The genetically altered pig’s heart “worked like a rock star, beautifully functioning,” said the surgeon who performed the pioneering January 7 xenotransplant procedure in a press statement on the death of the patient, David Bennett Sr.
“He wasn’t able to overcome what turned out to be devastating — the debilitation from his previous period of heart failure, which was extreme,” said Bartley P. Griffith, MD, clinical director of the cardiac xenotransplantation program at the University of Maryland School of Medicine (UMSOM), Baltimore.
Representatives of the institution aren’t offering many details on the cause of Bennett’s death on March 8, 60 days after his operation, but said they will elaborate when their findings are formally published. But their comments seem to downplay the unique nature of the implanted heart itself as a culprit and instead implicate the patient’s diminished overall clinical condition and what grew into an ongoing battle with infections.
The 57-year-old Bennett, bedridden with end-stage heart failure, judged a poor candidate for a ventricular assist device, and on extracorporeal membrane oxygenation (ECMO), reportedly was offered the extraordinary surgery after being turned down for a conventional transplant at several major centers.
“Until day 45 or 50, he was doing very well,” Muhammad M. Mohiuddin, MD, the xenotransplantation program’s scientific director, observed in the statement. But infections soon took advantage of his hobbled immune system.
Given his “pre-existing condition and how frail his body was,” Mohiuddin said, “we were having difficulty maintaining a balance between his immunosuppression and controlling his infection.” Bennett went into multiple organ failure and “I think that resulted in his passing away.”
Beyond Wildest Dreams
The surgeons confidently framed Bennett’s experience as a milestone for heart xenotransplantation. “The demonstration that it was possible, beyond the wildest dreams of most people in the field, even, at this point — that we were able to take a genetically engineered organ and watch it function flawlessly for 9 weeks — is pretty positive in terms of the potential of this therapy,” Griffith said.
But enough questions linger that others were more circumspect, even as they praised the accomplishment. “There’s no question that this is a historic event,” Mandeep R. Mehra, MD, Harvard Medical School and director of the Center for Advanced Heart Disease at Brigham and Woman’s Hospital, Boston, told theheart.org | Medscape Cardiology.
Still, “I don’t think we should just conclude that it was the patient’s frailty or death from infection,” Mehra said. With so few details available, “I would be very careful in prematurely concluding that the problem did not reside with the heart but with the patient. We cannot be sure.”
For example, he noted, “6 to 8 weeks is right around the time when some cardiac complications, like accelerated forms of vasculopathy, could become evident.” Immune-mediated cardiac allograft vasculopathy is a common cause of heart transplant failure.
Or, “it could as easily have been the fact that immunosuppression was modified at 6 to 7 weeks in response to potential infection, which could have led to a cardiac compromise,” Mehra said. “We just don’t know.”
“It’s really important that this be reported in a scientifically accurate way, because we will all learn from this,” Lori J. West, MD, DPhil, said in an interview.
Little seems to be known for sure about the actual cause of death, “but the fact there was not hyperacute rejection is itself a big step forward. And we know, at least from the limited information we have, that it did not occur,” observed West, who directs the Alberta Transplant Institute, Edmonton, and the Canadian Donation and Transplantation Research Program. She is a professor of pediatrics with adjunct positions in the Departments of Surgery and Microbiology/Immunology.
West also sees Bennett’s struggle with infections and adjustments to his unique immunosuppressive regimen, at least as characterized by his care team, as in line with the experience of many heart transplant recipients facing the same threat.
“We already walk this tightrope with every transplant patient,” she said. Typically, they’re put on a somewhat standardized immunosuppressant regimen, “and then we modify it a bit, either increasing or decreasing it, depending on the post-transplant course.” The regimen can become especially intense in response to new signs of rejection, “and you know that that’s going to have an impact on susceptibility to all kinds of infections.”
The porcine heart was protected along two fronts against assault from Bennett’s immune system and other inhospitable aspects of his physiology, either of which could also have been obstacles to success: genetic modification (Revivicor) of the pig that provided the heart, and a singularly aggressive antirejection drug regimen for the patient.
The knockout of three genes targeting specific porcine cell-surface carbohydrates that provoke a strong human antibody response reportedly averted a hyperacute rejection response that would have caused the graft to fail almost immediately.
Other genetic manipulations, some using CRISPR technology, silenced genes encoded for porcine endogenous retroviruses. Others were aimed at controlling myocardial growth and stemming graft microangiopathy.
Bennett himself was treated with powerful immunosuppressants, including an investigational anti-CD40 monoclonal antibody (KPL-404, Kiniksa Pharmaceuticals) that, according to UMSOM, inhibits a well-recognized pathway critical to B-cell proliferation, T-cell activation, and antibody production.
“I suspect the patient may not have had rejection, but unfortunately, that intense immunosuppression really set him up — even if he had been half that age — for a very difficult time,” David A. Baran, MD, a cardiologist from Sentara Advanced Heart Failure Center, Norfolk, Virginia, who studies transplant immunology, told theheart.org | Medscape Cardiology.
“This is in some ways like the original heart transplant in 1967, when the ability to do the surgery evolved before understanding of the immunosuppression needed. Four or 5 years later, heart transplantation almost died out, before the development of better immunosuppressants like cyclosporine and later tacrolimus,” Baran said.
“The current age, when we use less immunosuppression than ever, is based on 30 years of progressive success,” he noted. This landmark xenotransplantation “basically turns back the clock to a time when the intensity of immunosuppression by definition had to be extremely high, because we really didn’t know what to expect.”
Emerging Role of Xeno-Organs
Xenotransplantation has been touted as potential strategy for expanding the pool of organs available for transplantation. Bennett’s “breakthrough surgery” takes the world “one step closer to solving the organ shortage crisis,” his surgeon, Griffith, announced soon after the procedure. “There are simply not enough donor human hearts available to meet the long list of potential recipients.”
But it’s not the only proposed approach. Measures could be taken, for example, to make more efficient use of the human organs that become available, partly by opening the field to additional less-than-ideal hearts and loosening regulatory mandates for projected graft survival.
“Every year, more than two-thirds of donor organs in the United States are discarded. So it’s not actually that we don’t have enough organs, it’s that we don’t have enough organs that people are willing to take,” Baran said. Still, it’s important to pursue all promising avenues, and “the genetic manipulation pathway is remarkable.”
But “honestly, organs such as kidneys probably make the most sense” for early study of xenotransplantation from pigs, he said. “The waiting list for kidneys is also very long, but if the kidney graft were to fail, the patient wouldn’t die. It would allow us to work out the immunosuppression without putting patients’ lives at risk.”
Often overlooked in assessments of organ demand, West said, is that “a lot of patients who could benefit from a transplant will never even be listed for a transplant.” It’s not clear why; perhaps they have multiple comorbidities, live too far from a transplant center, “or they’re too big or too small. Even if there were unlimited organs, you could never meet the needs of people who could benefit from transplantation.”
So even if more available donor organs were used, she said, there would still be a gap that xenotransplantation could help fill. “I’m very much in favor of research that allows us to continue to try to find a pathway to xenotransplantation. I think it’s critically important.”
Unquestionably, “we now need to have a dialogue to entertain how a technology like this, using modern medicine with gene editing, is really going to be utilized,” Mehra said. The Bennett case “does open up the field, but it also raises caution.” There should be broad participation to move the field forward, “coordinated through either societies or nationally allocated advisory committees that oversee the movement of this technology, to the next step.”
Ideally, that next step “would be to do a safety clinical trial in the right patient,” he said. “And the right patient, by definition, would be one who does not have a life-prolonging option, either mechanical circulatory support or allograft transplantation. That would be the goal.”
Mehra has reported receiving payments to his institution from Abbott for consulting; consulting fees from Janssen, Mesoblast, Broadview Ventures, Natera, Paragonix, Moderna, and the Baim Institute for Clinical Research; and serving on a scientific advisory board NuPulseCV, Leviticus, and FineHeart. Baran discloses consulting for Getinge and LivaNova; speaking for Pfizer; and serving on trial steering committees for CareDx and Procyrion, all unrelated to xenotransplantation. West has declared no relevant conflicts.
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