Two men with almost no chance of finding a kidney match have now received transplants. Both had a calculated panel reactive antibody (cPRA) score above 99.99%. They got there after just one round of dual-targeted CAR T-cell therapy. This is the first time engineered immune cells have broken through such a tough barrier in transplantation.
Anti-HLA antibodies have blocked highly sensitized kidney transplant candidates for decades. A cPRA of 99.998% means a patient matches only one in 50,000 donors. That leads to years on the waitlist and a much higher risk of dying before a kidney appears. Standard desensitization—plasmapheresis, IVIG, B-cell depletion, or IgG-cleaving enzymes—rarely works for long. Antibody-producing cells stick around. Rebound is common.
Sensitization in kidney transplant candidates often develops after previous transplants, blood transfusions, or pregnancy, leading to significantly longer wait times for highly sensitized patients.
The new method, described in the New England Journal of Medicine, uses deep B-cell and plasma-cell depletion with chimeric antigen receptor (CAR) T-cell therapy. The team took cues from recent autoimmune disease trials. They used autologous CAR T cells that target both CD19 and BCMA. The goal: wipe out all antibody-producing cells. Both patients, aged 54 and 47, had already lost two kidney allografts to antibody-mediated rejection. They entered the trial with cPRA values of 99.998% and 99.993%.
Each patient first got a lymphodepleting regimen with cyclophosphamide. Then, they received 5 × 10^7 CD19-directed and 5 × 10^7 BCMA-directed CAR T cells. One month later, both had five sessions of plasmapheresis with IVIG to help clear antibodies faster. The treatment went smoothly. There was no high-grade cytokine release syndrome, no neurotoxicity, and only short-term blood side effects. Both CAR T-cell products expanded well in the body. B-cell depletion lasted three to four months. After that, B cells came back, mostly as naïve and transitional types. This hints at immune system remodeling. But it is still unclear how long this effect on HLA-specific memory will last.
Both patients saw steady drops in anti-HLA antibody levels. This let doctors remove some previously unacceptable HLA antigens from their lists and lower their cPRA scores. Patient 1’s cPRA dropped from 99.998% to 99.516%. He got a transplant on day 229 after infusion. Patient 2’s cPRA fell from 99.995% to 99.567%. He received a kidney on day 93. Both have stable graft function. There has been no sign of antibody-mediated rejection or donor-specific antibody rebound during follow-up. Patient 2 did develop BK viremia. This is a known risk after transplant immunosuppression. It shows why bigger studies are needed to sort out infection risks when combining CAR T-cell therapy with standard immunosuppression.
For highly sensitized kidney transplant candidates, finding a compatible donor remains extremely challenging due to the presence of multiple pre-existing HLA antibodies. A negative virtual crossmatch is considered a mandatory prerequisite before transplantation.
Tissue tests confirmed how deep the immune cell depletion went. Fine-needle aspiration of a lymph node in patient 1 showed no B cells two months after infusion. Bone marrow samples from both patients showed almost no plasma cells. The plasma-cell type was different in each patient. This suggests the best CAR T-cell target—CD19, BCMA, or both—may need to be chosen for each person. There are still no biomarkers to guide this choice.
Other studies back up these results. Earlier reports have shown CAR T cells can modulate the immune system beyond cancer. In this trial, doctors used lower CAR T-cell doses for safety. It is not yet clear if higher doses could wipe out more pathogenic cells without more risk. The field also needs to find out if dual targeting is needed or if CD19-directed therapy alone is enough. New data suggest BCMA-directed agents may have broader effects than once thought.
Despite these advances, Reuters and other major wire services report that as of late September 2026, there are no confirmed regulatory approvals or widespread use of this dual CAR T-cell approach for kidney transplants. CAR-T in nephrology and transplantology is still discussed mainly for highly sensitized patients who are hard to match. No official regulatory decisions or clinical standards exist yet.
As desensitization strategies change, future studies will need to use cPRA scores, antibody strength, and serum dilution tests to tailor therapy. CAR T cells will be compared to T-cell engagers, which redirect polyclonal T cells without genetic changes and are already showing promise in early results. The evidence is clear. CAR T-cell therapy is moving beyond cancer and rare autoimmune diseases. It could change what is possible in organ transplantation. The proof-of-concept is here. The next step is to turn these early wins into safe, scalable, and lasting options for the thousands still waiting for a transplant.
