Forging New Frontiers in Health Care

Volume 6

Forging New Frontiers in Health Care

CHOP’s Frontier Programs accelerate medical breakthroughs for children

By Michelle Andrews



Every day, children of all shapes, sizes, and backgrounds come through the doors of Children’s Hospital of Philadelphia. While routine care meets the needs for some patients, other children face life-altering - sometimes life-threatening - conditions that require a whole different level of expertise. In those most difficult cases, CHOP’s top-notch professionals are committed to finding answers –- sometimes where none have existed before.


Advancing visionary research and cutting-edge clinical care is critical not only to the children who are CHOP patients today, although that is paramount. It’s also vital to the institution’s reputation as a premier children’s hospital and its long-term success in helping future patients and attracting top-notch staff.


In a place like CHOP, there is no shortage of game-changing thinking. But how to identify the institution’s best ideas and nurture them for the future? Faced with this challenge, leaders at CHOP developed a system to provide extra funding and support for several of their most promising enterprises. Nearly three years after the first Frontier Programs were launched, the hospital is seeing results.


A storied history


Children’s Hospital of Philadelphia has been in the business of helping children longer than anyone else. Established in 1855, the hospital was the first in the country dedicated to treating pediatric patients. Since its beginning as a 12-bed facility, the hospital has grown to more than 500 beds and now includes a rehabilitation facility, a renowned research institute, and a regional Care Network with more than 50 locations. Families from all over the world bring their children to see the specialists at CHOP; the hospital has more than a million patient visits annually.


Many of the children who come to CHOP are treated for rare diseases that require complex, interdisciplinary care.


The goal for the many children’s hospitals and facilities around the country is to bring breakthrough research to the patient’s bedside quickly. When Dr. Joseph St. Geme arrived as CHOP’s Physician-in-Chief in July 2013, then CEO Dr. Steven Altschuler, tasked him with developing a blueprint to standardize that process. In a series of brainstorming sessions, St. Geme and a group of the hospital’s clinical and administrative staff worked toward answering the question: How can we promote innovation that unravels the mysteries of complex conditions, helping more children and in the process enhancing CHOP’s reputation?


Blueprint for excellence


In addition to supporting the provision of extraordinary, complex, interdisciplinary clinical care and breakthrough research, the group agreed the new initiative, whatever it was, had to provide the opportunity for a return on investment. At first it defined ROI narrowly, focusing on translating research and clinical ideas into intellectual property that could be commercialized.


But then it broadened the focus.


“We were interested in programs that might expand our patient numbers, expand the intersection with other care providers and augment the vitality of the institution as well,” St. Geme says.


That was the genesis of the Frontier Programs. The way they work is simple but effective: through a competitive process, Hospital leadership identifies two to three pioneering programs each year that receive extra funding and programmatic guidance from a multidisciplinary steering committee. Applicants must describe how Frontier Program funding could help them provide extraordinary patient care and develop breakthrough translational therapies. Programs that are selected receive support for an initial three-year period, with the intent that the combination of their clinical volume and/or research breakthroughs will enable them to transition to a self-sustaining model over time.


In 2015, the hospital selected the Lymphatic Imaging and Interventions program and the Cancer Immunotherapy program as the inaugural Frontier Programs.. The success of these programs drew significant attention from across CHOP. The following year, the hospital received 19 applications from across the hospital and winnowed the group to four, and then to two. The winning programs were the Center for Thoracic Insufficiency Syndrome and the Center for Pediatric Inflammatory Bowel Disease.


Later, it repeated the process, this time reviewing 15 applications. It funded three: the Mitochondrial Medicine Center, the Center for Pediatric Airway Disorders, and the Newborn and Infant Chronic Lung Disease Program.


There are currently seven Frontier Programs, with two new programs scheduled to be added in July, 2019. To gauge how well they’re accomplishing their goals, the selected programs are required to report on a variety of performance metrics, including the number of patients served and outside grant support.


Collectively, the first seven Frontier Programs have provided care for more than 3,000 patients from more than 40 states and at least fifteen different countries. These children have had more than 400 surgeries and received nearly 8,500 infusions. Four of the programs have already sought some type of intellectual property protection on their discoveries. While this intensity of care and discovery reflects remarkable impact, the numbers tell only part of the story.


“We were interested in programs that might expand our patient numbers, expand the intersection with

other care providers, and augment the vitality of the

institution as well,” St. Geme says.

Cancer immunology breakthrough


To understand the significance of the work performed by the Cancer Immunotherapy group led by Dr. Stephan Grupp, look no further than the treatment called chimeric antigen receptor (CAR) T-cell therapy.


Cure rates for childhood acute lymphoblastic leukemia (ALL) have improved dramatically. But there is a subset of patients for whom no traditional therapies are effective. Until recently, most of these children had run out of options.


With CAR T-cell therapy, a patient’s own immune cells are genetically altered to seek and destroy the cancerous cells in his or her body. In 2012, CHOP treated the first pediatric patient as part of an experimental protocol, and has since treated more than 170 leukemia patients whose disease hadn’t responded to other therapies or had relapsed. To date, 94% of children who receive this treatment at CHOP achieve initial remission.


Drug manufacturer Novartis licensed the therapy, and Grupp was the lead investigator for the global trial that in August 2017 led to the first approval by the Food and Drug Administration of a CAR T-cell therapy, for patients up to age 25 with ALL that has relapsed or not responded to treatment.


“From my perspective, I’m especially pleased that this was the first FDA approval and that it was in children,” Grupp says.


Grupp and researchers at the University of Pennsylvania had been working on developing CAR-T therapy long before the Frontier Program was created. But the Frontier funds accelerated the research and provided the infrastructure to support the safety monitoring, documentation, and other requirements for the clinical trials to gain FDA approval, Grupp says.


Crucially, the money helped them scale up so they could treat multiple patients each week instead of just one or two, Grupp adds.


With the FDA approval, CAR-T therapy will soon be available in 35 cancer centers nationwide. But Grupp hopes that CHOP’s unique level of experience providing this therapy and dealing with its side effects will make the hospital a compelling choice for parents of children with the disease.


“We have more experience treating immunotherapy patients than anywhere else in the world right now,” Grupp says.


Treating IBD gets personal


Inflammatory bowel disease (IBD) is the fastest-growing autoimmune disorder in children. A term used to describe a number of disorders that involve chronic inflammation of the digestive tract, IBD can stunt children’s growth and delay the onset of puberty, among other things. Tackling the disease aggressively on multiple fronts is crucial to minimizing the damage to a patient’s development.


CHOP is a world leader in the diagnosis and treatment of IBD. It is making strides on clinical and research fronts to develop more targeted, effective treatments for the more than 1,900 affected children who visit the hospital every year.


CHOP researchers are working to tease out the interplay between genetic and environmental factors that causes the disease. Working with the hospital’s Center for Applied Genomics, the IBD team has identified a number of genes related to the onset of pediatric IBD. At the same time, it’s clear that environment plays an important role. For example, children in developed countries get IBD in far greater numbers than those who aren’t exposed to processed foods, antibiotics, and other amenities associated with developed nations. Understanding why is another key question for scientists.


To that end, researchers at CHOP are working with a pharmaceutical company to develop a drug to reduce inflammation in the roughly 20 percent of children who have a genetic mutation that causes low levels of a protein called DC3R that helps regulate inflammation.


The researchers are ready to begin testing the drug in children for whom other therapies have failed, Baldassano says.


In the meantime, clinicians have more drugs at their disposal than they did in the days when steroids were the primary treatment option. In addition to medical therapies, CHOP IBD team members address the disease from other angles, focusing on diet and nutrition, and helping children cope with the psychological stress of managing their condition.


The hospital funding has also helped the program add staff and build an infrastructure so that it can see children more quickly. On the research side, the extra funds have helped to push the work forward more quickly to understand the genetics of the disease and study the role of the microbiome environment in the gut.



Championing mitochondrial medicine


Mitochondria — tiny organelles that produce energy to power the cells in our bodies — are present in every organ and tissue. When  they malfunction, the result can be massive disruption, including strokes, seizures, heart problems, cognitive and developmental disabilities, gastrointestinal problems, hearing and vision impairment, fatigue, and weakness.


“On average, people with mitochondrial disease have 16 different medical problems, but there can be up to three dozen,” says Dr. Marni Falk, executive director of CHOP’s Mitochondrial Medicine Center. Children with mitochondrial disease often spend years shuttling from one specialist to another before they receive a correct diagnosis.


A genetic mutation is frequently the culprit. More than 300 are associated with mitochondrial disease. Currently, there is no cure, so the focus is on providing supportive care for these very sick patients and conducting research to develop effective therapies.


Unlocking the secrets of mitochondria and their effect on health is one of the most promising and exciting areas of pediatric medicine today. The center received its Frontier Program designation in 2017, and Falk’s team is moving forward with alacrity.


It is using a sizable chunk of the new funding to set up diagnostic genetic, biochemical, and tissue testing to confirm patients’ diagnoses. To understand the impact of particular therapies, it is moving to rigorously track patient outcomes: If someone is put on a supplement, does his balance improve? Does a particular medication reduce the number of seizures someone has?


Because the children typically have many medical problems, they often see many specialists and spend hours at the clinic. Frontier Program funds have allowed the center to add doctors and nurse practitioners to ensure that patients’ care is integrated across all specialties, coordinate tests to eliminate duplication, and provide each specialist with up-to-date, well-organized information about the care the child is receiving.



Doctors without borders


The mission of Children’s Hospital of Philadelphia has not changed in its 163-year history: to improve the health and the lives of children. But today, there is the opportunity – and the responsibility -- to have a far-reaching impact on children’s health in ways never before imagined, says St. Geme.


 “We want to think about how we as an institution can remain a leading children’s hospital, both nationally and internationally. The Frontier Programs help us provide unique care for children from across the globe.”