Amplifying Our Impact and Expanding Opportunities

Children's Hospital of Philadelphia researchers are part of two global teams awarded Cancer Grand Challenges funding to find treatments for some of the most impenetrable childhood cancers. Co-founded by the National Cancer Institute and Cancer Research UK, the initiative selected five teams — chosen from 176 initial applicants — to receive grants of up to $25 million.

Yael Mossé, MD, the Patricia Brophy Endowed Chair in Neuroblastoma Research and an attending physician at CHOP's Cancer Center whose clinical and research specialty is neuroblastoma, is leading Team KOODAC to tackle the challenge of solid tumors in children. The team includes researchers at 10 institutions from the United States, Austria, France, Germany, and the United Kingdom, as well as an industry partner, Nurix Therapeutics. CHOP researchers John Maris, MD, the Giulio D'Angio Chair in Neuroblastoma Research, and Adam Wolpaw, MD, PhD, an Assistant Professor of Pediatrics, are also part of Team KOODAC as co-investigators.

"Team KOODAC brings together an interdisciplinary, international team of scientific experts, all sharing the vision of developing safe and effective drugs against previously undruggable childhood cancers," Dr. Mossé said.

Nikolaos Sgourakis, PhD, core faculty in CHOP's Center for Computational and Genomic Medicine, is investigating T-cell receptors (TCR) as part of Team MATCHMAKERS, made up of researchers from Germany, the Netherlands, Norway, the U.K., and the U.S.

"Integration of advanced structural biology tools with deep learning techniques has a lot of potential for deciphering the TCR recognition 'code.' Once this is complete, we can develop software that could be used in any lab, anywhere in the world," Dr. Sgourakis said. "This will allow for better matching of patients with safe, less toxic therapies that could lead to immune rejection of tumor cells while preserving the surrounding healthy tissue."

A newly launched funding initiative will accelerate groundbreaking cystic fibrosis (CF) treatment research by bringing together multiple investigators with diverse areas of expertise to jointly tackle challenges in the development of novel CF therapeutics.

Emily's Entourage, a nonprofit that accelerates research for CF therapies, awarded a Collaborative Grant to researchers from Children's Hospital of Philadelphia, the University of Iowa, and the Rochester School of Medicine and Dentistry.

Beverly Davidson, PhD, Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics and Chief Scientific Strategy Officer at CHOP, will co-lead the Emily's Entourage project to develop a first-of-its-kind targeted therapeutic option for individuals living with CF.

CF is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that severely affects the lungs, digestive system, and other organs. Significant advancements have been made in CFTR therapies, improving the quality of life and life expectancy for individuals with CF. However, approximately 10% of individuals with CF still lack effective treatment options.

The goal of the project, "Enhanced Airway Transduction and Therapeutic Cargo Delivery with Novel Adeno-associated Virus (AAV) Capsid Variants," is to enhance the delivery of emerging technologies that restore CFTR function in people with CF. The research team aims to identify the most efficient variants for cargo delivery to human airway epithelia and assess the efficacy of leading capsids for therapeutic cargo delivery.

When Swiss businessman Hansjörg Wyss met the late Dr. Robert Campbell, he saw the lifesaving potential of the vertical expandable prosthetic titanium rib (VEPTR) for children with thoracic insufficiency syndrome (TIS). Wyss agreed to manufacture the device through the medical device company he founded. Thousands of pediatric patients have since received the world's first expandable rib, and it remains the only device to treat TIS approved by the Food and Drug Administration.

Today, the legacy of that partnership lives on, with the announcement of $5 million in additional funding to Children's Hospital of Philadelphia from the Wyss Foundation to support innovations that improve the lives of patients with TIS. The Wyss/Campbell Center for Thoracic Insufficiency Syndrome was established at CHOP in 2019 with an initial gift from Dr. Wyss, chairman of the Wyss Foundation.

The additional funding will ensure the Center's continued progress in the years ahead, and it will help to bring technologies developed by CHOP researchers to market, said Center Director Patrick Cahill, MD, the Robert M. Campbell Jr. Endowed Chair in Thoracic Insufficiency Syndrome and a pediatric spine specialist.

"It's extraordinarily exciting to be in a place where there is an almost instantaneous impact of research on clinical care, and, in turn, where patient problems inform the direction of research," Dr. Cahill said. "The gift from the Wyss Foundation makes that possible."

A multimillion dollar gift from the Holveck Family will propel translational research at Children's Hospital of Philadelphia to find new therapies for osteosarcoma, an aggressive form of bone cancer that mainly affects adolescents and young adults.

Pediatric oncologist Theodore Laetsch, MD, will lead the Holveck Family-funded project — the "Connor Initiative: Precision Therapeutics for Osteosarcoma & Rare Cancers"— in honor of the Holveck’s grandson Connor Boyle.

Working alongside Dr. Laetsch are researchers in the Mitochondria and Cancer Connections (MC²) Research Program at CHOP, which the Holveck Family helped to establish with a gift in 2021 to uncover new insights into disease processes and novel therapeutics opportunities at the intersecting points of osteosarcoma and mitochondrial disease. The team is studying omics data to understand the metabolic strategies cells adopt to survive and grow, so new strategies can be devised to target their proverbial "Achilles heel" and ultimately beat osteosarcoma.

Adam Kraya, PhD

"We're unlocking potential connections at the crossroads of cancer and mitochondrial disease," said Adam Kraya, PhD, Technical Director of Clinical and Translational Data Science for the Center for Data Driven Discovery in Biomedicine. "Leveraging the rare link between these conditions, we can target cancer's metabolic roots while revitalizing mitochondrial function."

As part of the Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC), Rebecca Ahrens-Nicklas, MD, PhD, physician scientist in the Division of Genetics, and Laura Adang, MD, PhD, MSTR, attending physician in the Division of Neurology at CHOP, are leading a study to better understand multiple sulfatase deficiency (MSD), an ultra-rare condition that robs children of their neurologic function.

Laura Adang, MD, PhD, MSTR

Their study team is among a select group who received grant support from the Foundation for the National Institutes of Health to develop first-in-human gene therapy trials and build a knowledge base about how to move gene therapies forward for eight rare conditions. The unique public-private partnership includes academic and industry leaders, the National Institutes of Health, and the Food and Drug Administration.

"What we learn from our roadblocks and successes in this model can be applied to the thousands of other ultra-rare conditions for which people are trying to develop gene therapy," Dr. Ahrens-Nicklas said. "It is an unprecedented opportunity to dismantle barriers and optimize care not only for MSD, but all rare diseases."

The BGTC will develop a rare disease clinical trial playbook that includes ideas for preclinical testing models, best practices for manufacturing a vector, and tips on how to interact with the FDA. This learning will occur in the public domain to increase the level of transparency about how to successfully take a gene therapy program through Investigational Drug Application and approval.

Amazon Web Services (AWS) awarded a $1 million grant to the Children's Brain Tumor Network (CBTN) at Children's Hospital of Philadelphia as part of the inaugural AWS IMAGINE Grant: Children's Health Innovation Award. The goal of the award is to harness the power of the AWS cloud to advance pediatric causes worldwide.

Adam Resnick, PhD, the Alexander B. Wheeler Endowed Chair in Neurosurgical Research and Director of the Center for Data-Driven Discovery in Biomedicine (D3b), which functions as the CBTN's operations center, delivered a keynote address at the AWS summit in June. Dr. Resnick highlighted the connection between artificial intelligence (AI) and brain tumor research, showcasing how innovative approaches at D3b are making a difference. This grant will significantly boost research efforts and accelerate the development of AI-driven technologies aimed at understanding and treating brain tumors.

"We're so excited by the initiative that AWS is launching because it dovetails so perfectly into our narrative that despite being a rare disease, pediatric cancers truly provide a unique proving ground for new technology because of their dependency on real-time discovery and collaborative networks," Dr. Resnick said.

AWS provides a place where researchers can securely manage de-identified and anonymized data while safeguarding the privacy of patients and clinical study participants. Through the co-development of a suite of cloud-based data platforms that allow researchers worldwide to access rich collections of brain tumor data, CBTN has helped accelerate the research process by enabling members of the scientific and patient communities to partner. This grant reinforces CBTN's commitment to pioneering advancements in brain tumor research.

A $1 million grant from the Pediatric Cancer Foundation will fund a Phase 1 clinical trial led by Sarah Tasian, MD, that will use immunotherapy to target the FLT3 receptor protein in high-risk pediatric leukemias.

Chemotherapy fails many patients with high-risk leukemias, particularly infants with acute lymphoblastic leukemia (ALL) and children with acute myeloid leukemia (AML) with high-risk genetic alterations who have poor long-term survival. Recent CAR T-cell therapies targeting the CD19 protein on ALL cells have been effective in overcoming chemotherapy resistance and can now cure many children with relapsed ALL. However, some leukemias have learned to outsmart these therapies in various ways.

To address this problem, Children’s Hospital of Philadelphia’s collaborative research team, led by Dr. Tasian and colleagues at Children's Hospital Colorado, developed and tested a CAR T-cell immunotherapy targeting an alternative protein called FLT3 that occurs at high levels in a type of AML and in infant ALL. In the laboratory, FLT3 CAR T cells were very effective at attacking and killing both AML and ALL cells in both in vitro and in vivo models of the disease.

Based upon the promising lab results, the team now aims to test FLT3 CAR T cells in pediatric patients through a first-in-human/child Phase 1 clinical trial.

"Our research team has a strong track record of bench-to-bedside translation of CAR T cells for high-risk pediatric leukemias and is uniquely poised to undertake this challenge," said Dr. Tasian, the Joshua Kahan Endowed Chair in Pediatric Leukemia, a pediatric oncologist, and Chief of the Hematologic Malignancies Program at CHOP. "We hope that this clinical trial will have significant potential to credential a promising immunotherapy against a shared target in two major types of high-risk childhood leukemias."