Tomorrow’s paediatric care: from harnessing gut microbes to gene treatment for the brain

One experimental setback can spawn a medical success. Such an evolution could be underway in the lab of Andrew Koh, a paediatric haematologist and infectious disease expert at UT Southwestern (UTSW) who practices at Children’s Medical Center Dallas — a leading hospital in Texas. At the end of the 1800s, American bone surgeon William Coley injected cancer patients with bacteria in hopes that the resulting infection might fight the cancer¹. “It shrunk lots of tumours, but it also put a lot of patients into sepsis,” says Koh. “This put a halt to Coley’s approach.”

Koh’s lab is trying it again, but with a twist: Coley used bacteria known as ‘Coley’s toxins,’ but Koh’s team is using non-toxic bacterial-derived therapies that help the human immune system fight infections. “Not all microbes are created equal in terms of the immune response that they elicit,” Koh adds. Although this work remains in preclinical stages, preliminary results indicate cancer-fighting potential with limited safety concerns.

That’s just one example of how Children’s Health and UTSW scientists strive to turn basic research into treatments. Physician-scientists in the paediatric department at UTSW explore new approaches to treating childhood cancers, neurological disorders, and more.

“Children’s Health and UT Southwestern integrate two environments on a single platform that catalyses innovation,” says Jorge Bezerra, paediatric gastroenterologist at both institutions. “UT Southwestern clinicians, surgeons, radiologists, and anesthesiologists working at Children’s Health identify questions at the bedside,” says Bezerra. “They take those questions to the laboratories at UTSW hoping to bring back solutions to the children who need them.”

A bacterial boost to immunotherapy

The journey from a child’s hospital bed to a lab bench and back depends on integrating a collection of information. That’s just what Koh’s lab did when exploring the use of microbiota to fight cancer, and the journey started in the gut. As part of Koh’s work as the director of UTSW’s Pediatric Cellular and ImmunoTherapeutics Program (CITP) at Children’s Health, he already knew that melanoma patients respond better to immune checkpoint inhibitors², which block cancer’s attempt to stop the immune system from fighting the disease, if the patient’s gut is enriched with specific microbes. But how do microbes in the gut affect therapies targeting cancer in other organs?

“We found that in order for microbes to influence antitumour responses outside the gut, they needed to be able to move into lymphoid tissues and, ultimately, the tumour,” Koh explains. Even a tiny abrasion inside the gut allows microbes to enter the bloodstream. “Through an unknown mechanism, immune checkpoint therapy even increases the number of bacteria escaping the gut³, but the treatment is only enhanced if the escaping microbes affect immune-cell receptors targeted by the particular therapy.

“We think the bacteria act like an innate immune activator,” Koh says. “This could work with many types of immunotherapy — all of which probably need sufficient innate immune activation to prime the T cells to kill the cancer.”

Hopes of getting an even bigger treatment effect drove the work to ultimately develop injectable therapies using non-live products derived from the gut microbiome — an upgrade on Coley’s toxins. Instead of pretreating patients with live probiotics and hoping that enough of the right bacteria escapes, treatments will involve injecting specific immune enhancers purified from the gut microbiota to improve response to chemotherapy. While other potential cancer immunotherapies are on the horizon, targeting gut microbes is an exciting new approach.

Advanced treatments need targets

As oncology evolved from generally toxic chemotherapies to more specific treatments, it all depended on finding and attacking specific targets. That’s the objective behind chimeric antigen receptor (CAR) therapies, where cells from a patient are engineered to fight cancer. Although CAR-T cell therapies work well with some cancers, others resist such treatments — often because there’s no known target.

With acute myeloid leukemia (AML), for example, scientists could not find a way to make CAR-T cells attack this cancer. Existing treatments failed many children, leaving about 30% to die of the disease within five years of diagnosis⁴.

Nonetheless, the surface of AML cells includes molecules in the leukocyte immunoglobulin-like receptor-B (LILRB) family. By labeling specific LILRBs and then analyzing samples with flow cytometry, Samual John, a UTSW paediatric haematologist-oncologist at Children’ Health, who is the CAR-T medical director for CITP, and colleagues found that nearly all AML cells include these receptors⁵.

From that discovery, John’s team developed an anti-LILRB CAR-T cell. It targets AML cells and created no toxicity in preclinical studies. In the next few years, this potential therapy should start human clinical trials.

Getting to the brain

In brain-related diseases, even getting a therapy to the organ creates a huge challenge. “When treating neurological diseases in general, it’s difficult to deliver drugs to the brain,” says Steven Gray, a molecular biologist at UTSW whose research benefits patients at Children’s Health. “Plus, most of these disorders are genetic.” Even when the precise genetic cause is known, clinicians lacked a way to get a gene therapy to its target because of the difficulty in crossing the blood-brain barrier. Gray hopes to change that with gene therapies carried by modified adeno-associated virus (AAV) delivery systems.

Traditionally, delivering AAV-based gene therapies to the brain required drilling a hole in the skull and injecting the viral particles. “That approach usually treats only very small pockets in the brain, and it’s very invasive,” Gray says.

Some AAVs can cross the blood-brain barrier. So, Gray and his colleagues develop AAV-based gene therapies that can be injected into a child’s spinal fluid, “which distributes them more broadly across the brain,” he explains.

Gray’s team already used this method to test a treatment for giant axonal neuropathy⁶, which he describes as “a devastating paediatric disease with basically no treatments.”

Many other diseases might also be treated by using different AAVs and arming them to deliver various gene therapies. We’re investigating their application for additional diseases, but we have to be deliberate and proceed carefully,” Gray explains.

One day, scientists at UTSW, in collaboration with Children’s Health, hope to use these technologies and ones yet to be developed to personalize treatment for a specific patient.

“We want to develop new therapies to treat children not only with options we have, but with what the child needs now and in the future,” says Bezerra. “That day is coming soon.”