CHOP Oncologist Leads First Pediatric Dream Team as Stand Up to Cancer and St. Baldrick’s Take Aim at Children’s Cancers
A physician-researcher from The Children’s Hospital of Philadelphia will lead the first-ever pediatric “Dream Team” solely focused on creating new treatments for the most challenging childhood cancers. Stand Up to Cancer (SU2C) and the St. Baldrick’s Foundation, along with the American Association for Cancer Research (AACR), SU2C’s scientific partner, announced this Dream Team today during a press conference at the AACR Annual Meeting 2013 in Washington, D.C.
John M. Maris, MD, director of the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia, and professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, will lead the pediatric Dream Team, which will have $14.5 million in funding over four years, provided by SUC2 and St. Baldrick’s. Crystal L. Mackall, MD, chief of the Pediatric Oncology Branch of the National Cancer Institute (NCI), is the co-leader of the Dream Team.
The title of the research project, “Immunogenomics to Create New Therapies for High-Risk Childhood Cancers,” reflects the melding of two powerful disciplines that have historically functioned independently: immunotherapeutics and genomics. The goal is to rapidly translate promising basic research into transformative, targeted treatments that will improve cure rates in children’s cancer.
“The motivation for the creation of this collaborative research project is the realization that completely new strategies are needed if we are to have curative therapies for all childhood cancers,” said Maris. “Our Team hopes to rapidly develop more precise and effective treatments based on the unique characteristics of each child’s tumor, here focusing on the genetic changes that make the cancer cells different from the rest of the child’s body.”
Immunotherapeutics focuses on developing treatments that harness the body’s own immune system to fight disease. Genomics, the field that analyzes the broad landscape and fine details of the genetic code in DNA, reveals potential targets for disease treatments.
At today’s press conference, Emily (Emma) Whitehead and her parents Kari and Tom provided dramatic evidence of the power of these scientific tools to treat cancer. Emily, age 7, had a dramatic recovery from a relapsed form of childhood leukemia following an experimental treatment at The Children’s Hospital of Philadelphia (CHOP) which used her own immune cells. Researchers from CHOP and the University of Pennsylvania genetically engineered Emily’s T cells to find and destroy leukemia cells. Emily, who was featured in news stories last December, remains healthy and cancer-free, nearly a year after receiving the highly innovative therapy.
The new pediatric Dream Team addresses a crucial need in treating children’s cancers. After dramatic progress throughout the last half of the 20th century, cure rates for pediatric cancers plateaued in the 1990s. “Very few new therapies have been developed for pediatric cancer in the past 20 years,” said Maris. In addition, he added, current therapies for childhood cancers often have severe side effects that reduce quality of life for survivors who enter adulthood.
Hence, there is a need for new classes of treatments to improve both survival and quality of life. The researchers on the new Dream Team, said Maris, have deep expertise in the most lethal pediatric cancers, and will combine their experience and commitment to a sustained effort improve cure rates.
Realizing the ambitious Dream Team efforts, stresses Maris, will rely on the talents of many collaborators. The researchers represent seven institutions: CHOP, NCI, the Baylor College of Medicine, Seattle Children’s Hospital, the University of British Columbia, the Hospital for Sick Children in Toronto, and the University of Wisconsin.
The Dream Team also includes important patient advocates: Kelly Cotter, a childhood cancer survivor; Jay Scott and Liz Scott, of the Alex’s Lemonade Stand Foundation; Patrick Sullivan, of the Team Finn Foundation; and Lisa Tichenor and Mac Tichenor, of the What Would Willy Want Foundation (Quad W Foundation).
Maris draws on the internationally prominent expertise of Stephan A. Grupp, MD, PhD, and Tom Curran, PhD, to lead the CHOP-based research programs. Grupp has developed the first highly effective childhood cancer immunotherapy, in collaboration with Carl H. June, MD, of the Perelman School of Medicine at the University of Pennsylvania. It was Grupp’s efforts that resulted in Emily Whitehead’s remarkable recovery from her lethal leukemia and her attendance at the press conference today.
“We were excited to experience this great outcome with Emily,” said Grupp, who added, “Although this is an early result, it offers the promise of a significant advance against this high-risk childhood leukemia. Our goal on the Dream Team is to emulate this success in treating other pediatric cancers.”
Oncology researcher Tom Curran is a member of the Institute of Medicine, and was recently named to the AACR’s inaugural class of Fellows of the AACR Academy. He will lead the brain tumor discovery efforts at CHOP, interacting closely with Maris’s own research program in neuroblastoma. CHOP will serve as the central hub for data analysis and new therapy development across the Dream Team consortium. The full list of Dream Team leaders and investigators at CHOP can be viewed here: bit.ly/CHOPDreamTeam.
The Dream Team will focus on the four most deadly pediatric cancers: malignant brain tumors, high-risk leukemias (such as the type of acute lymphoblastic leukemia that Emily Whitehead had), neuroblastomas (which affect the peripheral nervous system) and sarcomas (other tumors of bone and other tissue).
Recent research in genomics, said Maris, has shown that pediatric cancers are fundamentally different from adult cancers. Children’s cancers are less likely to arise due to recurring mutations that can be countered with small molecule drugs. Instead, this Dream Team will exploit the unique feature of molecules on cell surfaces of childhood cancer cells that are not present on normal cells, and thus offer targets for treatments employing bioengineered agents working through the immune system.
In transforming this scientific knowledge into treatments, the Dream Team members will take a three-step approach. First, they will discover cell-surface molecules offering promising targets in high-risk children’s cancers. Secondly, they will create immunotherapy-based proteins to attack those molecules. The third step is to carry out multi-institutional clinical trials of these treatments in children.
“The success of the program will ultimately be judged by the number of lives saved through our efforts,” concluded Maris.
Learn more about our Dream Team here.
The American Society of Clinical Oncology (ASCO) today announced it will confer one of its highest awards on pediatric oncologist Garrett M. Brodeur, M.D., of the Cancer Center at The Children’s Hospital of Philadelphia. Brodeur will receive the Pediatric Oncology Award and deliver the Pediatric Oncology Lecture on Friday, May 31 during the ASCO annual meeting in Chicago.
The Award and Lecture recognize “outstanding scientific work of major importance to the field of pediatric oncology” during the course of a career. Brodeur is an expert in neuroblastoma, the most common solid tumor of childhood.
A cancer of the peripheral nervous system that typically appears as a tumor in a child’s abdomen or chest, neuroblastoma varies greatly in severity, ranging from forms that spontaneously disappear to high-risk subtypes that are difficult to cure. Because of this variability, researchers have sought ways to predict the course of disease in order to select the most appropriate treatment for each patient. The underlying assumption of this approach is that better understanding of the biology of this cancer will allow pediatric oncologists to avoid undertreating or overtreating a child.
Over his career, Brodeur has focused on identifying the genes, proteins and biological pathways that give rise to neuroblastoma and drive its clinical behavior. He also has built on this knowledge to develop more effective and less toxic treatments for children by targeting specific pathways.
His research first demonstrated in the 1980s that when neuroblastoma cells developed multiple copies of the MYCN gene, a process called amplification, a high-risk subtype of neuroblastoma occurs, necessitating more aggressive treatment. This discovery ushered in the current era of genomic analysis of tumors, both in adult and pediatric oncology. Profiling specific molecular alterations in a given patient’s tumor helps oncologists to predict that patient’s outcome and select the most appropriate treatment.
Brodeur and his colleagues also identified deletions of important genes on chromosome 1 and on chromosome 11 as markers of high-risk neuroblastoma. He has collaborated 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 has concerned receptor tyrosine kinases, a family of signaling proteins that control the clinical behavior of neuroblastomas. His preclinical work led to a clinical trial with a novel drug that selectively blocks TRK signaling. He is now working on second-generation TRK inhibitors, as well as on nanoparticle delivery systems to treat patients more effectively, and with less toxicity.
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 also is 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. Before arriving at CHOP, Brodeur did his fellowship in Pediatric Hematology-Oncology at St. Jude’s Children’s Research Center and a postdoctoral fellowship in Molecular Genetics at Washington University School of Medicine in St. Louis, where he remained until coming to CHOP.
Two children with an aggressive form of childhood leukemia had a complete remission of their disease—showing no evidence of cancer cells in their bodies—after treatment with a novel cell therapy that reprogrammed their immune cells to rapidly multiply and destroy leukemia cells. A research team from The Children’s Hospital of Philadelphia and the University of Pennsylvania published the case report of two pediatric patients Online First today in The New England Journal of Medicine. It will appear in the April 18 print issue.
One of the patients, 7-year-old Emily Whitehead, was featured in news stories in December 2012 after the experimental therapy led to her dramatic recovery after she relapsed following conventional treatment. Emily remains healthy and cancer-free, 11 months after receiving bioengineered T cells that zeroed in on a target found in this type of leukemia, called acute lymphoblastic leukemia (ALL).
The other patient, a 10-year-old girl, who also had a complete response to the same treatment, suffered a relapse two months later when other leukemia cells appeared that did not harbor the specific cell receptor targeted by the therapy.
“This study describes how these cells have a potent anticancer effect in children,” said co-first author Stephan A. Grupp, MD, PhD, of The Children’s Hospital of Philadelphia, where both patients were treated in this clinical trial. “However, we also learned that in some patients with ALL, we will need to further modify the treatment to target other molecules on the surface of leukemia cells.”
Grupp is the director of Translational Research for the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia, and a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Michael Kalos, PhD, an adjunct associate professor in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine at Penn, is co-first author on the study.
Study builds on successful results of prior trial
The current study builds on Grupp’s ongoing collaboration with Penn Medicine scientists who originally developed the modified T cells as a treatment for B-cell leukemias. The Penn team reported on early successful results of a trial using this cell therapy in three adult chronic lymphocytic leukemia (CLL) patients in August of 2011. Two of those patients remain in remission more than 2½ years following their treatment, and as the Penn researchers reported in December 2012 at the annual meeting of the American Society of Hematology, 7 out of 10 adult patients treated at that point responded to the therapy. The team is led by the current study’s senior author, Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and the Perelman School of Medicine at the University of Pennsylvania and director of Translational Research in Penn’s Abramson Cancer Center.
“We’re hopeful that our efforts to treat patients with these personalized cellular therapies will reduce or even replace the need for bone marrow transplants, which carry a high mortality risk and require long hospitalizations,” June said. “In the long run, if the treatment is effective in these late-stage patients, we would like to explore using it up front, and perhaps arrive at a point where leukemia can be treated without chemotherapy.”
The research team colleagues adapted the original CLL treatment to combat another B-cell leukemia: ALL, which is the most common childhood cancer. After decades of research, oncologists can currently cure 85 percent of children with ALL. Both children in the current study had a high-risk type of ALL that stubbornly resists conventional treatments.
The new study used a relatively new approach in cancer treatment: immunotherapy, which manipulates the immune system to increase its cancer-fighting capabilities. Here the researchers engineered T cells to selectively kill another type of immune cell called B cells, which had become cancerous.
T cells are the workhorses of the immune system, recognizing and attacking invading disease cells. However, cancer cells fly under the radar of immune surveillance, evading detection by T cells. The new approach custom-designs T cells to “see” and attack the cancer cells.
The researchers removed some of each patient’s own T cells and modified them in the laboratory to create a type of CAR (chimeric antigen receptor) cell called a CTL019 cell. These cells are designed to attack a protein called CD19 that occurs only on the surface of certain B cells.
By creating an antibody that recognizes CD19 and then connecting that antibody to T cells, the researchers created in CTL019 cells a sort of guided missile that locks in on and kills B cells, thereby attacking B-cell leukemia. After being returned to the patient’s body, the CTL019 cells multiply a thousand times over and circulate throughout the body. Importantly, they persist for months afterward, guarding against a recurrence of this specific type of leukemia.
While the CTL019 cells eliminate leukemia, they also can generate an overactive immune response, called a cytokine release syndrome, involving dangerously high fever, low blood pressure, and other side effects. This complication was especially severe in Emily, and her hospital team needed to provide her with treatments that rapidly relieved the treatment-related symptoms by blunting the immune overresponse, while still preserving the modified T cells’ anti-leukemia activity.
“The comprehensive testing plan that we have put in place to study patients’ blood and bone marrow while they’re undergoing this therapy is allowing us to be able to follow how the T cells are behaving in patients in real time, and guides us to be able to design more detailed and specific experiments to answer critical questions that come up from our studies,” Kalos said.
The CTL019 therapy eliminates all B cells that carry the CD19 cell receptor: healthy cells as well as those with leukemia. Patients can live without B cells, although they require regular replacement infusions of immunoglobulin, which can be given at home, to perform the immune function normally provided by B cells.
The research team continues to refine their approach using this new technology and explore reasons why some patients may not respond to the therapy or may experience a recurrence of their disease. Grupp said the appearance of the CD19-negative leukemia cells in the second child may have resulted from her prior treatments. Unlike Emily, the second patient had received an umbilical cord cell transplant from a matched donor, so her engineered T cells were derived from her donor (transplanted) cells, with no additional side effects. Oncologists had previously treated her with blinatumomab, a monoclonal antibody, in hopes of fighting the cancer. The prior treatments may have selectively favored a population of CD19-negative T cells.
“The emergence of tumor cells that no longer contain the target protein suggests that in particular patients with high-risk ALL, we may need to broaden the treatment to include additional T cells that may go after additional targets,” added Grupp. “However, the initial results with this immune-based approach are encouraging, and may later even be developed into treatments for other types of cancer.”
Funding from the National Institutes of Health (grants 1RO1 CA165206, R01 CA102646 and R01 CA116660), the Leukemia and Lymphoma Society, and the Alliance for Cancer Gene Therapy supported this study.
In August 2012, the University of Pennsylvania and Novartis announced an exclusive global research and licensing agreement to further study and commercialize these novel cellular immunotherapies using chimeric antigen receptor (CAR) technologies. As part of the transaction, Novartis acquired exclusive rights from Penn to CART-19, the therapy that was the subject of this clinical trial and which is now known as CTL019.
Read the study abstract
“Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia,” New England Journal of Medicine, Online First, March 25, 2013. To appear in print April 18, 2013.
About The Children’s Hospital of Philadelphia
The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 516-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.
About Penn Medicine
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation’s top "Honor Roll" hospitals by U.S.News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.
$500,000 Endowment Gift from GlaxoSmithKline Foundation Expands Program to Help Patients with Cancer and their Families at The Children’s Hospital of Philadelphia
Contact:Rachel Salis-Silverman, Children's Hospital of Philadelphia, 267-426-6063 or
The Children’s Hospital of Philadelphia is proud to announce a $500,000 gift from the GlaxoSmithKline (GSK) Foundation. The donation will greatly enhance the GlaxoSmithKline Hope for Families Fund, an endowment fund which was established in 2008 with a $1 million gift from The GlaxoSmithKline Foundation and GlaxoSmithKline, and matched by The Children’s Hospital of Philadelphia. This Fund provides vital assistance to financially eligible families that need assistance for travel and living expenses they may incur while their child is enrolled in investigational and/or novel treatments offered at the Cancer Center at Children’s Hospital.
“Financial burdens such as missed time from work, airfare and other expenses can really take a big toll on a family dealing with cancer,” said Paolo Paoletti, MD, president, GlaxoSmithKline Oncology. “Through the GSK Hope for Families Fund, our goal is to alleviate some of the financial burden so that families can focus on helping their child get well.”
The GlaxoSmithKline Hope for Families Fund is a permanent endowment that helps children and young adults with relapsed cancers gain access to innovative therapies at Children’s Hospital. Specifically, the Fund reimburses the families for expenses related to their travel and stay in Philadelphia, including airfare and ground transportation, lodging, and meals.
“The generosity of GlaxoSmithKline has relieved many boundaries to care and has allowed families to get the world’s best treatment for pediatric cancers at The Children’s Hospital of Philadelphia,” said Steven M. Altschuler, MD, chief executive officer of The Children’s Hospital of Philadelphia. “By growing the Fund, we will be able to help even more families access innovative treatments and the care offered here.”
Since July 1, 2008, the GSK Hope for Families Fund has assisted 94 families with travel and living expenses relating to assessment for and/or enrollment in clinical trials at The Children’s Hospital of Philadelphia’s Cancer Center. Families have come from 20 U.S. states and six foreign countries. The youngest patient helped was 3 years old and the oldest was 27.
Worsening economy increases need for support for patients enrolled in clinical trials
Many families using the Fund are low-income or one-income families, and there has been increased usage of the Fund due to the worsening economy. Many parents do not get paid if they have to take days off while their child is receiving treatment for their cancer. This is an acute burden, as many of the patients enrolled in clinical trials are required to come to Children’s Hospital frequently, sometimes as often as weekly, over a long period of time.
Each year, more families need assistance, and this new gift from the GlaxoSmithKline Foundation will allow Children’s Hospital social workers to better meet the growing need. Additionally, the GSK Hope for Families Fund has supported qualifying international families.
Cancer Center is largest developmental therapeutics program in U.S., receives patient referrals from across the nation
The Cancer Center at Children’s Hospital has been ranked #1 in the country by U.S.News & World Report and Parents magazine. With the largest developmental therapeutics program in the United States, the Cancer Center and its Center for Childhood Cancer Research are beacons of hope for families around the globe, providing advanced treatments not found in most patients’ home healthcare institutions.
“Recently, our program has focused heavily on developing new drugs for childhood cancer, and the national referral-basis for these unique clinical trials led to the need for a program such as the Hope for Families Fund,” said John M. Maris, MD, director of the Center for Childhood Cancer Research at Children’s Hospital. “Therefore with the help of the funds from the GlaxoSmithKline Foundation, Children’s Hospital is moving one step closer to ensuring all children with cancer are provided the best possible care.”
Corporate philanthropy critical to providing best care
“Corporate philanthropy is critical to furthering our mission to provide the very best family-centered care possible,” Altschuler said. “We are extremely grateful to the GlaxoSmithKline Foundation for this remarkable donation.”
The Cancer Center at Children’s Hospital is a Phase I institution and leader within the Children’s Oncology Group. The Center strives to provide the most skilled, compassionate care available. State-of-the-art facilities enable it to offer comprehensive, family-centered care from 69 nationally and internationally renowned pediatric oncologists and specialists. Their combined expertise spans every major form of childhood cancer. Each year, the Cancer Center treats more than 500 new patients and follows nearly 5,000 patients, making the program one of the largest pediatric cancer programs in the world.
GSK has been a steadfast philanthropic partner to the community and The Children’s Hospital of Philadelphia is grateful for the difference GSK’s support has made to our patients and families.
One of the world’s leading research-based pharmaceutical and healthcare companies, GSK is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information go to us.gsk.com, follow us on twitter.com/GSKUS or visit our blog: www.morethanmedicine.us.gsk.com/blog/.
The GlaxoSmithKline Foundation, which was established in 1990, administers the employee matching gifts program for charitable organizations. It also has provided select endowment gifts to support the health and education needs at the local community level.
About The Children’s Hospital of Philadelphia
Founded in 1855, The Children’s Hospital of Philadelphia is the birthplace of pediatric medicine in America. Throughout its history, a passionate spirit of innovation has driven this renowned institution to pursue scientific discovery, establish the highest standards of patient care, train future leaders in pediatrics and advocate for children’s health. A haven of hope for children and families worldwide, CHOP is a nonprofit charitable organization that relies on the generous support of its donors to continue to set the global standard for pediatric care.
Philadelphia, Pa. (February 4, 2013) – The Children’s Hospital of Philadelphia has been named the nation’s best pediatric hospital by Parents magazine. In addition to the overall ranking, CHOP was ranked in the top 3 in all 6 specialties included in the survey. Parent’s magazine ranked Children’s Hospital’s Cancer Center and emergency medicine first; the Cardiac Center tied for first; neonatology ranked second and orthopedics and pulmonology ranked third.
“We are honored by this recognition, particularly as it comes from a source so many families trust for advice about their children’s wellbeing,” said Steven M. Altschuler, M.D., chief executive officer of The Children’ Hospital of Philadelphia. “Accomplishments like this one are a testament to our staff, whose commitment to every child and family in our care is extraordinary. To be ranked #1 in the nation affirms our mission and reminds us of our continued and profound responsibility to advance pediatric health.”
The “10 Best Hospitals” list will appear in the March 2013 issue of Parents that will be available on newsstands nationwide on February 12 as well as online at www.parents.com
Parents magazine’s exclusive list of 10 Best Children’s Hospitals provides the most comprehensive family focused data-driven comparison of pediatric facilities. In compiling the list, Parents focused on key areas including treatment success, groundbreaking research and family-friendly facilities.
The hospitals on the list were ranked by Parents editors, with input from a team of medical advisors, based on their responses to detailed questions in the following areas: survival rates for childhood cancer, pediatric heart disease, and other critical conditions; experience in performing certain complex procedures; depth of the research program; safeguards to prevent medical errors; staffing ratios and quality; community outreach; and services that address the emotional needs of families of patients. All surveyed hospitals are members of the National Association of Children’s Hospitals and Related Institutions.
For more information on the hospital and the six ranked specialty areas, please visit www.chop.edu
The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 516-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.
A recent genomic study of neuroblastoma reinforces the challenges of treating the most aggressive forms of this disease. Contrary to expectations, the researchers found relatively few recurrent gene mutations — mutations that would suggest new targets for neuroblastoma treatment. Instead, the investigators have refocused on how neuroblastoma tumors evolve in response to medicine and other factors.
Read more about how studying tumor biology at the molecular level is helping researchers gain a deeper understanding of drug resistance — and how to avoid it by designing pediatric cancer treatments tailored to specific mutations in a child’s DNA.