Kidney Transplantation Without Lifelong Immunosuppression Edges Toward Reality

Three-fourths of patients avoided long-term immunosuppression after matched kidney transplant procedures involving donor stem cells, a small randomized trial showed.

More than 2 years after transplantation, 15 of 20 patients remained off all immunosuppression after receiving the allogeneic cellular product MDR-101. No deaths, graft loss, donor-specific antibodies (DSA), or graft-versus-host disease (GVHD) occurred, and patients treated with MDR-101 had improved quality of life, compared with a control group treated with conventional immunosuppression, reported Dixon Kaufman, MD, PhD, of the University of Wisconsin in Madison, and co-authors in the American Journal of Transplantation.

“One of the most important things about this protocol is that it really showed proof of principle, that you can actually do this,” co-author Mark Stegall, MD, of the Mayo Clinic in Rochester, Minnesota, told MedPage Today. “Yes, it’s in a smaller patient population, but [the results showed] that patients can go through this and get off immune suppression. And it’s really reproducible.”

Other strategies to wean patients off immunosuppression have been evaluated, “but they haven’t been as successful. The thing about highly matched [procedures], the donor cells don’t attack the recipient, so [the patients] don’t get graft-versus-host disease. From an immunologic point of view, it shows that you can get these [donor] cells in there, and the patients won’t have to take any immunosuppression.”

Achieving chimerism has been a major goal of transplantation science from the very beginning, and this study represents a major step toward reaching that goal, said Amit Tevar, MD, of the University of Pittsburgh Medical Center.

“This is an important, landmark study,” Tevar told MedPage Today. “It looks at MDR-101, which is a brand new investigational cellular therapy, but more important, their study was well done, well devised, and had tremendously good outcomes. When you look at the endpoint of 75% of their patients were immunosuppression free for greater than 2 years, that’s remarkable. That’s something we really have not seen before.”

“I think it accomplished everything that the phase III study wanted to accomplish and represents an important stepping stone in moving the field forward into [immune] tolerance,” he added.

In their introduction, Kaufman and co-authors noted, “Rarely can some transplant patients develop ‘tolerance’ of their donated transplant and not require life-long IS [immunosuppression]. This occurs more often in closely ‘matched’ donor and recipient pairs that share the same ‘transplant antigens’ or human leukocyte antigens (HLAs). A key component of successful tolerance seems to be the establishment of ‘chimerism’ where the recipient has evidence of circulating donor hematopoietic (blood) cells.”

Transplant researchers have attempted to induce tolerance in transplant recipients with conditioning regimens involving intensive chemotherapy and whole-body irradiation to eliminate the recipient’s hematopoietic cells and immune system and replace with donor bone marrow or hemopoietic stem cells, the authors continued. Some protocols have achieved 100% chimerism but are associated with limited success in HLA-mismatched recipients and an unacceptable incidence of GVHD.

More than 30 years ago, an alternative approach to chimerism was developed, using nonmyeloablative, lymphocyte-depleting rabbit-antithymocyte globulin and total lymphoid irradiation. The strategy achieved mixed or low-level chimerism. Data from a series of single-center studies showed that 24 of 29 HLA-matched patients with persistent mixed chimerism for at least 6 months withdrew from all immunosuppression, and 20 of 24 remained rejection free for at least 2 years.

The MDR-101-MLK (matched living kidney) trial continued evaluation of the nonmyeloablative strategy to achieve chimerism with MDR-101 in 2-haplotype HLA-matched living kidney donor transplant procedures. Investigators at 16 sites in the United States and one in Canada randomized participants 2:1 to nonmyeloablative conditioning and MDR-101 or standard conditioning and immunosuppression.

All patients initially received standard immunosuppression with methylprednisolone, tacrolimus, and mycophenolate mofetil (MMF). In the MDR-101 arm, steroids were tapered to withdrawal by day 10 and MMF by day 39. Tacrolimus was continued for 6 months and then tapered to withdrawal at 1 year if chimerism ≥5% was achieved. Patients in the control group received immunosuppression in accordance with local standards.

The primary endpoint was functional immune tolerance, defined as off all immunosuppressive drugs 24 months after immunosuppression withdrawal with no episodes of biopsy-proven acute rejection, DSA, GVHD, organ loss, or death.

The results showed that 19 of 20 patients in the MDR-101 arm achieved mixed chimerism for at least 6 months. All but two of the 19 patients had evidence of mixed chimerism at withdrawal of tacrolimus. By day 1,095 (3 years post-transplant), nine of 16 patients still exhibited mixed chimerism. Patients remained off immunosuppression even after loss of chimerism.

All patients in the MDR-101 group would have been expected to require lifelong immunosuppression with conventional conditioning, said Stegall.

“All of the data show that if you take them off, if they have to stop taking their medicines or have to decrease their medicines for some other reason, they will reject [the donor kidney] completely,” he said. “This is not a process that would exist without all the conditioning regimen and all that [the patients] went through.”

An optimal duration of immunosuppression has yet to be determined, “but I think a year is probably a really good time.”

Next steps for the strategy are to win FDA approval and become standard of care and then try to determine whether the strategy can be applied to a broader audience of less well-matched recipients, said Stegall. Because a living donor is required, the strategy has limited applicability beyond kidney transplantation, he acknowledged. Partial liver transplants and lung transplants are theoretically possible but represent relatively uncommon transplant situations.