Background: Antibodies narrow transplant opportunities

Two highly sensitized patients who had extreme difficulty finding a compatible kidney received transplants after combination treatment with chimeric antigen receptor T cells (CAR T cells) targeting CD19 and B-cell maturation antigen (BCMA). These findings come from the safety lead-in cohort of a multicenter phase 1 clinical trial. Reductions in some antibodies expanded the opportunity to find a crossmatch-compatible donor kidney.

Antibodies against human leukocyte antigens (HLA) are a major immunologic barrier to kidney transplantation. The calculated panel-reactive antibody (cPRA) percentage indicates the proportion of deceased donors for whom a patient’s antibodies would make transplantation difficult; it is distinct from antibody concentration or titer. Patients with a cPRA of 99.9% or higher face particular difficulty finding a compatible donor.

There is no established standard approach to desensitization for reducing antibodies in these patients. Plasma exchange and intravenous immunoglobulin (IVIG) are used, but antibody rebound and the risk of antibody-mediated rejection remain limitations. The research team targeted memory B cells and plasma cells involved in producing the antibodies already present.

Key findings: Crossmatch-compatible kidney transplantation after antibody reductions

Both patients received CD19-targeted huCART-19 and BCMA-targeted CART-BCMA after lymphodepleting chemotherapy. About a month later, they underwent five plasma-exchange sessions, with low-dose IVIG administered at each session. The outcomes therefore cannot be attributed to CAR T cells alone.

After the mean fluorescence intensity (MFI) of some anti-HLA antibodies fell below 1,000, the team removed the corresponding antigens from the unacceptable-antigen list in the transplant allocation system. However, antigens corresponding to donor-specific antibodies (DSA) against a previous kidney graft remained on the list. The first patient’s cPRA fell from 99.998% to 99.516%; the second patient’s fell from 99.995% at enrollment to 99.567%. Sensitization remained high, but both patients received offers of crossmatch-compatible kidneys and underwent transplantation 229 and 93 days, respectively, after CAR T-cell infusion.

At the reported follow-up of nine months after transplantation, the first patient had stable serum creatinine, with no observed DSA rebound. The second patient’s graft function gradually recovered without post-transplant dialysis, and DSA remained negative through month four, according to the report. The reported biopsies from both patients showed no evidence of rejection. Both also received induction and maintenance immunosuppression after transplantation, a factor that must be considered when interpreting these outcomes.

Meaning and outlook: Improving transplant access rather than eliminating all antibodies

The main finding is the possibility of expanding transplant opportunities without eliminating all antibodies. B-cell depletion was profound but temporary, while a substantial proportion of pre-existing protective antibodies was preserved. The researchers interpreted this preservation as suggesting incomplete plasma-cell depletion. The results do not demonstrate a complete reset of the immune system or permanent antibody elimination.

Safety also requires careful consideration. Transient cytopenias occurred. In the second patient, grade 3 leukopenia and grade 4 neutropenia were reported between leukapheresis and kidney transplantation. After transplantation, this patient’s immunosuppressant doses were adjusted because of BK viremia, but biopsy showed no evidence of BK virus nephropathy or rejection.

With only two patients and no comparison group, the study cannot establish superiority over existing desensitization treatments. The individual contributions of the two CAR T-cell products and the effects of the combination treatment are difficult to separate. Immunosuppression may also have contributed to the absence of DSA rebound after transplantation. Larger comparative studies are needed to assess the durability of antibody reductions and the risks of cytopenias and infection. The study design and results can be found in the provided author-approved manuscript after peer review and the Europe PMC bibliographic record and abstract.