Scientists have been puzzled for many years about why 20 to 30 percent of patients with hemophilia type A form inhibitory antibodies to protein replacement therapy that prevents it from working. With a new grant from the National Heart, Lung, and Blood Institute (NHLBI), Valder Arruda, MD, PhD, a researcher in the Division of Hematology, developed a multi-pronged plan to test the problem from diverse perspectives and overlapping angles. The funding will support Children’s Hospital of Philadelphia’s establishment of one of three Centers for the Investigation of Factor VIII Immunogenicity.

Dr. Arruda, who also is an associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, assembled a team of investigators at different stages of their careers and from a wide range of backgrounds — structural biology, immunology, genomics, and cancer immunotherapy — to launch the Center. It also will incorporate a skills development core to support the next generation of interdisciplinary scientists interested in building expertise in hemophilia.

“We need friends and colleagues from other areas who might help us to train the younger generation with different eyes rather than using the same typical approaches what we already know,” Dr. Arruda said. “At CHOP, we have built a culture where the bridge between basic and clinical science is very big.”

Clinicians in the Hemophilia and Bleeding Disorders program at CHOP provide care for about 100 boys with hemophilia A, which is a lifelong disease caused by a lack of the blood clotting factor VIII. In order to maintain clotting factor levels, they may receive factor replacement infusions. Patients who form FVIII inhibitors in response to the therapy face serious obstacles that make it difficult and extremely expensive to treat their hemophilia, lead to complications such as joint disease, and increase mortality.

CHOP’s new FVIII Center has four projects under way — each with a different and broad perspective — to reveal new mechanistic insights into the multiple facets of the immune response to FVIII, Dr. Arruda said. The investigators will share their progress and findings with the other two FVIII centers the NHLBI designated at Emory University and Temple University so that they can exchange ideas and refine each other’s research questions related to FVIII immunogenicity.

Due to the rarity of kidney disease in children, collaboration between pediatric research institutions is critical for mounting efficient and effective clinical trials in nephrology. In 2018, with funding from the National Institute of Diabetes and Digestive and Kidney Diseases, researchers in the Division of Nephrology at Children’s Hospital of Philadelphia led the development of a new Pediatric Center of Excellence in Nephrology (PCEN) at CHOP, the first of its kind to be devoted to translational research and clinical trials for children with kidney disorders. In partnership with other regional and national children’s hospitals, the PCEN seeks to address current barriers to clinical trial implementation.

“Kidney diseases are rare in children, which is a good thing,” said Susan Furth, MD, PhD, chief of the Division of Nephrology at CHOP. “But in order to find out if a treatment is effective, you really need to have a substantial number of children to enroll, and you have to get individuals at a number of centers to agree on things like the definition of who you will include in the study, how are you going to measure the outcomes of the study, and then get everybody to adhere to the protocols over time.”

The PCEN’s learning health system (LHS) core leverages electronic health records (EHR) across eight large children’s hospitals through PEDSnet, in order to identify pediatric patients with particular kidney disorders. With this information in hand, nephrology researchers can study patient outcomes, identify treatments that appear to be effective, and investigate specific laboratory markers that might predict who might or might not respond to a certain intervention. Ultimately, the EHR will allow researchers to recruit more patients into clinical trials. Alongside the LHS core, the PCEN houses a clinical phenotyping core focused on cardiovascular risk factors and measurements of growth and bone health, and also provides design and analysis expertise to the investigators making up the research base at CHOP, Penn, Johns Hopkins, and across the PEDSNet institutions.

In the PCEN’s first year, two primary investigators have made significant progress utilizing the PCEN cores: Michelle Denburg, MD, MSCE, attending physician in Nephrology at CHOP, leads a study of skeletal health in chronic kidney disease, while Gregory Tasian, MD, MSc, MSCE, pediatric urologist at CHOP, investigates the use of ultrasound imaging of kidneys as a biomarker for how quickly a child’s kidney might fail. In addition, the Center has fueled the design of future clinical trials with its launch of a pilot feasibility program and the award of two pilot grants and numerous mini-grants for study design and analysis support.

In the next five years, Dr. Furth hopes to see the PCEN mount clinical trials of new therapies for children with glomerular disease through a glomerular disease learning network (GLEAN) co-led by Dr. Denburg. Glomerular diseases are uncommon but can be extremely aggressive in terms of progressive kidney damage, and researchers in the network have already begun to lay the groundwork for clinical trials by coming together to standardize the data collected on patients.

More than 20 years ago, Tyra Bryant-Stephens, MD, then medical director at a Children’s Hospital of Philadelphia primary care center, learned from colleagues in the emergency department that children were visiting the ED with asthma-related problems at a concerning frequency. After pulling charts, probing practices, and talking with parents, Dr. Bryant-Stephens learned that the problem lay not in what primary care doctors prescribed, but in their communication with parents at home: Doctors could not address everything they needed to about managing asthma — a complex disease heavily influenced by a child’s environment — in a 15- to 20-minute visit.

Nearly two decades later, after the implementation of home visits by community health workers, free asthma education classes across the city, and rigorous research to improve the way pediatricians support parents, particularly in low-income neighborhoods, the Community Asthma Prevention Program (CAPP) continues to thrive as a nationally recognized initiative. In June 2018, the U.S. Environmental Protection Agency bestowed to CAPP their prestigious Leadership Award for Communities in Action in Asthma Management.

“The heart of CAPP are the home visits and education, and the heartbeat of CAPP are the community health workers who, by definition, understand the stresses of the community and know how to navigate it,” said Dr. Bryant-Stephens, founder and medical director of CAPP. “Having said that, we are now trying to address every sector that the child is in, to utilize and collaborate with community partners to change the environment wherever they are.”

Collaboration truly lies at the core of CAPP, and this is most strikingly evident in one of its most recent projects, the West Philadelphia Asthma Care Collaborative (WEPACC). In May 2018, the National Heart, Lung, and Blood Institute named CAPP one of four grant recipients tasked with developing sustainable programs to improve outcomes in communities with especially high rates of childhood asthma.

With the support of the grant, Dr. Bryant-Stephens and her team established a network of stakeholders representing public housing, community organizations, school districts, Medicaid managed-care companies, and more. The WEPACC network connects four sectors in childhood asthma care — the home, the community, medical professionals, and family — by utilizing community health workers. Through the project, Dr. Bryant-Stephens and her team study outcomes for 600 school-aged children with asthma assigned to one of four study arms: primary care community health workers, school community health workers (or “school ambassadors”), both primary care and school community health workers, and a control group. The community health workers will deliver patient-centered, evidence-based interventions developed by CAPP.

“One of the interesting outcomes may be finding which level of intervention is needed for different severities of the disease,” Dr. Bryant-Stephens said. “A child with severe asthma may need the school ambassador-primary care connection more than somebody who only has occasional flares. As we’re getting to personalized medicine and realizing that one size doesn’t fit all, I hope that it helps us to see what works best for children.”

Learn more about the Community Asthma Prevention Program.

The rapid pace of immune therapy advancements worries David Barrett, MD, PhD, to some degree.

“Many, many drugs are coming forward that target the immune system,” said Dr. Barrett, a pediatric oncologist in the Cancer Center at Children’s Hospital of Philadelphia. “Many of these drugs are tried in adult cancers, and have some success. The drugs are then applied to children and their unique cancers without any thought over whether that makes sense for their immune systems. I fear we will abandon immune therapies too quickly because they ‘don’t work’ when in reality we just didn’t apply them right.”

Conducting basic and translational research on samples from children with actual pediatric cancers will aid in applying immune therapy correctly, he said. To that end, Dr. Barrett has begun work on “Characterizing Immuno-variability in Children Following Standard of Care Treatment to Enable Precision Assignment to Immunotherapy Trials.”

He received the 2018 Stand Up to Cancer (SU2C) Phillip A. Sharp Innovation in Collaboration Award with his collaborator, Trevor Pugh, PhD, a scientist at Toronto’s Princess Margaret Cancer Center. Dr. Barrett met Dr. Pugh for the first time at January’s SU2C Scientific Summit, which connects researchers and encourages them to forge new collaborations on the spot. CHOP oncology colleague John Maris, MD, introduced the two because he thought their “techniques could be merged to do something more powerful,” recalled Dr. Barrett, noting they will receive $125,000 annually for two years. “We talked and wrote the grant over two days.”

Through the funding, they will examine 100 children with cancer and analyze their immune systems with multiple complementary approaches using specialty assays they developed.

“These assays will help define which therapies each tumor type, or even possibly each child, might respond to so we can better apply the right therapy in the right context,” Dr. Barrett explained.