A novel approach to organ transplantation allowed patients to wean off anti-rejection drugs after two years, according to the results of a phase 3 clinical trial presented Monday.
The drugs, called immunosuppressants, are an essential part of any transplant recipient’s life: They help ensure that the immune system doesn’t attack the donated organ as a “foreign” object, leading to rejection. In doing so, however, they come with a host of toxic side effects, including harming the donated organ and increasing the recipient’s risk of infection and cancer.
And they must be taken for life.
“The holy grail of organ transplantation is achieving tolerance,” said Dr. Dorry Segev, a transplant surgeon at NYU Langone Health in New York City. That is, to be able to transplant people without the need for immunosuppressive drugs.
“When we say tolerance, we’re basically saying can the body accept someone else’s kidney without rejecting the kidney,” said Dr. Sanjeev Akkina, medical director of the kidney transplant program at Loyola Medicine in suburban Chicago. “The idea that you can actually be off of anti-rejection drugs for the rest of that life — there’s a lot of benefit in that.”
Akkina is one of the researchers involved with a phase 3 trial in organ transplant patients that uses stem cells taken from the organ donor in an attempt to wean the recipients off of these drugs. The results, presented Monday at the American Transplant Congress in Philadelphia, found that after two years, 16 of 19 patients were able to come off their anti-rejection drugs entirely. The three other patients had to go back on the drugs due to either a rejection episode or worsening kidney function.
The trial, funded by biotechnology company Medeor Therapeutics, is centered around MDR-101, a stem cell therapy that is derived from the person donating the organ. The findings have not yet been published in a peer-reviewed journal.
“These are excellent results,” said Dr. Jeffrey Veale, a urologist at UCLA Health who specializes in kidney transplantation. Not only were a majority of the patients able to stay off of the drugs for two years, the authors also showed a significant benefit in quality of life for the patients, added Veale, who was not involved with the research.
Kidneys are the most commonly transplanted organs in the United States with around 25,000 kidney transplants performed in recent years, according to the Organ Procurement and Transplantation Network. Around 10% of them, however, are repeat procedures after a transplanted kidney fails.
One reason this happens, Veale said, is because anti-rejection drugs can actually damage the kidney to the point that a new one is needed. If patients are able to ultimately get off of these drugs, the transplanted kidney should theoretically last a lifetime.
“That would expand the pool of organs available because you wouldn’t have people coming back for their second or third or fourth transplant,” he said.
A kidney and stem cells from his sister
Alex Hernandez was 27 when he received a kidney transplant and a dose of stem cells from his sister as one of Akkina’s patients and a trial participant.
Hernandez, of Milwaukee, was born with vesicoureteral reflux, a condition that causes urine to flow backward in the urinary tract, leaving his kidneys scarred and ultimately causing permanent kidney damage. In college, his kidneys started to fail, and he had to go on dialysis.
In order to prepare his body for the stem cells, Hernandez had radiation therapy just days after his surgery. That temporarily suppressed his immune system so the stem cells would be accepted. Eleven days after surgery, the new cells were transferred, mixing with Hernandez’s immune system to become a hybrid of both donor and recipient, a phenomenon called “mixed chimerism.”
This prevents the body from attacking the new kidney and allows the patient to eventually stop all those immunosuppressant drugs.
“The stem cells basically reprogram your immune system, telling them to recognize that this donor kidney coming in is actually going to be part of your own,” Akkina said.
For Hernandez, now 30 and about to start his second year of dental school at Marquette University, the results have been life-changing. His surgery was in 2021 and he was fully off of all of the anti-rejection drugs that same year.
“I had to carry this pill container labeled Monday, Tuesday, Wednesday, Thursday, Friday,” he said. “It’s empty now.”
What’s next?
The results are an “important next step” in the field of organ transplantation, but Segev stressed that there is a lot more work to be done in the field of tolerance.
The results presented Monday were for those who had received organs from closely matched siblings who are genetically similar, he said — that’s not the majority of transplant recipients.
“Ultimately we need to figure out a way for this to apply to many more patients who undergo transplants, which is why we’re still very early in this field,” Segev said.
Veale said the goal is to get everyone to come off their anti-rejection medications, not just those who get an organ from a sibling.
The approach used in the clinical trial also requires both the transplant and stem cell donation to occur within a two-week period, which can be a significant burden on patients, donors and health care systems.
Veale’s own research focuses on extending the amount of time that can elapse between the organ transplant and the stem cell transplant. He’s had success weaning patients off anti-rejection drugs as many as five years after their transplant.
“They may already be starting to feel the toxic effects of those medications, so I wanted to open up tolerance to that pool of patients,” he said.
Doctors are also hopeful this could one day apply to other types of organ transplants beyond the kidney.
“I think as we understand how chimerism occurs and what we can do to successfully achieve chimerism, we would be able to apply that to any solid organ transplant,” Segev said.
