Accepting hearts
Clinical trial in Spokane will ‘delete’ immune systems of patients whose antibodies are working against them
Dr. Timothy Icenogle has been on Spokane’s leading edge of heart transplant surgery and research since soon after he arrived at Providence Sacred Heart Medical Center to launch its transplant program. He performed some of the area’s first heart transplants in the early 1990s, around the same time starting to implant mechanical hearts in patients who couldn’t wait for organs.
This month he started recruiting participants for a six-year study that will use drugs to delete the immunological memory of heart patients whose own antibodies would otherwise fight off a donated heart.
About 10 percent of potential heart-transplant patients have developed antibodies against other people’s “transplant antigens,” making a compatible donor hard to find, said Dr. David Taylor, president of the International Society for Heart & Lung Transplantation. Most of them are women who developed the antibodies through pregnancy; others developed them after blood transfusions or previous transplants.
Currently, there’s no way to “desensitize” heart patients to the antigens present in most organ donors.
“Basically, you put them on the list, and they never get a transplant,” said Taylor, a cardiologist at the Cleveland Clinic in Ohio who is familiar with Icenogle and his research.
Icenogle, who is with the Inland Northwest Thoracic Transplant and Mechanical Heart Program at Sacred Heart, developed his interest in immunology as a surgeon at the University of Arizona Medical Center in Tucson, where he worked before coming to Spokane. He treated three women, all young mothers who died, the third one on the operating table.
Each suffered from myocarditis, an autoimmune disease most likely caused by a virus, Icenogle said.
“It was emotionally gripping to see these young moms all die,” Icenogle said. “Their husbands are standing around with the moms, the dads, the baby. The mom slips away and dies.”
Under a microscope, samples from those women’s own hearts resembled those of transplant patients whose transplants hadn’t taken – their bodies had rejected the donor hearts.
In these women’s cases, “they were rejecting their own hearts,” Icenogle said.
So, in Spokane, he began to successfully treat myocarditis patients by suppressing their immune systems. The first such case came 23 years ago, and it worked, Icenogle said.
Now he sees about a person a year with myocarditis. By suppressing their immunologic memory, he suppresses the antibodies hurting their hearts. “Basically, 90 percent of people with myocarditis are destroying their hearts because of antibodies,” he said.
Feeling sick on Jan. 2, Spokane resident Brian Starr was diagnosed with high blood pressure and sent home from his doctor’s office with medication. His condition worsened. He spent his 50th birthday, Jan. 7, in the emergency room with symptoms he mistook for those of a heart attack: chest pain, pain in his left arm, a clammy feeling. He was diagnosed with what doctors called a mild case of myocarditis and prescribed some more medication.
By Jan. 22 he was in V-tach, ventricular tachycardia, “when your heart’s racing quickly but not doing much pumping,” Starr said. Back in the ER, they used injections to stop and restart his heart twice.
Placed under Icenogle’s care, his condition declined over the next couple of days.
With Starr unconscious, his wife and son faced a decision: Have the doctors put a mechanical device while he waited for donor heart, or try suppressing his immune system to rub out the antibodies attacking his heart. They chose the latter.
“(Icenogle) explained it to me the surgery was a parachute. If the plane was crashing, we could still jump,” said Darlene Starr. “We didn’t really have anything to lose, and everything to gain.”
Starr spent a week in quarantine, contact limited to a scrubbed-up visitors in gowns, hair nets, masks and booties. Now he wears a mask when he leaves his house, Starr said, and visitors wear them when they come in. He’ll learn more this week from Icenogle about his status, what vaccinations he’ll have to repeat.
Starr said he felt “blessed.”
“I’m feeling much better than I was a month ago,” he said. “It’s just going to take some time for the heart to come back.”
‘Back to your baby state’
The trial for heart-transplant patients builds on the idea Icenogle applies to patients like Starr, taking advantage of new understanding of the human immune system as well as recently developed drugs. But rather than suppress the immune system, Icenogle hopes to delete it.
Antibodies are proteins that fight off harmful invaders, aka antigens, such as bacteria, viruses, parasites or venom. But some antibodies also fight off cells and tissues – including those, such as in a transplanted heart, you want to keep.
Immunologic memory runs on three redundant systems: T-cell memory, B-cell memory and plasma-cell memory. Memory T and B cells can last for decades, while memory plasma cells can last a lifetime, Icenogle said.
Icenogle’s trial will use a combination of drugs – including bortezomib, approved by the Food and Drug Administration in 2008 to treat multiple myeloma – to delete patients’ immunologic memory and, along with it, those transplant-fighting antibodies.
Other transplant centers have taken similar tacks, but just a few patients at a time.
“We’re going to take them back to their neonatal state,” Icenogle said. “That’s the really big thing – no one’s ever deleted immunologic memory before. We’re going to first kill their memory T cells, then we’re going to kill their memory B cells. Then we’re going to go after plasma cells. The idea is we’re going to erase the memory of that initial attack, or threat that the body saw, from their body.”
Patients will be left without the defenses built up over a lifetime of immunizations and exposure to everyday germs. They’ll be revaccinated, starting with the ones normally delivered during infancy. They’ll also have to rebuild the immunological defenses they’ve built through exposure to bacteria and viruses in the environment – the result of the “glazed doughnut” years of early childhood, Icenogle said, when children pick up and develop antibodies against lots of illnesses.
“You’re back to your baby state,” he said. “And therefore you have to be reprogrammed.”
‘Life or death for them’
While his memories of the women in Arizona endured, Icenogle has focused on his job – performing heart transplants. In terms of research, he worked mostly on implanting and testing mechanical devices, participating in national trials and securing permission to send patients home with models not otherwise allowed outside of hospitals.
Sometimes considered “destination therapy” for people who don’t qualify for a donated heart, pumps are most often used to keep patients alive until a match is found.
“Unless you live in a few areas of the country, it takes a long time to get a transplant,” said Alexa Schmitt, a mechanical heart engineer at Providence who works with Icenogle. “So most patients have to be on a mechanical heart to even make it to a transplant.”
Mechanical devices have made strides since the first ones were implanted in the early 1980s. But in terms of long-term survival, a heart pump still falls short of a successful transplant.
Nationally, heart transplant survival averages around 10 years, regardless of age. Patients at the Providence center tend to live longer.
“Our survival for five years (on a heart pump) is looking pretty promising now, but with a heart transplant, we have pretty promising survival to 20 years,” Schmitt said. “So even though the mechanical hearts are moving in that direction, they’re not there yet.”
As technology improves, patients on heart pumps are growing closer to matching the survival rates of patients with donor hearts, said Taylor, of the Cleveland Clinic. Most heart doctors believe the best way to help the most people is to keep improving mechanical hearts.
“We do about 2,200 heart transplants a year in the United States,” Taylor said. “There’s probably anywhere from, who knows, 30, 40, 50,000 patients who could potentially benefit from a heart transplant if we had enough hearts. We’re never going to do enough heart transplants to provide this type of care.”
In the meantime, for patients whose antibodies prevent them from finding compatible donors, trials like Icenogle’s are critical, Taylor said: “Literally, it’s life or death for them.”
‘Moral purchase’
Study participants will face not only the unknown risks associated with their “deleted” immune systems, but also the side effects of drugs; fatigue, fever, chills, peptic ulcers, osteoporosis and diarrhea are just a few. And while the potential side effects are known of each individual drug, they’re unknown of the drugs in combination.
Icenogle said the trial could have implications for patients with a host of other autoimmune diseases. The antibody problem extends beyond heart transplantation to all the autoimmune diseases – type 1 diabetes, multiple sclerosis and others.
Of those groups, Icenogle he said he believes patients who need heart transplants are the “easiest niche” to study. In the case of heart rejection, doctors know which antibodies they’re dealing with – not the case in many other autoimmune problems – and can measure them relatively easily.
And when patients get to Icenogle, they tend to be very sick. Without a transplant, they won’t survive. With their bodies poised to fight off foreign cells, they have little chance of getting a transplant.
“I think a study like this has moral purchase,” he said, “because all these people are going to die.”