CAR T-Cell Therapy Enabled Kidney Transplant in Highly Sensitized Patients

Patients highly sensitized to HLA successfully underwent kidney transplantation after desensitization with the use of dual chimeric antigen receptor (CAR) T-cell therapy.

In a safety run-in cohort of an ongoing phase I trial, two patients received lymphodepleting chemotherapy followed by an infusion of both CD19-targeted and B-cell maturation antigen (BCMA)-targeted CAR T cells to eliminate the cellular sources of preformed anti-HLA antibodies, reported Ali Naji, MD, PhD, of the University of Pennsylvania’s Smilow Center for Translational Research in Philadelphia, and colleagues in the New England Journal of Medicine (NEJM).

“This is the first demonstration that CAR T cells can be used not only to treat cancer, but also to help patients who previously had no opportunity to receive a compatible donor kidney,” Naji said in a statement. “For patients who have spent years on the kidney transplant waiting list, this approach could be transformative.”

The first patient was a 54-year-old man with end-stage kidney disease who had undergone two previous kidney transplantations and was on the waiting list for a third. The second was a 47-year-old man with a history of focal segmental glomerulosclerosis who had also undergone two previous deceased-donor kidney transplantations, both of which failed due to refractory antibody-mediated rejection.

Both patients had a calculated panel-reactive antibody (cPRA) score of 99.9% or higher, making the odds of matching with a compatible donor kidney near-zero. Patients with these scores have the longest waiting times, the lowest likelihood of undergoing transplantation, and the highest risk of death while on the waiting list, Naji and team noted.

Roughly 5,000 of the more than 91,000 patients currently awaiting a kidney transplant in the U.S. have a high level of sensitization to HLA.

Two main approaches have previously been used to boost transplantation odds in highly sensitized patients. The first is to expand opportunities for immunologically compatible transplantation through deceased-donor kidney allocation policies and kidney paired donation programs. However, highly sensitized patients are more likely to die or be removed from the waiting list than to undergo transplantation with this approach, Naji and colleagues pointed out.

The second approach is to desensitize patients. There is currently no standard method of desensitization, but strategies have included intravenous immune globulin (IVIG) treatment, plasmapheresis, and the use of imlifidase, an IgG-cleaving protease. Antibody rebound remains a significant risk with this strategy, the authors noted.

“Attempts at antibody elimination (desensitization) have had inconsistent efficacy and have often failed to produce sustained reductions in anti-HLA antibodies in patients with the highest level of sensitization,” they explained. “Other options are being investigated that target either B cells or plasma cells, including treatment with proteasome inhibitors; antibodies against CD20, interleukin-6, or CD38; or T-cell-engaging bispecific antibodies.”

The dual CAR T-cell therapy used in these two patients worked by depleting both B cells and plasma cells to promote a durable reduction in anti-HLA antibodies, essentially resetting the immune system and boosting compatibility with donor kidneys.

Both patients underwent five sessions of plasmapheresis beginning 1 month after the CAR T-cell infusion. Each session was followed by an infusion of low-dose IVIG to accelerate the clearance of circulating alloantibodies. Testing for anti-HLA antibodies was performed using a single-antigen bead assay. If the anti-HLA antibody level fell below a threshold of 1,000 mean fluorescence intensity, the antibody was considered eliminated, and the corresponding “unacceptable” HLA antigen could be removed from the patient’s file, thereby reducing their cPRA score.

Immunosuppression after transplantation involved induction therapy with antithymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and prednisone.

Following the transplants, no donor-specific antibody rebound was observed in either patient, and no high-grade adverse events occurred.

“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 co-author Robert Montgomery, MD, PhD, of the NYU Langone Transplant Institute, in a statement. “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.”

In another report in NEJM, a team led by Jens Schrezenmeier, MD, of Charité-Universitätsmedizin Berlin, treated a 35-year-old woman with KYV-101, a fully human anti-CD19 CAR T-cell product.

This patient had developed hemolytic uremic syndrome caused by enterohemorrhagic Escherichia coli during childhood. She received a kidney transplant from her mother at age 21, but the graft failed 11 years later due to chronic active antibody-mediated rejection that was refractory to plasmapheresis, IVIG therapy, and rituximab.

Her antibody percentage was 99.84% during evaluation for a second transplant, leaving the probability of finding an HLA-matched, ABO-compatible donor at just 0.08%.

After receiving the CAR T-cell therapy, three previously incompatible living donors became compatible. She successfully underwent transplantation, with CAR T cells still persisting 15 months after infusion. No major infectious complications occurred.

“This case provides proof-of-principle that anti-CD19 CAR T-cell therapy can enable kidney transplantation in patients with broad HLA sensitization by inducing a profound, durable contraction of cross-reactive anti-HLA antibodies,” Schrezenmeier and co-authors noted.