StemCell Therapy

When Charlie Luckesen turned 2 the Wednesday before Thanksgiving, his family celebrated with a golden balloon nearly twice his height, a construction-paper banner that spelled out Oh Twodles, and an enormous, icing-swirled cake. But the whole day was tinged with unease.

Before his birth, a flock of cells that should have swept around from his nascent spinal cord to his chest was somehow thrown off, and he never developed an organ called the thymus. Not having a thymus meant not having T cells, and not having T cells meant not having a functional immune system. This ultra-rare condition, known as pediatric congenital athymia, left Charlie deeply unprepared for life outside the womb. To him, a common cold or an everyday speck of bacteria could be deadly.

My oldest the one thats 7 hes frequently asked what happens if Charlie dies, said their mother, Katie Luckesen, who lives in San Diego. To her, its a legitimate question: Her whole family knows that without treatment, Charlies disorder is usually fatal by 2. And here he is, at two years old

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All that was supposed to change on Wednesday, when the Food and Drug Administration had to decide whether it was approving a tissue implant that can dramatically increase such childrens chances of survival. Since 1993, 101 children have gotten the experimental treatment at Duke University Hospital, and 73 of them are still alive. With numbers like that, the approval seemed like a shoo-in, almost a formality. As soon as the positive decision was announced, the Luckesens were told, theyd get a call about scheduling Charlies surgery.

On Wednesday, Katie Luckesen checked her phone again and again while snuggling with her daughter, while helping the kids with schoolwork, while making stovetop Christmas toffee but the good news never came. Only the next morning did she learn that regulators had rejected the application. The issues raised were not about how safe or effective the treatment was, but rather about certain manufacturing problems, according to Enzyvant, the Cambridge, Mass., company that commercialized the treatment.

Everyones kind of reeling today, Luckesen said. I dont think anyone knows what to think yet. Does it mean they can continue doing transplants or does it mean theyre going to go back on hold?

Enzyvant declined to disclose the specific issues that led to the FDA rejection of the therapy, called Rethymic. This is definitely a surprise, said Rachelle Jacques, the companys CEO, adding that its priority is to make sure patients get treated as quickly as possible. She wasnt sure what would have to happen for doctors at Duke to continue performing the procedure as an experimental treatment while Enzyvant responds to the FDAs concerns.

I tell ya, everybody in their lives has a time when theyre knocked down, said Dr. Louise Markert, the Duke immunologist who pioneered the technique. And you know, what you have to do is get back up and keep working. Its not pleasant being knocked down at all, but you just have to get back at it.

For parents, though, every moment of delay is another one in which they might lose their child to an infection. Unfortunately some have passed in the wait, said Maggie Shaw, of Orillia, Ontario, whose daughter, Aunika Kerr, received Markerts treatment in the summer of 2017.

Katie and JD Luckesen have already taken Charlie for countless tests to show hes eligible. Theyve already fought two insurance denials to make sure that the therapy will be covered even if it hasnt yet been approved. Theyve already waited through all of 2018, while Markert stopped treating kids to compile data for the FDA. Theyve already waited through much of 2019, knowing that experimental operations had started up again and hoping Charlies turn would come.

Occasionally, they disagree about how best to handle the uncertainty. JD is a military chaplain who spends his days talking over Navy members darkest fears and memories. He believes in addressing issues head on. Weve had discussions If Charlie were to pass, where would we bury him? said Katie. Because hes a chaplain, he feels, its important to have the discussion ahead of time, and I would rather bury my head in the sand and not think about it sometimes.

Even within herself, though, shes divided. The intellectual part of her understands that the FDAs work is important, that it helps keep treatments safe. But the mother in her hates it. I just want to send them pictures of my son, to say Look at this face, how can you not approve something that is his only chance at life?

It all began with an unexpected call in 1991. Markert happened to be on duty when the phone rang, and she found herself talking to her counterpart at a hospital in Knoxville, Tenn. He said he had an infant on his hands that he didnt know what to do with. Out of the nearly 4 million babies born each year in the United States, only 20 or so are born without a thymus, and because of genetic mutations or chemical imbalances during development or causes still unknown, this kid was unlucky enough to be one of them. There was no accepted treatment. Did Markert want to take charge of his care?

Sure, she said, and the child was transferred from Knoxville to Durham, N.C. The baby came and unfortunately had a medical event and died, she recalled. But I was already on my way: I was trying to learn how to slice thymus so that it might be implanted in a patient.

To most of us, the thymus is one of our obscurer bits, belonging with the pineal gland and the gall bladder on the list of lumps you may have heard of but couldnt pinpoint on a bodily map. To a pediatric cardiac surgeon who is trying, say, to patch up a hole in a newborns heart with cloth or with tissue taken from the thorax of a cow, the thymus occupies a slightly different role: Its a nuisance, an obstacle to work around. Peel away the layers of an infants chest, and youd see only part of the heart, strawberry-sized and pulsing. Whats covering the top half is the thymus.

If you were to take the whole thing out and splay it out youd think, That looks kind of like a butterfly, said Dr. Joseph Turek, chief of pediatric cardiac heart surgery at Duke. He doesnt do that. Instead, with his forceps, he pulls apart the ghostly membrane around it, cauterizes any blood vessels he needs to sever, and lifts out most of the organ, knowing that a pennys width of thymus is enough for the rest to grow back. In operating rooms around the country, the part thats cut away is just trash, to be carted off along with bloodied drapes and plastic suction tips and other surgical tools that arent reused.

Thats what Markert was trying to slice. It sounds almost too convenient: Some babies missing a gland, others who need to have most of theirs resected. But she knew it wasnt that simple.

To explain why, she likes to imagine T cells as kids. Like other white blood cells, these ones are born and bred in the bone marrow but unlike some, they get trained in the thymus. Thats where they learn to recognize whats foreign and whats self, what to attack and what to leave be. This is like a real schoolhouse: it takes about six months for the graduation, and the blood cells that come out of the thymus, they wear a graduation cap, she said.

If she had transplanted a lump of thymus from one baby into another, as you might with a piece of liver, all those newly graduated T cells wouldve recognized the recipients body as foreign and mounted an attack. Earlier doctors were aware of this. Theyd been slicing up the organ into bits long before 1991, and were already vigilant for signs of rejection. But they didnt have a foolproof way of detecting those molecular graduation caps. They couldnt tell whether a babys thymus was producing real, well-trained T cells, or whether the chemistry of the bone marrow had forged a kind of feral militia, good at charging but bad at discerning friend from foe.

Around the time that baby arrived from Knoxville, that was starting to change. Another researcher at Duke, an infectious disease specialist and immunologist named Dr. Barton Haynes, had spent years unraveling the mysteries of the thymus. His team had picked apart samples, classifying cells, poring over tissue swirls. They concocted chemicals that would glow in the presence of different components, could tell a T cell from an imposter. We learned how the schoolhouse is built, he said. We learned how the roof came on and how the rooms were made.

That meant they could tell Markert whether her thymus slices were worth implanting. Her task was tricky: The tissue needed to be alive but mostly emptied of its T cells. So, using previous research as a guide, she turned a Petri dish into a kind of amphibious terrarium for tissues. Shed set sponges in a nutritious broth, with her organ slices on top. Every day, shed drip a solution over her pets, both to keep them moist and to wash out most of their T cells. At first, the liquid in the dish would become milky with these remnants of the donors immune system. But then, day by day, as the ritual progressed, and fewer white cells were left, the stuff grew clear.

In retrospect, it sounds easy. It wasnt. Markert brought every sample to Haynes, who would freeze it and slip it under the microscope. Hed say, Oh, Louise, its all dead. You can never put this into a patient. Go back and try again, she remembered. So shed go back and try again. It was only after three or four tries, long after that first baby had died, that his fluorescent markers gave off the kind of light show he was looking for. Finally, the tissue was alive.

In a traditional transplant, an organ goes where the body normally grows it. But as she prepared to try out her carefully tended slices in a child for the first time, Markert asked an endocrine surgeon where might be the best place to implant them. He suggested the quadriceps, at the front of the thighs: It was easily accessible and chock full of blood vessels through which T-cells-to-be could arrive. In the operating room, the surgeon didnt even have to cut away muscle to make room for the thymus tissue; instead, he poked little troughs into the flesh, the way a gardener might in soil, and then seeded rows of thymus bits into the babys legs. Its like planting tulips, Markert said.

The change didnt happen immediately. The child was still vulnerable to infections for a while. But six months to a year after their first implantation, the team could tell that the patient had a working immune system. That meant that cells had left their home in the bone marrow and successfully finished schooling at this line of mini-thymuses in the childs thighs.

Its an amazing testament to her doggedness, Dr. Kathleen Sullivan, division chief of allergy and immunology at Childrens Hospital of Philadelphia, who was not involved in the research, said of Markert. She built this up; she overturned paradigms. No one thought thymic transplantation would work.

The treatment didnt just work. It worked so well that there was an imbalance in supply and demand, so well enough that people went into debt.

Shaw remembers how scared she was when an immunologist who didnt know much about Markerts work explained Aunikas athymia. He basically said, Shes not going to make her first birthday, enjoy her while you can, Shaw recalled.

Hed mentioned some unproven procedure, though, and so Shaw found and contacted Markert herself, and then convinced Ontarios health ministry to cover the implantation. One Friday in the spring of 2017, the family got an unexpected call. It was Markert. She had a potential thymus for Aunika; could they be in North Carolina by Monday? They drove the 13 hours nonstop, in shifts. That thymus didnt seem healthy enough after all, but in July of that year, six thymuses later, Markerts team found one that worked. Now, Aunika is 3, and ready to start preschool next September.

Were still in debt, Shaw went on. One of her medications that she had to have was $900 every 10 days. That adds up. Even with the familys own fundraising and insurance coverage for the procedure itself, the parents had to take time off from their teaching jobs, and found themselves spending exorbitant amounts on the suction machines, IV poles, and feeding tubes required by their daughters complex medical problems. It was expensive just to keep her infection-free. I became a thief every time we went to the hospital. I was pocketing boxes of gloves, pocketing boxes of masks, Shaw said. Were all guilty of it, in our community.

Markerts program was in a similar kind of trouble. She said that even with external grants, because of government restrictions about billing for investigational products and the extensive follow-up her patients needed, her work was in a precarious state. Thank God for Enzyvant. You lose money doing this. I was going to run out of money in January 2017. We would have stopped thymus implants, she said. Thank goodness they were interested in helping this tiny group of patients.

Enzyvant licensed the technology and began paying for the work needed to seek FDA approval. (Markert and Duke have received royalties from the company.)

Financial considerations are part of the reason that families and physicians were so eagerly awaiting the official acceptance: The regulatory change would open the door to more insurers agreeing to cover the procedure, and would allow more hospitals to eventually start performing it. Enzyvant estimates that four out of five patients who need the procedure have been unable to get it while its still experimental.

Since now all 50 states are screening for T cell deficiency, the detection rate for congenital athymia has increased, and its becoming obvious that there are more of these babies being born than we realized, said Dr. Ivan Kinyue Chinn, assistant professor of pediatric allergy and immunology at Baylor College of Medicine.

But only two hospitals in the world have been doing this work Duke and Great Ormond Street Hospital, in London, where Markerts group taught their techniques to a team of specialists which creates a bottleneck in treating an illness that often presents a race against time. Even if you keep a child in isolation, visiting only in gowns and gloves, its hard to keep infection at bay.

Someone uses their gloved hand to push their glass up their nose and suddenly theres some germ on their hands it doesnt take much, Markert said.

Thats exactly what the Luckesens are worried about. For much of Katies pregnancy JD had been away, aboard the USS Princeton, cruising through Asia and the Middle East, the details of his travels classified. He got home the day before Charlie was born. We had one week of bliss, where everyone was home and happy and healthy, she said.

Then, the results of the newborn screening came in. They went to see an immunologist, who walked in wearing full isolation regalia; thats when Luckesen knew the problem was serious. One of the first things they said was: Stop breastfeeding immediately. It can be fatal to these kids, she said. They said it cant be powdered formula, it has to be liquid. So I go to BabiesRUs, Im buying those little newborn two-ounce bottles, Im just bawling walking around the store.

To protect Charlie, she pulled her older kids out of school and starting teaching them at home. In a sense, the whole family went into a kind of isolation. The oldest remembers the feeling of being in a real classroom, going to friends houses, touching the rough skin on a stingrays back at SeaWorld. Hes always asking when are we going to get to friends houses or when can we go to the zoo, she said.

Now, she doesnt know. She prays with her kids at dinnertime and at bedtime. They belong to the Church of Jesus Christ of Latter Day Saints, though they havent been to a service since Charlie was diagnosed. Our church believes that families are forever, thats something that really helps us discussing with our kids if Charlie were to pass, she said.

Still, she is trying to keep her mind off the FDA decision so she doesnt get too angry. Everything is ready should Charlie get a chance at an operation. Their military benefits even include being flown privately from California to North Carolina. We cant take a commercial plane, because thats a germ box, she said. For Charlie, with no immune system, thats a death trap.

All theyre waiting on are these regulatory issues, a call from Duke, and a suitable piece of thymus.

See the article here:
Families reeling after FDA rejects therapy for kids without a thymus - STAT

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