Life-saving transplant surgeries currently come with a lifetime commitment to anti-rejection drugs, medications with serious side effects that cumulate with time.
A study out of the University of Pittsburgh’s School of Medicine, published Wednesday in the journal Science Translational Medicine, points to the potential for that standard of care to change, so that transplant recipients might reduce and perhaps someday even remove such immunosuppression medications from their treatment regimens.
As anti-rejection drugs often taken across decades, this has long been a goal within transplantation, with researchers in recent years pursuing various approaches under the banner of cell therapy.
The Pitt scientists, including lead study author Dr. Angus W. Thomson, distinguished professor of immunology and surgery at Pitt, conducted a small clinical trial of 15 patients awaiting liver transplants from living donors. In an effort to boost reception of the organ, the trial participants were, one week prior to their transplantations, administered immune cell infusions — specifically, of regulatory dendritic cells — that originated with the donors. Dendritic cells, so named because they resemble tree branches, govern immune responses.
The hope was that the infusions — administered just that one time, and followed by the usual protocol of anti-rejection drugs — would help the recipients’ bodies better accept the donated livers.
Dr. Thomson and his fellow researchers monitored patients, via tissue and blood samples, for a year following their transplants, with the patients compared to a group of 40 living donor liver transplant (LDLT) patients who did not receive a donor cell infusion. While the trial remains ongoing — trial patients will be followed until about mid-2024, Dr. Thomson said — the 12-month-mark findings show promise.
“The exciting and important thing so far is that we are able to show that a new form of what we call cell therapy in organ transplantation is feasible. It’s also safe,” said Dr. Thomson, a member of the Thomas E. Starzl Transplantation Institute who’s been with Pitt for nearly 33 years. He collaborated on the trial with the Starzl Transplantation Institute’s clinical director Dr. Abhinav Humar, who is also chief of the Division of Transplantation at UPMC
The team also proved efficacy.
“[T]he intervention, the administration of these cells to liver transplant patients, before they received their transplant, has an effect on the host immune response that we hope will be conducive to reduce dependence on anti-rejection drugs,” Dr. Thomson said.
While the ultimate goal is to remove the need for still-crucial anti-rejection drugs, complications and side effects from these immunosuppressants are serious enough that even a lessening of doses would constitute a major step forward.
“If we can come up with other types of treatments, like cellular therapies … even if we can’t completely stop these drugs, we can at least reduce the doses, which really correlates with the incidence of these cancers and infections,” said Dr. Timucin Taner, division chair of transplant surgery at Mayo Clinic (and who was quick to point out that Dr. Thompson was his mentor when he was pursuing his PhD at Pitt years ago). “So even if we can reduce them a little bit, it will help.”
As anti-rejection drugs are taken over time, the risk for some cancers and for infections increases. Then there’s the impact on the kidneys, which take the brunt when attempting to filter the medications, potentially necessitating dialysis after years of decreasing function.
“The possibility of being able to withdraw anti-rejection drugs relatively early after transplant — within two, three years of the transplant — could be of great benefit, because it would eliminate the longer term cumulative effects of the anti-rejection drugs that the patients have to take in order to sustain their transplant,” Dr. Thomson said.
Not to position anti-rejection drugs as a boogeyman. Harsh as their side effects can be, without them — including the frequently used Tacrolimus, which Dr. Thomson noted was invented in Pittsburgh by transplant pioneer Dr. Thomas Starzl — immunosuppression is key to helping the body not view a transplanted organ as a foreign object that must be attacked.
Other, similar pursuits of paths to weaning transplant recipients from anti-rejection drugs have been percolating in recent years, including studies looking at therapies utilizing regulatory T cells. Notable to Penn State Health transplant cardiologist Dr. John Beohmer about the new Pitt study, which he did not review, was the element of time: giving patients the immune cell infusions prior to surgery.
Developing what researchers call “transplantation tolerance” is “the goal of treatment for patients receiving solid organ transplant of any sort,” Dr. Beohmer said. “The ability to give [the infusion] to them a week in advance so that that tolerance can begin even before you first introduced the organ is a great idea, because if the recipient is preconditioned to accept the organ, it will make everything just go more smoothly.”
Dealing with the heart, Dr. Beohmer wouldn’t generally have access to living donors, but the direction is an important one, for “not just liver transplant, but all of solid organ transplant,” he said.
The liver was selected for the study for a number of reasons: As Dr. Thomson said, “We could spend all day talking about this.”
For one, he said, “the liver has a number of very distinct and unique properties that render it, investigators believe, less susceptible to rejection.” And the liver can regenerate — that’s why partial liver transplants work.
Also of interest to the scientists, Dr. Thomson said, is the existence of a small number of liver transplant recipients who grew to tolerate their transplanted livers. This “spontaneous liver transplantation tolerance” isn’t fully understood, he said, but it does open up the possibility for future studies.
The next step of this particular study, however, will find Dr. Thomson and his team sticking with regulatory dendritic cell infusions in advance of surgeries, with an expanded patient pool about twice the size of the Phase I trial. Anticipating that to begin in about a year, the larger study potentially, he said, “enhances the power of the study, our ability to discriminate whether it is a truly significant advance with clinical implications beyond current standard of care.”
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