Waning treatment for immune deficiency is a warning for all ‘one-and-done’ therapies

By ERIC BOODMAN

As a new mother, she didn’t know to look for blue-tinged lips. She could just tell her baby’s color was off. On a chest X-ray, the clean, white-against-dark curves of his ribs were obscured, clouded by fluid. Pneumonia. That tipped Ray Ballard’s physicians off: He had a form of severe combined immunodeficiency — SCID, for short — a genetic mutation that hampered the growth of crucial immune cells, leaving him utterly vulnerable to infection.

The best fix was a transplant of his mother’s bone marrow. “The attitude was that in three to six months, you should be able to go back to normal life,” recalled his mom, Barb Ballard.

That was true — at least sort of. He got two more booster transplants before he hit 10. An antibiotic left him with hearing loss, and a virus with digestive tract damage. His lack of B cells meant he needed regular injections of other people’s antibodies, and his T cell counts were never ideal. But he was healthy enough to go to public school, to move through the hallways high-fiving half the guys, to slowly inhale and take aim during rifle team practice.

“His T cells had to be working well enough that he wasn’t coming down with everything that walked into the classroom,” Ballard said.

Then, when Ray was around 18, his immunity began to wane. For him, it came in the form of a norovirus he couldn’t shake. For others with the same rare disease, it appears as pneumonia or gastrointestinal trouble or an unexpected T cell decline. Over the last 10 years, the trend has become increasingly clear: The bone marrow transplants that kept certain babies with SCID alive sometimes stop working after years or decades of providing fairly reliable immune defenses.

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Now, to patient advocates, this has become an urgent lesson in the language people use to talk about treatment — and not just for SCID. They see their community’s experience as a cautionary tale for anyone developing or receiving a therapy that’s marketed as potentially curative.

“There’s an expectation and a hope: When they hear about bone marrow transplants, it sounds like a lifetime deal, a forever fix,” said John Boyle, president and CEO of the Immune Deficiency Foundation. “We’ve discovered, as a result of this issue, that bone marrow transplant ended up not being the forever fix we thought it was.”

Experts have known for years that some of these transplants wouldn’t provide full immune protection over the course of a SCID patient’s entire life. They say clinicians should have avoided the word “cure.” But even scientific papers that hinted at such complications called the treatment “curative.” Just this year, an Immune Deficiency Foundation employee was given the unenviable task of sifting through the organization’s thousands of pages of online material, scrubbing out every “cure” that popped up. It was only there a handful of times — sometimes in quotes from clinicians, Boyle said — but it was there and it needed to be removed.

The language patients hear can sometimes even change their outcomes. “We’ve heard of cases where, years later, they realized their immune system isn’t as healthy as they thought, but nobody was tracking that because they hadn’t maintained a relationship with the physician, or the physician didn’t maintain a relationship with them,” explained Ballard. “The word cure, it gives them a false sense of security.”

At a time when seemingly every biotech is promoting the idea of “one-and-done” therapies — and setting prices accordingly — these advocates hope companies, too, will be more wary. “One of the things I’m trying to make them very aware of is the need for lifelong follow-up,” said Heather Smith, who runs the SCID Angels for Life foundation. For her, it’s personal: This summer, her son took part in a clinical trial for a gene therapy in the hope that it would provide the immune protection that his decades-old bone marrow transplant no longer could. “My son will be followed for 15 years,” she said. “But what about after that?”

Part of the issue with bone marrow transplants from one person to another is the natural genetic variation between us, particularly in the proteins that help our bodies distinguish its own cells from foreign ones. Receiving cells from someone whose proteins don’t match yours could cause a civil war within you. That’s why bone marrow transplants began back in the 1950s with identical twins: Sharing those genes meant increasing the likelihood of harmony between the body and the graft.

But the vast majority of people don’t have a protein-matched sibling, let alone an identical twin. So researchers set about figuring out how to transplant bone marrow from a parent to a child — in spite of only sharing half of their genes — and from a matched unrelated donor to a stranger. Like cooks intent on refining recipes to their taste, the doctors who adapted the technique for SCID often did so slightly differently from one another. Over the past 35 years, those idiosyncrasies have hardened into habits. “Right now, everybody transplants their patients their way,” said Dr. Sung-Yun Pai, an immune deficiency researcher and co-director of the gene therapy program at Boston Children’s Hospital.

Perhaps the most vociferous controversy has been about whether to use chemotherapy to wipe out the existing stem cells within a recipient’s bone marrow to make room for the donors’. The doctors who do use chemo before a transplant might prescribe different doses; others forego it entirely.

The arguments were sound on both sides. On the one hand, the toxic drugs could clean out the niches within our bone and increase the chances that the donor’s cells take root. On the other, these chemicals could hamper growth, brain development, and fertility, could make an infant who was already sick even sicker, and could increase the likelihood of certain cancers later in life. “It’s like being exposed to a bunch of X-rays and sunlight, or other DNA-damaging agents,” Pai explained.

Because SCID is so rare — the most common subtype is thought to occur in 1 out of every 50,000 to 100,000 newborns — and because every hospital was doing transplants slightly differently, it was hard for physicians to systematically study what was working best. But even early on, they could tell that some of the infants who’d gotten no chemo were developing incomplete immune systems. They didn’t produce their own B cells, for instance, and so needed regular injections of antibodies collected from other people’s blood.

Ray Ballard in 2012, when he was 18.COURTESY BARB BALLARD

In healthy infants, stem cells migrate from the crevices of the skeleton to an organ in the chest called the thymus, where they’re trained to become T cells. In these infants, the T cell counts grew after transplant — but it wasn’t necessarily because the sludge was securely taking hold in the niches of their bones. Rather, immunologists say, the donor’s progenitor cells were only transient. Some were able to head toward the thymus for schooling. Some graduated and started fighting off infections. But as those populations were depleted with age, there weren’t robust reserves of stem cells in the bone marrow that could arrive to produce more. To Pai, it’s like trying to fill a kindergarten class in a neighborhood where no one’s having babies.

“You and I continue to have a slow trickle of new T cells coming out,” said Dr. Harry Malech, a senior investigator at the National Institutes of Health, who sits on the board of a gene therapy company, Orchard Therapeutics (ORTX), but does not receive any financial compensation. “Instead of a torrent becoming slower, in these patients it goes from a trickle to practically nothing.”

That’s why immunity starts to wane in kids like Ray Ballard. To many immunologists, it isn’t a surprise, though they still aren’t sure why chemo-less transplants last longer for some of these kids than others. They can also understand how some families and clinicians might have viewed this treatment as a lifetime fix.

As Malech put it, “If I said to you, ‘Your child, instead of dying in infancy, will likely get to adulthood, go to school, have a normal life,’ you might think the word ‘cure’ in your mind.”

Even for parents who knew the protection might not last forever, the failure of a long-ago bone marrow transplant puts them in a bind. If they do nothing, their child will once again be vulnerable to any passing infection, which could prove fatal. They can try another round of the same procedure, though booster transplants sometimes come with added complications. Or they can try getting their child into a research trial for gene therapy, which comes with the risks of any experimental treatment.

Some feel an irrational guilt when the bone marrow they donated to their child stops functioning. “It’s your cells, and if it doesn’t work, you failed them,” said Ballard, who lives in Clifton, Va., about a 40-minute drive from Washington, D.C. Her son Ray had already had three transplants as a child. When his immune system started to fail again in early adulthood, gene therapy at the NIH seemed like the only reasonable choice.

Related: Families are reeling after FDA rejects therapy for kids born without a thymus gland
That would involve researchers removing cells from his bone marrow, using an engineered virus as a kind of molecular syringe to slip in a healthy copy of the gene in which he had a defect, and then threading these corrected cells back into his veins — a bone marrow transplant to himself. But preparing a virus can be tricky, and there were delays.

Meanwhile, Ray’s condition was getting worse. His norovirus was preventing him from absorbing much nutrition, and as Ballard put it, “his bone structure was just crumbling at that point.” His doctors told her he had the skeleton of an 85-year-old.

He died this past February, at 25 years old. One friend got his birth and death dates tattooed onto her shoulder. Another painted a portrait of him for Ballard, in which his arms are crossed, his lips pressed together in a wry smile.

At Boston Children’s, Pai is now helping to lead a randomized trial to better understand what dose of chemo works best for SCID patients receiving transplants. Over the last decade or so, she, Malech, and many other clinicians have also teamed up to track the long-term results of immune deficient patients who’ve received someone else’s bone marrow.

Pai is hopeful that knowing about the phenomenon of waning immunity will give gene therapies a better shot at becoming a durable fix. “They probably have a better chance of achieving a one-time, lifelong cure, but it’s never wrong to be humble,” she said. “Only after decades more and hundreds or thousands of patients will we know for sure.”

Patient advocates point out that even then, these patients will still have the capacity of passing on their SCID-causing gene to future generations, and so the word “cure” is overly optimistic. “That’s why I like the word ‘remission,’” said Smith. “That still gives you the hope. If you were given a cancer diagnosis, you wouldn’t go through treatment and then just forget about it for the rest of your life.”

As Boyle put it, “We’ve seen the promise and then we’ve seen the reality. Everyone who is looking at a transformational therapy should be optimistic, but also realistic, and not assume that this is truly one and done.” (Boyle’s foundation has received financial support from Orchard Therapeutics, which is developing a gene therapy for a form of SCID.)

To Amy Saada, of South Windsor, Conn., that isn’t theoretical. Her son Adam is now 12, and the immunity from the bone marrow transplant he got as a baby is wearing off. He isn’t yet sick, but his parents know they need to decide between gene therapy or another transplant soon. She has a very clear memory of how long and uncertain the recovery from treatment felt. In some ways, she wishes she didn’t know quite as much as she does; that way, she would feel less trepidation about what lies ahead.

“Your heart kind of sinks,” she said. “You’ve already been through it once, and it was hell. It’s harder the second time.”

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