Emily Hood had already beaten the odds. At age 17, she had been diagnosed with an extremely rare, inoperable tumour lurking at the bottom of her brain. A year and a half later, she was still alive, which put her in a very fortunate minority. People with her form of brain cancer, known as diffuse intrinsic pontine glioma (DIPG), generally survive for only 8–11 months after diagnosis.
At 18 years old, Emily, in a last-ditch attempt to combat the cancer, decided to volunteer for an experimental cell therapy that harnesses the power of the immune system.
Part of Nature Outlook: Children‘s health
Part of Nature Outlook: Children‘s health
Scientists at Seattle Children’s Hospital in Washington collected immune cells called T cells from Emily’s blood and equipped them with a surface protein known as a chimeric antigen receptor (CAR). This protein binds to a specific target on cancer cells, creating tumour-fighting T cells that can home in on and kill cancerous tissue. In October 2020, physicians injected the genetically reprogrammed cells through a port implanted under Emily’s scalp. She was the first person with DIPG in the world to receive CAR-T-cell therapy administered directly into the brain.
CAR-T cells have revolutionized the treatment of some blood cancers, including a paediatric form of leukaemia that accounts for around one-quarter of all childhood malignancies. But the cellular immunotherapy has so far failed to make a dent in reducing the burden of solid tumours, such as the one that was spreading throughout Emily’s brain stem. And, although there is an immense clinical need to extend CAR-T-cell therapies into all realms of solid-tumour oncology, regardless of the age of the person, physicians who treat childhood cancers of organs such as the brain, bone and muscles say that the need is particularly acute in those under the age of 18.
A chance to grow up
“In paediatric oncology, there is not much alternative,” says Claudia Rössig, a cellular immunotherapist at University Hospital Münster in Germany. For adult cancers, there are targeted agents and immune-modulating drugs that can extend the lives of people, often for many years. But for children, these types of cutting-edge therapeutics have largely fallen flat.
What’s more, notes Rössig: “In the paediatric setting, it’s not enough for us to gain time. We have to cure [the cancer],” she says, “and because T cells have this endogenous property of being able to persist, stay behind and control the disease for a long time, they have the ability to be curative.”
That’s been shown already for paediatric leukaemia. Solid tumours could be next.
Emily’s CAR-T-cell treatment bought her some time, but it wasn’t the panacea she had hoped for. Emily died earlier this year, shortly after her 20th birthday. The fact that the CAR-T cells proved tolerable, with hints of anti-cancer activity, means that the effort was not for nothing.
As her mother Sharon Hood recalls, Emily was motivated in part by the quest to advance medical progress towards new treatments for the disease. “She was always doing it not just for herself, but so that hopefully little kids [with DIPG] would have a chance to grow up.”
Emily won’t get to see that happen. But physicians who have run trials of CAR-T-cell therapies in people such as Emily are more optimistic than ever that such a day will come.
“There are several patients — a sizeable fraction — who are experiencing benefit,” says Crystal Mackall, a cancer immunotherapy researcher at Stanford University School of Medicine in California. Together with her colleagues, Mackall has treated around a dozen children with DIPG with a different CAR-T-cell product. The researchers have even observed a near-complete elimination of the brain cancer in one teenage recipient.
“It’s not a home run,” Mackall says. But it’s an indication of the treatment’s potential — which, as Nicholas Vitanza, a neuro-oncologist at Seattle Children’s Hospital who treated Emily, points out, “is what drives us to make the next generation of CAR-T cells better”.
Improvements are coming from a number of different directions. Researchers are discovering new targets that could lead to safer, more-effective therapies. They are incorporating additional genetic circuitries to help the cells persist longer and stay active in the body. And they are finding ways to subvert tumours’ ability to suppress immune responses.
Many of these innovations will be needed to deliver on the immense promise of CAR-T cells for solid tumours in adults and children alike. But the biology of paediatric tumours, which mostly stem from irregularities in early-life stages of cellular development, is fundamentally different from that of adult cancers, which arise typically through a lifetime of acquired mutations. And given those distinct mechanisms of disease, researchers say, a dedicated discovery effort is needed to tailor the design of CAR-T cells to childhood cancers.
The typical trickle-down approach of repurposing therapies that have been developed for adult cancers just won’t do, researchers say. And with few treatment options available for the 20% of children whose tumours cannot be contained by chemotherapy, surgery and radiation alone, there is an urgent need for new therapeutic approaches that can wipe the cancer slate clean.
CAR-T cells, if constructed just right, offer that sort of treatment potential, which explains why so much effort is being put into getting the platform to work for children. “Our vision is to make T-cell therapies standard of care for paediatric solid tumours within a decade,” says Catherine Bollard, who is a paediatric cell therapist at Children’s National Hospital in Washington DC. “It’s really bold,” she concedes — but also, she argues, an achievable goal.
So far, most clinical trials involving CAR-T cells for paediatric solid tumours have focused on a select number of targets — mostly proteins such as B7-H3 (also known as CD276) or complex sugar–fat molecules, such as GD2, that are commonly expressed at high levels on the surface of childhood cancer cells but rarely expressed in normal tissues.
“So, with one CAR-T-cell product we can treat patients with many different diseases,” says Christopher DeRenzo, a paediatric oncologist at St. Jude Children’s Research Hospital in Memphis, Tennessee, who is currently running a study for people under the age of 21 with any cancer expressing B7-H3.
That’s important, says Seattle Children’s oncologist Katie Albert, because even the most common solid tumours are exceedingly rare in children — each cancer typically affects only a few hundred youngsters annually in the United States. That scarcity makes it hard to develop therapies and run trials for a single type of cancer. But it becomes feasible when those rare cancers share a common antigen. As Albert explains: “The goal is to choose targets with the biggest impact.”
Still, the targets pursued are far from ideal. Many of the antigens are not universally expressed on all cells in a tumour, and it only takes a small cluster of evasive cells to seed a relapse. What’s more, because the target molecules are not essential to cellular survival, tumours can evolve ways of ditching them to become resistant to the cellular immunotherapies.
“There’s no perfect target,” says Rössig. Perhaps it is no surprise then that only a smattering of children have seen their solid tumours drastically shrink after CAR-T-cell therapy.
Vitanza, for instance, has led trials of three antigen-directed CAR-T-cell products and administered hundreds of cell infusions to more than 60 children. And although the tumour of one young boy with DIPG has been successfully beaten back for more than 14 months and, with infusions every 2 weeks, has no signs of growth, the responses of most children have been much more muted1.
That echoes the findings of others. In the United Kingdom2 and China3, for example, investigators have evaluated anti-GD2 CAR-T cells in small cohorts of people with relapsed neuroblastoma, a paediatric cancer of the nerve tissue. The therapies passed safety tests, but no child experienced tumour shrinkage in either study.
With feasibility now established, one way to improve on these early CAR-T-cell constructs is with new targets that better represent the peculiarities of various childhood cancers — and leading the hunt for new tumour antigens is Misty Jenkins, a cancer immunologist at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. Concentrating on paediatric brain tumours, Jenkins and her colleagues have systematically characterized the proteins found on the surface of biopsied tissues. In unpublished work, she says, “we’ve identified a bunch of new targets”, including many that, although not genetically mutated, are altered in ways that could allow them to be selectively targeted.
Researchers at the Children’s Hospital of Philadelphia (CHOP) in Pennsylvania have another approach. Instead of looking for suitable cell-surface proteins, the team has focused on proteins normally found only inside the cell, the presence of which is displayed on the surface through a specialized immune-alert mechanism. The researchers showed that CAR-T cells directed against one such target could eliminate neuroblastoma in mouse models4. They are planning to begin a clinical trial in 2023.
Even with the existing suite of antigens, better outcomes could come from administering more potent CAR-T cells. Bollard thinks that this might be achievable, in part, by pre-screening the immune cells of people with cancer for T cells already primed to detect tumours, and then engineering CAR constructs into those pre-activated cells. Now, through a 5-year, US$25-million grant awarded in June 2022, Bollard is putting the idea to the test.
Together with collaborators at University College London and Stanford, Bollard plans to run three parallel clinical trials of CAR-T cells that target B7-H3 for paediatric cancers. Two trials will focus on soft-tissue sarcomas, with one key difference: one will use unselected T cells with no pre-screening step; the other will deploy T cells chosen for their ability to recognize a common tumour antigen known as PRAME. A third trial will use unselected T cells that, after engineering, are administered by direct injection into the brains of children with high-risk tumours.
“We’ll be able to do a direct head-to-head comparison in clinical trials about whether the T cell that you’re engineering is important,” Bollard says.
In addition to the CAR construct, the T cells in all three of these trials will get one additional genetic tweak: they will carry an extra protein that mops up growth factors that normally block the ability of T cells to strike their target. What’s more, these growth-factor-hoovering proteins are designed to transform the usually repressive signal into one that revs up T-cell activity instead. “It’s making a negative into a positive,” Bollard says.
That’s just one of many modifications that researchers are now incorporating into refinements of CAR-T-cell therapy to treat solid tumours in children. Others are adding signalling molecules or co-stimulatory receptors that give T cells an extra push to proliferate. Some are incorporating factors that help to prevent T cells from becoming overstimulated and entering a dysfunctional, exhausted state. “From an engineering point of view, the possibilities are numerous,” says Karin Straathof, a paediatric oncologist at University College London Great Ormond Street Institute of Child Health.
At the University of Colorado School of Medicine in Aurora, paediatric oncologist Michael Verneris and his colleagues have enhanced the ability of CAR-T cells to travel to their target tumour site. In a study of childhood sarcomas5, the researchers found that, after radiation treatment, cancer cells begin to spew out the signalling molecule interleukin-8. This molecule is known to attract some types of immune cell, but not T cells — usually, T cells don’t express the receptor for interleukin-8 on their surface.
So, Verneris’s team engineered that function into its CAR-T cells. The researchers showed that these receptor-enhanced cells were more potent cancer killers in mice than normal CAR-T cells. According to Verneris, the added functionality promoted cell movement to tumours and, as a bonus, triggered metabolic changes that made the cells more active once they reached the tumour site.
Even the best-designed cells can still face stiff challenges, however, unless researchers also address the immune-suppressive conditions that surround most tumours. “That is one of the really important variables that will really define the success of CAR-T cells and other immunotherapies in childhood solid tumours,” says Paul Ekert, a cancer geneticist at the Children’s Cancer Institute of Australia in Kensington. “But it presupposes that we know all the mechanisms that are excluding T cells from high-risk childhood tumours,” he adds, “and that’s where I think we have a lot to learn.”
One clue to the challenges that CAR-T cells could face in tackling children’s tumours emerged earlier this year, when researchers showed in cancer-bearing mice that the tumour environment in young pups is especially hostile to infiltrating T cells6. Although the researchers didn’t study CAR-modified cells, they did find that non-engineered T cells were shut down more quickly in young mice than in older animals. Such age-associated differences in the tumour microenvironment could stymie efforts to develop effective CAR-T cells for paediatric cancers.
The first CAR-T-cell therapy to win marketing approval was actually one for children and young adults, rather than for older adults. But that was a “bit of an accident of history”, says Stephan Grupp, director of cancer immunotherapy at CHOP. The commercial sponsor of the therapy for acute lymphocytic leukaemia (ALL), Novartis, wasn’t originally intending to develop a treatment for children.
Back in 2012, when the Swiss pharmaceutical giant entered into a strategic alliance with the University of Pennsylvania and its affiliated hospitals (including CHOP) to develop CAR-T-cell therapies, it was focused on adult leukaemia. The initial push into ALL, the most common type of childhood cancer, was purely an academic effort. And according to Grupp, it was only after he and his colleagues had treated more than a dozen young people7 — inducing lasting remissions in nearly all of them — that Novartis took an interest in the programme and started funding trials of its own.
Outside academia, few other CAR-T-cell developers have devoted substantial resources to childhood cancers, and no comparable products have been approved for under-18s. Most companies instead focus on adult cancers that are more common and, therefore, present more lucrative market opportunities.
There are exceptions, however, such as Umoja Biopharma in Seattle. The company’s first clinical-stage candidate is a CAR-T-cell platform that takes advantage of a tumour-tagging system developed in the laboratory of one of the co-founders, chemist Philip Low at Purdue University in West Lafayette, Indiana, to combat bone cancers of childhood and adolescence. A clinical trial began enrolling teenagers and young adults earlier this year. “It’s a technological leap that is playing out for the first time in kids,” says Michael Jensen at Seattle Children’s Hospital and co-founder of Umoja Biopharma.
Ivan Horak, chief medical officer and chief scientific officer at Tessa Therapeutics, a CAR-T-cell therapy developer based in Singapore, predicts that the industry will eventually dedicate more effort to childhood cancers of the brain, bone and other organ systems — but only after scientists first solve many of the biological challenges that have precluded the success of CAR-T-cell strategies in solid tumours of any kind. “We have to see some light at the end of tunnel for solid tumours in adults before we aggressively move to children,” he says.
Oncologists who treat dying youngsters don’t want to wait that long. And they are continuing with CAR-T-cell trials for solid tumours in the hope that they can generate enticing data of the kind that Grupp and his team presented to Novartis. The field isn’t there yet, says Jensen, but “I’m more optimistic than ever that we’re getting really close”.