are rare and standard desensitization often fails. Transplant programs need options that reliably lower pathogenic antibodies without prohibitive toxicity. To help address this challenge, researchers have now used chimeric antigen receptor (CAR) T‑cell therapy to reduce antibody burden and enable transplantation in patients who were previously considered nearly impossible to match.

Investigators at the Perelman School of Medicine at the University of Pennsylvania (Philadelphia, PA, USA) developed a dual CAR T‑cell desensitization strategy that repurposes cancer immunotherapy for transplantation. In a Phase I clinical trial (NCT06056102) conducted with NYU Langone and Massachusetts General Hospital, the team combined CD19‑targeted CAR T cells to eliminate memory B cells with B‑cell maturation antigen (BCMA)‑targeted CAR T cells to deplete antibody‑secreting plasma cells. The approach aimed to reduce circulating anti‑donor antibodies and reset humoral immunity to broaden donor compatibility.

More than 91,000 Americans are awaiting a kidney transplant, and about 5,000 are highly sensitized, including candidates with calculated panel reactive antibody (cPRA) scores of 99.9% or higher who match with fewer than one in 1,000 donor kidneys. For this group, plasma exchange and antibody‑blocking drugs often fail to produce durable compatibility. The trial targeted this need by enrolling patients with near‑100% cPRA who had spent years on waitlists without a single viable offer.

Two participants at Penn Medicine received the dual CAR T regimen and experienced marked declines in anti‑donor antibodies, with cPRA reductions sufficient to identify acceptable matches. Both subsequently underwent kidney transplantation. To date, neither patient has shown donor‑specific antibody rebound or organ rejection.

Early safety signals were favorable. The regimen was tolerated without severe cytokine release syndrome or neurotoxicity, and B‑cell populations gradually recovered as immune reconstitution proceeded. The findings were published in The New England Journal of Medicine and future trial phases will test higher CAR T‑cell doses and enroll more patients to evaluate safety, durability, and overall effectiveness. The multicenter effort also benefited from leadership and advice from the National Institute of Allergy and Infectious Diseases.

"In this early trial, the CAR T-cell treatment was tolerated well, with no severe side effects, and the immune system began to recover as expected," said study co-author Robert Montgomery, MD, Ph.D., the H. Leon Pachter, MD, Professor of Surgery, chair of the Department of Surgery at NYU Grossman School of Medicine, director of the NYU Langone Transplant Institute. "This early success reflects what's possible when teams across institutions push the boundaries of what cell therapy can do for transplant medicine. This treatment opens up new options for patients and could save thousands more lives every year."

Related Links
Perelman School of Medicine at the University of Pennsylvania