CHOP Leader Examines Host-Pathogen Interactions

CHOP Leader Examines Host-Pathogen Interactions

Fiscal 2013 saw a change in leadership at The Children’s Hospital of Philadelphia: Noted microbiologist and Children’s Hospital alumnus Joseph W. St. Geme, III, MD, was named physician-in-chief and chair of the Department of Pediatrics at the University of Pennsylvania. Dr. St. Geme succeeds Alan R. Cohen, MD, who held the post of physician-in-chief for 12 years.

After receiving his medical degree from Harvard, Dr. St. Geme served his residency and chief residency at Children’s Hospital from 1984-88. He later performed postdoctoral research under Stanley Falkow, PhD, at Stanford, and in 1992 joined the faculty of the School of Medicine at Washington University in St. Louis. A progression of appointments followed, and in 2005 Dr. St. Geme moved to Duke University, where he served as chairman of the Department of Pediatrics and Chief Medical Officer of Duke Children’s Hospital.

Dr. St. Geme said his great respect and fondness for CHOP led him to return to Philadelphia. He called the opportunity to serve at the site of his medical training “very appealing and ultimately irresistible.” Since joining CHOP, Dr. Geme has continued his active research program examining host-pathogen interactions.

In particular, he has spent much of his career working to better understand why commensal microbes (which normally live in perfect harmony with our own cells) cause disease. The human body is a crowded place; while there are many types of human cells — numbering approximately 37.2 trillion, according to an Annals of Human Biology study — there are many more microbial cells that live in our bodies. Indeed, the NIH’s Human Microbiome Project notes “microbial cells are estimated to outnumber human cells 10 to one.” But sometimes these microbes can cause disease, such as when they leave their normal environment and enter the circulatory system.

For many years, Dr. St. Geme’s investigations were focused on the bacterium Haemophilus influenzae. Despite its somewhat misleading name, H. influenzae does not cause influenza, but is instead associated with invasive infections and localized respiratory tract disease. And more recently, Dr. St. Geme has been investigating Kingella kingae, an emerging cause of bone and joint infections in young children.

“In many ways the thrusts of the two projects, the two general themes, are similar,” Dr. St. Geme said. Both are investigations of “host-pathogen interactions, and understanding how organisms that are common, commensal organisms, common colonizers usually not associated with disease do, in some circumstances, produce disease.”

CHOP researchers Katherine Rempe, Brad Kern, and Eric Porsch (who all moved to CHOP from Duke with Dr. St. Geme), as well as Duke’s Sue Grass, Jessica McCann, and Kim Starr have contributed to the H. influenzae and K. kingae work. At the 2014 Scientific Symposium in May, Dr. St. Geme gave an in-depth talk on his research as the Symposium’s internal keynote speaker.

Saying he was “very pleased” that Dr. St. Geme had agreed to join CHOP, Children’s Hospital’s CEO Steven M. Altschuler, MD, noted he is “a distinguished researcher and member of the Institute of Medicine and is recognized nationally for his outstanding leadership at Duke.”

“In many respects CHOP sets the standard in pediatrics as a leading children’s hospital nationally and internationally, and I’m excited to participate in establishing the standards in pediatric clinical care, education, and research as a member of the CHOP community,” Dr. St. Geme said.

Prominent Gene Therapy Expert Joins CHOP

Prominent Gene Therapy Expert Joins CHOP

Many investigators at The Children’s Hospital of Philadelphia Research Institute are leaders in their fields, regularly making groundbreaking contributions to medical science. Children’s Hospital’s gene therapy researchers are no exception, as their work has led to advances in treating diseases such as hemophilia and congenital blindness.

During fiscal 2013, the Research Institute added another gene therapy specialist to its fold, welcoming Beverly L. Davidson, PhD, a nationally prominent expert in gene therapy. In addition to serving as the new director of the Center for Cellular and Molecular Therapeutics (CCMT), Dr. Davidson also joins the Hospital’s Department of Pathology and Laboratory Medicine.

By assuming the role of director of the CCMT, Dr. Davidson succeeds the Center’s inaugural director, Katherine A. High, MD, HHMI. The CCMT is “dedicated to the understanding, development, and application of gene and related cell and nucleic acid therapies, and the promotion of professional public education,” according to its website.

“I am thrilled that we have been able to recruit one of the premier translational investigators in the U.S. to serve as the next director of the Center,” Dr. High said. “I have led the Center for the last 10 years, and I eagerly look forward to the innovations of the next decade under Dr. Davidson’s leadership.”

In addition to her new roles at CHOP, Dr. Davidson is currently a member of the Scientific Advisory Board of the Hereditary Disease Foundation, and is chair of Medical Sciences Section of the American Association for the Advancement of Science. She is also a scientific co-founder and advisor at the gene therapy company Spark Therapeutics, which launched in late 2013 with a $50 million capital commitment from CHOP.

Dr. Davidson’s research has been concentrated on inherited genetic diseases that attack the central nervous system, with a particular focus on childhood-onset neurodegenerative diseases.

And although much of Dr. Davidson’s work has centered on delivering beneficial genes to the central nervous system, the novel methods she has developed are applicable to other organs and tissues — for example, in gene therapy directed to the lungs or the liver.

Dr. Davidson “will greatly enhance our abilities to translate important biological discoveries into pioneering treatments for deadly diseases,” said Robert W. Doms, MD, PhD, CHOP’s pathologist-in-chief.

New Leadership Fortifies Center's Success

New Leadership Fortifies Center's Success

The Center for Pediatric Clinical Effectiveness (CPCE) at Children’s Hospital diligently works to discover and spread knowledge about the best practices to treat pediatric diseases. It is a tremendous and important effort to advance the health and well-being of children, and the CPCE’s efforts are fortified by new leadership at the helm.

As the new CPCE director, Theoklis Zaoutis, MD, MSCE, does what he enjoys most — creating, developing, and building new ideas. Dr. Zaoutis co-founded the CPCE, a Center of Emphasis within the Research Institute. The Center provides critical infrastructure for training in and the performance of clinical effectiveness research, which is aimed at understanding the best ways to prevent, diagnose, and treat diseases in children.

One of his first priorities as director centers on “outreach to increase awareness of the CPCE by developing collaborations and synergies with other researchers,” Dr. Zaoutis said.

He sees tremendous opportunity for population level research to cross over to projects being conducted by bench scientists and translational researchers. “The link between these two can be phenomenally strong,” he said.

As Dr. Zaoutis describes it, the CPCE is an “intellectual home” for clinical researchers. In the same way that scientists learn essential skills at the bench, the CPCE uses a laboratory model to teach junior faculty and other interested clinicians the elements of good clinical research design, implementation, and practices.

“The CPCE has grown tremendously in the six years that it’s been in existence,” said Dr. Zaoutis, who previously served as its associate director of research, and during those half-dozen years the CPCE’s total grant funding has exceeded $71 million. In addition to providing a database of funded grants for investigators to use as examples of effective grant submissions, the CPCE established the Healthcare Analytics Unit, which has expertise in using large datasets to answer research questions.

Dr. Zaoutis is enthusiastic about taking the Center’s success to the next level. He envisions more partnership with the Hospital to create pathways and guidelines that are real-world applications of the CPCE’s research.

A recent example is a study led by CPCE faculty member Jeffrey S. Gerber, MD, PhD, assistant professor of pediatrics in the Division of Infectious Diseases at CHOP, published in the Journal of the American Medical Association that described an intervention to improve antibiotic prescribing at outpatient practices.

“The research is moving into the community and making an impact on care,” Dr. Zaoutis said, who added that he feels well-prepared to expand his responsibilities after working closely with the CPCE’s former director, Ron Keren, MD, MPH, who in fiscal 2013 was appointed CHOP’s vice president of quality and chief quality officer. In his new role, Dr. Keren will be a bridge for the CPCE to disseminate and implement research findings about best practices and safety, Dr. Zaoutis said.

“We have the unique advantage that Dr. Keren’s been on the research side creating this knowledge, and now we have a natural partnership to fulfill the CPCE’s whole mission,” Dr. Zaoutis said.

Dr. Zaoutis is also the Thomas Frederick McNair Scott Professor of Pediatrics and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania and associate chief in the Division of Infectious Diseases at CHOP.

Neonatologist Elected to Institute of Medicine

Neonatologist Elected to Institute of Medicine

An internationally prominent neonatologist and researcher, Phyllis A. Dennery, MD, FAAP, has received numerous awards and honors throughout her illustrious career. In fiscal 2013, she added another accolade to her roster when she was elected to the prestigious Institute of Medicine (IOM).

Dr. Dennery, chief of the Division of Neonatology and Newborn Services at Children’s Hospital and holder of the Werner and Gertrude Henle Endowed Chair in Pediatrics, was one of 70 new members elected to the IOM in recognition of their major contributions to the advancement of the medical sciences, healthcare, and public health.

The focus of her work centers on oxidative stress-mediated neonatal lung gene regulation and on the biology of lung injury and repair. She runs a National Institutes of Health-funded laboratory and has published her findings in highly respected peer-reviewed journals such as the Journal of Biological Chemistry, New England Journal of Medicine, and Blood, among others. Her clinical interests are in neonatal jaundice, bronchopulmonary dysplasia, and the long-term consequences of prematurity.

Throughout her career, Dr. Dennery has received the Andrew Mellon Fellowship, the Alfred Stengel Health System Champion Award from the Perelman School of Medicine at the University of Pennsylvania, and the Mentor of the Year Award from the Eastern Society of Pediatrics, among other awards and honors.

In 2010, she was appointed to the U.S. Secretary of Health and Human Services Advisory Committee on Infant Mortality, and she also has served on the Community Action Team of the Medical Examiner’s Office in Philadelphia focused on infant mortality.

After receiving her medical degree from Howard University College of Medicine, Dr. Dennery completed her residency at Children’s National Medical Center and a fellowship in neonatology at Rainbow Babies and Children’s Hospital. She was on the faculty at Stanford University where she served as director of Neonatology Research and associate division chief, before coming to Children’s Hospital in 2003 to assume the role of division chief of Neonatology.

The National Academy of Sciences established the IOM in 1970 to honor professional achievement in the health sciences and serves as a national resource for independent analysis and recommendations on issues related to medicine, biomedical sciences, and health. Current members of the Institute elect new members from a slate of candidates nominated for their professional achievement.

Novel Immunotherapy Work Leads to Honors

Novel Immunotherapy Work Leads to Honors

The Children’s Hospital of Philadelphia’s Stephan A. Grupp, MD, PhD, the director of Translational Research at the Center for Childhood Cancer Research, received a number of awards and honors for his groundbreaking immune therapy work during fiscal 2013. Dr. Grupp’s research was featured at the American Society of Hematology annual meeting, was honored by WebMD, and received awards from several professional societies.

Dr. Grupp has received a great deal of attention for his investigation of using cell therapy (known as CART19 or CTL019 therapy) to treat an aggressive form of childhood leukemia, acute lymphoblastic leukemia (ALL). The most common form of leukemia found in children, ALL is largely curable, with a roughly 85 percent cure rate. However, the remaining 15 percent of ALL cases resist standard therapy.

Last year his work — conducted in partnership with the University of Pennsylvania’s Carl June, MD — led to dramatic, extraordinary results published in the New England Journal of Medicine: Two children with chemotherapy-resistant ALL achieved a complete response after being treated with immune therapy, and since receiving the treatment, one of those patients remains healthy and cancer-free two years later.

At the American Society of Hematology (ASH) Annual Meeting, Dr. Grupp co-chaired a special session on immunotherapy and gave a talk on his ALL investigation. And Dr. Grupp and colleagues presented exciting follow-up results of their T cell clinical trial: Of the 24 pediatric and adult patients who have been treated for ALL, 18 had ongoing complete responses at a median of 2.6 months after treatment.

“Our results serve as another important milestone in demonstrating the potential of this cell therapy for patients who have no other therapeutic options,” said Dr. Grupp at ASH.

More recently, The Children’s Hospital of Philadelphia and the University of Pennsylvania received the Patient Impact Award from Pennsylvania Bio for their joint immune therapy research. Dr. Grupp also received the 2014 Herbert Pardes Clinical Research Excellence Award from the Clinical Research Forum, and a team of researchers led by Dr. Grupp received the 2014 van Bekkum Award from the European Society for Blood and Marrow Transplantation (EBMT).

The data presented at the Clinical Research Forum and EBMT updated the data published in the New England Journal of Medicine. “Our group has now treated 25 kids and five adults with relapsed/refractory ALL,” Dr. Grupp said. “We have seen unexpectedly high rates of complete remission: 90 percent in this group of patients, many of whom had no other treatment options. These results are leading to a phase 2 trial at six pediatric hospitals, with CHOP as the lead site.”

And last — but certainly not least — Dr. Grupp, along with his young patient Emily Whitehead, were named 2013 WebMD Health Heroes. When Emily came to Dr. Grupp, her ALL had relapsed for the second time and was resistant to chemotherapy. In April of 2012 she became the first pediatric patient to receive the engineered T cells. And though the treatment led to a life-threatening illness, Emily eventually recovered after Dr. Grupp and his team were able to treat her symptoms. Since receiving the T cells, Emily remains healthy and cancer-free.

“It’s an honor to have our cell therapy research recognized by such prestigious organizations,” Dr. Grupp said. “This is potentially revolutionary work, but its success to date — and going forward — would not have been possible without multidisciplinary, truly collaborative input from investigators across CHOP and Penn. I cannot thank my colleagues enough.”

Awards Celebrate Oncologists' Distinguished Careers

Awards Celebrate Oncologists' Distinguished Careers

The Children’s Hospital of Philadelphia Research Institute has long had a reputation for being home to world-class investigators, from those focused on genetics to behavioral specialists and childhood cancer experts. That reputation was strengthened during fiscal 2013 by the news that two CHOP oncologists received awards celebrating their careers.

Neuroblastoma expert Garret M. Brodeur, MD, received an award from the Advances in Neuroblastoma Research Association (ANRA), while Beverly J. Lange, MD, was honored by the American Society of Pediatric Hematology/Oncology (ASPHO).

Dr. Brodeur’s award singles out a researcher who has achieved worldwide scientific prominence in investigating neuroblastoma over the course of an exceptional career. The ANRA Lifetime Achievement Award, given at ANRA’s international meeting, is the association’s highest honor.

Over his career, Dr. Brodeur has focused on identifying the genes, proteins, and biological pathways that give rise to neuroblastoma and drive its clinical behavior. He has also built on this knowledge to help develop more effective and less toxic treatments for children.

Dr. Brodeur helped discover important neuroblastoma-related genetic changes, collaborating with other CHOP researchers who identified the ALK gene as the gene responsible for most cases of hereditary neuroblastoma. Another major focus of his research regards the role of TRK receptor tyrosine kinases, which control the clinical behavior of neuroblastomas. His work led to a clinical trial with a novel drug that selectively blocks these signals.

Dr. Brodeur has been a member of the CHOP medical staff since 1993 and holds the Audrey E. Evans Endowed Chair in Pediatric Oncology at the Hospital. He is also a professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania where he is an associate director of the Abramson Cancer Center.

Meanwhile, Dr. Lange’s ASPHO award is given to a professional whose career “has had a major impact on the subspecialty through some combination of research, education, patient care, and advocacy.” She received the award in recognition of her more than 40 years of outstanding contributions to the care of children with cancer.

Over the course of her career, Dr. Lange worked on numerous aspects of pediatric oncology, including spending many years focusing on acute myelogenous leukemia (AML). While AML is the second most common form of leukemia in adults, leading to roughly 15,000 new cases and 10,000 deaths every year in the U.S., the disease is rare in children, with only 500 to 600 children diagnosed per year. Since Dr. Lange began working on the disease, AML survival rates have greatly increased, with the five-year survival rate now around 85 percent.

Dr. Lange served as a senior physician and director of clinical affairs in the Division of Oncology at CHOP, where she worked from 1976 until her retirement in 2013. Over the course of her career, Dr. Lange published extensively in top-tier scientific journals, contributed expertise to professional organizations such as ASPHO and the multicenter Children’s Oncology Group, and mentored countless numbers of young investigators.