Cancer

Javad Nazarian

Liquid biopsy spots aggressive brainstem cancer earlier

Javad Nazarian

A Children’s National research team led by Javad Nazarian, Ph.D., M.S.C., tested whether circulating tumor DNA in patients’ blood and cerebrospinal fluid would provide an earlier warning that pediatric brainstem tumors were growing.

A highly aggressive pediatric brain cancer can be spotted earlier and reliably by the genetic fragments it leaves in biofluids, according to a study presented by Children’s National Health System researchers at the Society for Neuro-Oncology (SNO) 2017 Annual Meeting. The findings may open the door to non-surgical biopsies and a new way to tell if these tumors are responding to treatment.

Children diagnosed with diffuse midline histone 3 K27M mutant (H3K27M) glioma face a poor prognosis with a median survival time of only nine months after the pediatric brainstem cancer is diagnosed. Right now, clinicians rely on magnetic resonance imaging (MRI) to gauge how tumors are growing, but MRI can miss very small changes in tumor size. The Children’s research team led by Javad Nazarian, Ph.D., M.S.C., scientific director of Children’s Brain Tumor Institute, tested whether circulating tumor DNA in patients’ blood and cerebrospinal fluid would provide an earlier warning that tumors were growing. Just as a detective looks for fingerprints left at a scene, the new genetic analysis technique can detect telltale signs that tumors leave behind in body fluids.

“We continue to push the envelope to find ways to provide hope for children and families who right now face a very dismal future. By identifying these tumors when they are small and, potentially more responsive to treatment, our ultimate aim is to help children live longer,” says Eshini Panditharatna, B.A., study lead author. “In addition, we are hopeful that the comprehensive panel of tests we are constructing could identify which treatments are most effective in shrinking these deadly tumors.”

The researchers collected biofluid samples from 22 patients with diffuse intrinsic pontine glioma (DIPG) who were enrolled in a Phase I, Pacific Pediatric Neuro-Oncology Consortium clinical trial. Upfront and longitudinal plasma samples were collected with each MRI at various stages of disease progression. The team developed a liquid biopsy assay using a sensitive digital droplet polymerase chain reaction system that precisely counts individual DNA molecules.

“We detected H3K27M, a major driver mutation in DIPG, in about 80 percent of cerebrospinal fluid and plasma samples,” Panditharatna says. “Similar to adults with central nervous system (CNS) cancers, cerebrospinal fluid of children diagnosed with CNS cancers has high concentrations of circulating tumor DNA. However, after the children underwent radiotherapy, there was a dramatic decrease in circulating tumor DNA for 12 of the 15 patients (80 percent) whose temporal plasma was analyzed.”

Nazarian, the study senior author adds: “Biofluids, like plasma and cerebrospinal fluid, are suitable media to detect and measure concentrations of circulating tumor DNA for this type of pediatric glioma. Liquid biopsy has the potential to complement tissue biopsies and MRI evaluation to provide earlier clues to how tumors are responding to treatment or recurring.”

Support for this liquid biopsy study was provided by the V Foundation, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, the Zickler Family Foundation, the Piedmont Community Foundation, the Musella Foundation, the Mathew Larson Foundation and Brain Tumor Foundation for Children.

Combined FACT accreditation related to cellular immunotherapy spotlights Children’s ongoing commitment to revolutionary cancer therapies

DNA strand and Cancer Cell

As new immunotherapy treatments are starting to hit the market, care-delivery must adapt so that facilities are prepared to deliver these novel treatments to patients. Children’s National is proud to announce that it became the first pediatric medical institution in the United States to receive accreditations for both immune effector cells and more than minimal manipulation from the Foundation for the Accreditation of Cellular Therapy (FACT). Considered the threshold for excellence in cellular therapy, FACT establishes standards for high-quality medical and laboratory practice in the field.

“We are proud to receive these critically important seals of approval,” said David Jacobsohn, M.D., ScM, division chief of the Division of Blood and Marrow Transplantation at Children’s National. “Our patients are our highest priority and having these accreditations only further demonstrates our commitment to providing the most innovative care.”

The first new designation, FACT Accreditation for Immune Effector Cells, certifies that Children’s National is able to safely administer cutting-edge cellular therapies and monitor and report patient outcomes. The designation applies to CAR-T cells and therapeutic vaccines, among other therapies.

“We continuously set high standards for cellular therapy within the walls of Children’s National, and we are thrilled to be recognized for our leadership in this field,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research within the Children’s Research Institute. “Cell therapies represent the next generation of cancer treatment, and we are excited to continue our journey in revolutionizing patient care.”

Children’s National also received FACT Accreditation for More than Minimal Manipulation,

a designation that is unique to only a few pediatric institutions in the United States. This accreditation certifies that Children’s National is prepared to safely manufacture its own cellular therapies.

“Being accredited for More than Minimal Manipulation is a tremendous achievement for us as a stand-alone pediatric institution; it exemplifies our ability to manufacture our own innovative cellular therapy products for patients in need,” said Patrick Hanley, Ph.D., director of the Cellular Therapy Laboratory where the cells are manufactured for clinical use. “These two accreditations allow Children’s National to serve as a complex immunotherapy center that is capable of providing immunotherapies and gene therapies from external groups and companies.”

Catherine-Bollard-SIOP

Advancing cures for pediatric cancer: Highlights from leading Children’s National experts at SIOP 2017

In mid-October 2017, nearly 2,000 clinicians, scientists, nurses, health care professionals and cancer patients and survivors gathered in Washington, D.C., for SIOP 2017, the Annual Congress of the International Society of Paediatric Oncology. For four days, attendees heard from world-renowned experts while exchanging ideas and information, all in the name of advancing cures for childhood cancer.

Hosted in the hometown of Children’s National Health System and chaired by Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders and Chief of Oncology at Children’s National Health System, more than 20 doctors and nurses from Children’s National made an impact on participants through a series of widely attended sessions and addresses, including:

  • Symposium lecture on the latest approaches in anti-viral T-cell therapy to improve patient outcomes, given by Catherine Bollard, M.D., M.B.Ch.B.
  • Keynote lecture on DICER1 mutations in pediatric cancer, given by Ashley Hill, M.D., whose study of a rare childhood lung cancer and gene mutations set the stage for a better understanding of microRNA processing gene mutations in the development of pediatric cancer.
  • Education session on new therapies for sarcomas, led by AeRang Kim, M.D., Ph.D., and Karun Sharma, M.D., Ph.D., sharing research on new approaches for local control of sarcomas, such as surgery, radiation and other ablative measures.
  • Education session on new therapies for gliomas, led by Roger J. Packer, M.D., with presentations on immunotherapy from Eugene Hwang, M.D., and targeted therapy by Lindsay Kilburn, M.D.
  • Podium paper presentation on a new method to measure cancer treatment toxicities as reported by the child by Pamela Hinds, Ph.D., RN, FAAN, as well as an education session on advanced care planning, led by Hinds with a presentation from Maureen E. Lyon, Ph.D.

“These sessions and lectures provided a glimpse into the groundbreaking work by SIOP attendees from around the world,” says Dr. Dome. “Children’s National is proud to play an active role in the development of life-saving treatments for children with cancer and our clinicians look forward to another year of revolutionary developments.”

For more on this year’s SIOP, see the Children’s National press release.

  • Jeffrey Dome, M.D., Ph.D., addresses a group of international colleagues at a reception at Children’s National.

    Jeffrey Dome SIOP
  • Catherine Bollard, M.D., M.B.Ch.B., addresses a group of international colleagues at a reception at Children’s National.

    Catherine-Bollard-SIOP
  • Lindsay Kilburn, M.D., engages with peers from around the world at a reception at Children’s National.

    Lindsay-Kilburn-SIOP

Roger Packer, M.D., elected Pediatric Co-Chair by the National Cancer Institute’s Brain Malignancies Steering Committee

Roger Packer, MD

Roger J. Packer, M.D., Senior Vice President, Center for Neuroscience & Behavioral Health at Children’s National Health System, has been elected by the National Cancer Institute’s Brain Malignancies Steering Committee (BMSC) as the committee’s new Pediatric Co-Chair.

One of 16 steering committees formed in response to the recommendations of the Clinical Trials Working Group mandated by the National Cancer Advisory Board (NCAB), the BMSC’s goal is to promote the best clinical and translational research for patients with brain cancer by critically reviewing Phase 2 and Phase 3 clinical trial concepts.

Dr. Packer also directs the Brain Tumor Institute and is principal investigator for the Pediatric Brain Tumor Consortium (PBTC), formed under the auspices of the National Cancer Institute (NCI). He has worked closely with the NCI and the National Institute of Neurological Disorders and Stroke (NINDS), and has served on multiple committees setting the directions for neurologic clinical and basic science research for the future. Much of Dr. Packer’s clinical research has been translational in nature. He has been part of studies evaluating the molecular genetics of childhood and adult neurologic diseases, and has also coordinated the first gene therapy study for children with malignant brain tumors in the U.S.

Karun Sharma

Osteoid osteoma successfully treated with MR-HIFU

Karun Sharma

Doctors from the Sheik Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System have completed a clinical trial that demonstrates how osteoid osteoma, a benign but painful bone tumor that commonly occurs in children and young adults, can be safely and successfully treated using an incisionless surgery method called magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU).

Published in The Journal of Pediatrics on Aug. 17, 2017, the study compares nine patients, ages 6 to 16 years old, who were treated for osteoid osteoma using MR-HIFU with a nine-patient historical control group, ages 6 to 10 years old, who were treated at Children’s National using radiofrequency ablation (RFA) surgery, the standard treatment at most U.S. hospitals. The study results show that treatment using MR-HIFU is feasible and safe for patients, eliminating the incisions or exposure to ionizing radiation that is associated with the RFA procedure. Children’s National is the first U.S. children’s hospital to successfully use MR-HIFU to treat osteoid osteoma.

CT-guided RFA, the most commonly used osteoid osteoma treatment, requires drilling through muscle and soft tissue into bone and also exposes the patient and operator to radiation from the imaging necessary to guide the probe that is inserted to heat and destroy tumor tissue.

“Our objective is to provide a noninvasive treatment option for children with osteoid osteoma and we’re very pleased with the results of this clinical trial,” says Karun Sharma, M.D., Ph.D., director of Interventional Radiology at Children’s National and principal investigator for the osteoid osteoma trial. “We have now shown that MR-HIFU can be performed safely with clinical improvement that is comparable to RFA, but without any incisions or ionizing radiation exposure to children.”

High-intensity focused ultrasound therapy uses focused sound wave energy to heat and destroy the targeted tumor under MRI guidance. This precise and controlled method does not require a scalpel or needle, greatly reducing the risk of complications like infections and bone fractures. It is also a faster treatment option, with expected total procedure time of 90 minutes or less. In the U.S., MR-HIFU is used to treat uterine fibroids and painful bone metastases from several types of cancer in adults, but has not previously been used in children.

This breakthrough is the latest from the Image-Guided Non-Invasive Therapeutic Energy (IGNITE) program, a collaboration of the Sheikh Zayed Institute and the departments of RadiologyOncologySurgery, and Anesthesiology at Children’s National. The goal of the IGNITE program is to improve the quality of life and outcomes for pediatric patients through the development and clinical introduction of novel minimally invasive and noninvasive surgery technologies and combination therapy approaches. The team is led by Peter Kim, M.D., Ph.D., vice president of the Sheikh Zayed Institute.

“The use of MR-HIFU ablation of osteoid osteoma is a perfect example of our mission in the Sheikh Zayed Institute to make pediatric surgery more precise, less invasive and pain-free,” says Dr. Kim. “Our leading team of experts are also exploring the use of MR-HIFU as a noninvasive technique of ablating growth plates and pediatric solid tumors. We also have another clinical trial open for children and young adults with refractory soft tissue tumors, which is being performed in collaboration with Dr. Bradford Wood’s team at the National Institutes of Health, and if successful, it would be the first in the world.”

In addition to Drs. Sharma and Kim, the Children’s National team for the ablation of osteoid osteoma clinical trial included: AeRang Kim, M.D., Ph.D., pediatric oncologist; Matthew Oetgen, M.D., division chief of Orthopaedic Surgery and Sports Medicine; Anilawan Smitthimedhin, M.D., radiology research fellow; Pavel Yarmolenko, Ph.D., Haydar Celik, Ph.D., and Avinash Eranki, engineers; and Janish Patel, M.D., and Domiciano Santos, M.D., pediatric anesthesiologists. Ari Partanen, Ph.D., a senior clinical scientist from Philips, was also a member.

Jeffrey Dome

New approach improves pediatric kidney cancer outcomes

Jeffrey Dome

A recent study co-authored by Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders at Children’s National Health System, shows that a new approach to treating children diagnosed with bilateral Wilms tumors (BWT) significantly improved event-free survival (EFS) and overall survival (OS) rates after four years when compared to historical rates.

Wilms tumor, also known as nephroblastoma, is the most common pediatric kidney cancer, typically seen in children ages three to four. Compared to patients with unilateral Wilms tumors, children with bilateral Wilms tumors (BWT) have poorer event-free survival (EFS) and are at higher risk for later effects such as renal failure. The treatment of BWT is challenging because it involves surgical removal of the cancer, while preserving as much healthy kidney tissue as possible to avoid the need for an organ transplant.

A new Children’s Oncology Group (COG) study published in the September issue of the Annals of Surgery demonstrated an exciting new approach to treating children diagnosed with BWT that significantly improved EFS and overall survival (OS) rates after four years when compared to historical rates. Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders at Children’s National Health System, was co-senior author of this first-ever, multi-institutional prospective study of children with BWT.

Historically, patients with BWT have had poor outcomes, especially if they have tumors with unfavorable histology. In this study, Dr. Dome and 18 other clinical researchers followed a new treatment approach consisting of three chemotherapy drugs before surgery rather than the standard two drug regimen, surgical removal of cancerous tissue within 12 weeks of diagnosis, and postoperative chemotherapy that was adjusted based on histology.

The study found that preoperative chemotherapy expedited surgical treatment, with 84 percent of patients having surgery within 12 weeks of diagnosis. The new treatment approach also vastly improved EFS and OS rates for patients participating in the study. The four-year EFS rate was 82.1 percent, compared to 56 percent on the predecessor National Wilms Tumor Study-5 (NWTS-5) study. The four-year OS rate was 94.9 percent, compared to 80.8 percent on NWTS-5.

“I am very encouraged by these results, which I believe will serve as a benchmark for future studies and lead to additional treatment improvements, giving more children the chance to overcome this diagnosis while sparing kidney tissue,” says Dr. Dome.

A total of 189 patients at children’s hospitals, universities and cancer centers in the United States and Canada participated in this study. These patients will continue to be followed for 10 years to track kidney failure rates. This study was funded by grants from the National Institutes of Health to the Children’s Oncology Group.

Happy girl in hospital bed surrounded by doctors

Addressing MB-CLABSI through innovation – and dedication – to pediatric safety

Happy girl in hospital bed surrounded by doctors

With mucosal barrier central line-associated blood stream infections (MB-CLABSI) posing a serious risk to cancer and other immunocompromised patients, Children’s National Health System was intent on finding a way to prevent them. Through a focused initiative, the hospital experienced great success, cutting infection rates by more than half.

This was a daunting proposition. Historically MB-CLABSI has not been viewed as a preventable infection due to the side effects typically associated with bone marrow transplants in this patient population. Sores and mucosal disruption that develops in the oral cavity post-transplant are fairly common and make it exceedingly difficult to keep the mouth clean and clear of bacteria. Without regimented oral hygiene in this type of environment, the mouth can quickly develop bacteria putting the patient at risk of a MB-CLABSI.

“We challenged the notion that we could not prevent MB-CLABSI and set out on a journey to try to prevent these types of infections from occurring,” says vice president and chief quality and safety officer, Rahul Shah, M.D. “With leadership from our nursing teams and the infection control and prevention group working together with the physicians, we were able to approach this issue from a unique perspective.”

In 2013, Children’s National launched a MB-CLABSI prevention program focused around saline rinses to improve oral hygiene. The goal was to keep the mouth cleaner to avoid bacteria from forming and ultimately entering the blood stream.

Children’s National put the plan into action through the following measures:

Provider

  • Simplified ordering of saline rinses to increase accountability and compliance with the practice and make it easier for providers
  • Implemented reminders to order saline rinses during daily rounds
  • Added saline rinses to the Medication Administration Record to drive compliance in administration of the task

Administrative

  • Saline rinses were chosen as an indicator to be displayed on public-facing quality boards throughout the hospital
  • Implemented daily audits of the quality board to track opportunities for improving compliance and reducing omissions and errors
  • Standardized daily medical rounds to include review of the quality boards

Patient/Caregiver

  • Implemented discussion of saline rinses of the mouth for oncology and bone marrow transplant patients during daily rounds
  • Standardized education for caregivers of children with central lines

“Through strategic programs like this, our patients are safer and Children’s National continues to be a national pediatric quality leader,” says Dr. Shah.

Children's National Red Badge Project

The Red Badge Project: expediting ED care

Children's National Red Badge Project

A red badge allows newly diagnosed cancer patients and BMT patients to bypass security and triage so they can receive lifesaving antibiotics within an hour of fighting fever.

Chemotherapy and bone marrow transplant procedures leave cancer patients with compromised immune systems, leading many to develop life-threatening infections or other complications. In particular, neutropenia, or abnormally low levels of white blood cells that are critical to fighting off infections, is prevalent among this population. Fever with neutropenia can be fatal.

As part of the Children’s National Health System commitment to deliver better outcomes and safer care through innovative approaches, the Hematology/Oncology/Bone Marrow Transplant (BMT) Family Advisory team developed a protocol to rapidly identify BMT and cancer patients with suspected neutropenia to receive antibiotics within 60 minutes of arriving at the Emergency Department (ED). The Red Badge Project was born with the following goals:

• Decrease the median triage-to-antibiotic time in cancer patients with fever and suspected neutropenia or bone marrow transplant patients to 30 minutes
• Increase the proportion of patients receiving antibiotics within one hour to 90 percent

As part of the protocol, newly diagnosed cancer and bone marrow transplant patients receive a Red Badge and education regarding how to use it. If they run a fever and need medical attention, the patient and family present the Red Badge upon arrival at the ED in order to bypass the welcome desk and ED triage. This action accelerates the process, keeps the child from waiting in an area where there are other sick children and ensures the patient receives lifesaving antibiotics as fast as possible.

Work done before the patient walks through the ED doors contributes to the success of this program. When a patient runs a fever, the family is instructed to call the Hematology Oncology Fellow on-call. If it is determined that the patient needs to come to the ED, the Fellow then: 1) receives the patient’s estimated arrival time so that staff can clean and prep a room 2) reminds them to apply their topical analgesia to numb the port site where the antibiotic will be administered 3) reminds them to bring their Red Badge.

From there, swift action is taken. By the time the patient arrives, he or she has already been registered and the appropriate medications have been ordered. The patient bypasses security and triage using their Red Badge as a visual cue and is then directed to a prepped room complete with medications ready for administration.

To date, the median time from triage to administration of antibiotics has decreased nearly 50 percent while the proportion of patients who received antibiotics within 60 minutes of triage improved to 90 percent.

Leveraging that success, the next step is to develop education for non-English speaking families in order to extend the reach of this lifesaving practice.

Javad Nazarian

Advancing pediatric cancer research by easing access to data

Javad Nazarian

“This is a tremendous opportunity for children and families whose lives have been forever altered by pediatric cancers,” says Javad Nazarian, Ph.D., M.S.C., principal investigator in the Center for Genetic Medicine Research and scientific director of the Brain Tumor Institute at Children’s National.

Speeding research into pediatric cancers and other diseases relies not only on collecting good data, but making them accessible to research teams around the world to analyze and build on. Both efforts take time, hard work and a significant amount of financial resources – the latter which can often be difficult to attain.

In a move that could considerably advance the field of pediatric cancer, the National Institutes of Health (NIH), a body that funds biomedical research in the United States, recently awarded a public-private research collective that includes Children’s National Health System up to $14.8 million to launch a data resource center for cancer researchers around the world in order to accelerate the discovery of novel treatments for childhood tumors. Contingent on available funds, five years of funding will be provided by the NIH Common Fund Gabriella Miller Kids First Pediatric Research Program, named after Gabriella Miller, a 10-year-old child treated at Children’s National.

As principal investigators, researchers at Children’s Hospital of Philadelphia will lead the joint effort to build out the “Kids First” Data Resource Center. Children’s National in Washington, D.C., will spearhead specific projects, including the Open DIPG project, and as project ambassador will cultivate additional partnerships with public and private foundations and related research consortia to expand a growing trove of data about pediatric cancers and birth defects.

“This is a tremendous opportunity for children and families whose lives have been forever altered by pediatric cancers,” says Javad Nazarian, Ph.D., M.S.C., principal investigator in the Center for Genetic Medicine Research and scientific director of the Brain Tumor Institute at Children’s National. “From just a dozen samples seven years ago, Children’s National has amassed one of the nation’s largest tumor biorepositories funded, in large part, by small foundations. Meanwhile, research teams have been sequencing data from samples here and around the world. With this infusion of federal funding, we are poised to turn these data into insights and to translate those research findings into effective treatments.”

Today’s NIH grant builds on previous funding that Congress provided to the NIH Common Fund to underwrite research into structural birth defects and pediatric cancers. In the first phase, so-called X01 grantees—including Eric Vilain, M.D., Ph.D., newly named director of the Center for Genetic Medicine Research at Children’s National—received funding to sequence genetic data from thousands of patients and families affected by childhood cancer and structural birth defects.

This new phase of funding is aimed at opening access to those genetic sequences to a broader group of investigators around the globe by making hard-to-access data easily available on the cloud. The first project funded will be Open DIPG, run by Nazarian, a single disease prototype demonstrating how the new data resource center would work for multiple ailments.

DIPG stands for diffuse intrinsic pontine glioma, aggressive pediatric brain tumors that defy treatment and are almost always fatal. Just as crowd sourcing can unleash the collective brainpower of a large group to untangle a problem swiftly, open data sharing could accomplish the same for childhood cancers, including DIPG. In addition to teasing out molecular alterations responsible for making such cancers particularly lethal, pooling data that now sits in silos could help to identify beneficial mutations that allow some children to survive months or years longer than others.

“It’s a question of numbers,” Dr. Vilain says. “The bottom line is that making sense of the genomic information is significantly increased by working through large consortia because they provide access to many more patients with the disease. What is complicated about genetics is we all have genetic variations. The challenge we face is teasing apart regular genetic variations from those genetic variations that actually cause childhood cancers, including DIPG.”

Nazarian predicts some of the early steps for the research consortium will be deciding nuts-and-bolts questions faced by such a start-up venture, such as the best methods to provide data access, corralling the resources needed to store massive amounts of data, and providing data access and cross correlation.

“One of the major challenges that the data resource center will face is to rapidly establish physical data storage space to store all of the data,” Nazarian says. “We’re talking about several petabytes—1,000 terabytes— of data. The second challenge to address will be data dissemination and, specifically, correlation of data across platforms representing different molecular profiles (genome versus proteome, for example). This is just the beginning, and it is fantastic to see a combination of public and private resources in answering these challenges.”

Children’s National Chief of Allergy and Immunology helps move gene therapy forward

Catherine Bollard

Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology, recently shared her expertise on an FDA panel that unanimously expressed its support for a pediatric cancer T-cell therapy called CTL019.

On July 12, 2017, a U.S. Food and Drug Administration advisory committee unanimously expressed its support for CTL019 – a pediatric cancer T-cell therapy. If the FDA follows the advice from the 10-member Oncologic Drug Advisory Committee (ODAC) – which included Children’s National Health System’s Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology and Director of the Program for Cell Enhancement and Technologies for Immunotherapy – CTL019 will become the first gene therapy to hit the market.

“Many of these children with recurrent cancer are out of other options to treat their illness,” said Dr. Bollard. “We are encouraged by these findings and the potential for this therapy to improve outcomes and quality of life.”

CTL019 is a chimeric antigen receptor (CAR) T-cell therapy, comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells. Also known as tisagenlecleucel, the therapy targets a single type of cancer called acute lymphoblastic leukemia and was created by Novartis.

In clinical trials, CTL019 showed unparalleled effectiveness. Of the 68 patients who received the drug, 52 responded almost immediately, and their cancer disappeared within the first three months. Seventy-five percent of those patients remained cancer-free six months after treatment. The therapy has one main side effect: an immune reaction called cytokine release syndrome, which can be deadly, with extended spiking fevers and other symptoms.

However, because of CTL019’s high efficacy, FDA scientists asked the ODAC panel to focus on the therapy’s safety and manufacturing challenges rather than whether or not it works.

Several committee members, including Dr. Bollard, expressed apprehension about the T-cell subpopulations’ heterogeneity, which could affect safety and efficacy. Another issue for consideration by the ODAC panel was the long-term side effects of CTL019 and the possibility that the T-cell modification could go awry, causing secondary cancers in the future.

Despite these concerns, the committee concluded that the strong efficacy data and the near-term benefits of CAR-T therapy more than tipped the scales in favor of the therapy. ODAC members were also pleased with Novartis’ plan to minimize risk, which includes limiting CTL019 distribution to selected centers with CAR T-cell therapy experience, and extensive, long-term post-marketing surveillance plans.

The FDA is not required to follow the ODAC panel’s advice when making its final decision, but it often does so. A final decision by the FDA is anticipated by late September.

Read more about the story in the Philadelphia Inquirer, Medpage Today and Healio.com.

SIOP-Kim, Bollard, and Hill

17 Children’s doctors featured at SIOP

SIOP-Kim, Bollard, and Hill

AeRang Kim, M.D., Ph.D., Catherine Bollard, M.D., MBChB, and D. Ashley Hill, M.D. are among the Children’s National experts who will be speaking at the 49th Congress of the International Society of Pediatric Oncology.

This October, thousands of pediatric oncologists, researchers, nurses, allied health professionals, patients and survivors will gather in Washington, D.C., for the 49th Congress of the International Society of Pediatric Oncology (SIOP). Chaired by Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders and Chief of Oncology at Children’s National Health System, and Stephen P. Hunger, M.D., of the Children’s Hospital of Philadelphia, the meeting will feature talks by renowned experts in pediatric oncology, including 17 doctors from Children’s National.

Among these expert speakers are AeRang Kim, M.D., Ph.D., pediatric oncologist and Associate Professor of Pediatrics at the George Washington University School of Medicine & Health Sciences, who will present her latest research on new approaches to local control of sarcomas as part of the SIOP Education Day. Dr. Kim focuses on the development of novel agents and devices for pediatric cancer including pre-clinical testing of novel agents, pharmacokinetic analysis, developing innovative methods for toxicity monitoring and clinical trial design.

Also speaking is Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology at Children’s National, Professor of Pediatrics and of Microbiology, Immunology and Tropical Medicine at the George Washington University School of Medicine & Health Sciences and Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI). Dr. Bollard will present a talk as part of the SIOP-St. Baldrick’s Symposium on Cell Therapy for Viral Infections.  Her translational research focuses on developing and applying novel cell therapies to improve outcomes for patients with viral infections, cancer and immunologic disorders.

And, D. Ashley Hill, M.D., Chief of the Division of Anatomic Pathology and Professor of Pathology and Pediatrics at the George Washington University School of Medicine & Health Sciences, will be giving a keynote address on DICER1 mutations in pediatric cancer. Dr. Hill first reported the connection between pleuropulmonary blastoma, a rare childhood lung tumor, and mutations in DICER1, setting the stage for our understanding of microRNA processing gene mutations in the development of pediatric cancer.

Other speakers, session chairs and abstract presenters from Children’s National include:

US News Honor Roll 2017-18

Children’s National is #1 in Neonatology and Top 10 overall in U.S. News & World Report Survey

US News Honor Roll 2017-18Children’s National is proud to be named #1 in Neonatology in the U.S. News & World Report 2017-18 Best Children’s Hospitals survey. Also, Children’s National was once again named to the coveted Honor Roll, placing them among the Top 10 children’s hospitals in the country.

Being the #1 ranked Neonatology program reflects the quality of care throughout Children’s National because it requires the support and partnership of many other specialties, including cardiology, neurology and surgery. In addition to this honor, Children’s National ranked in the Top 10 in four additional services: Cancer (#7), Neurology and Neurosurgery (#9), Orthopedics (#9) and Nephrology (#10).  For the seventh year in a row, Children’s National has ranked in all ten services, a testament to the pediatric care experts across the organization and their commitment to children and families.

“This recognition is a great achievement for Children’s National, affirming our place as a premier destination for pediatric care, and the commitment of our people, partners and supporters to helping every child grow up stronger,” said Kurt Newman, M.D., President and CEO of Children’s National. “I’m particularly proud of our #1 ranking in Neonatology as, in many ways it reflects the quality of care across our hospital. Treating these tiny patients often encompasses many other specialties, including our Fetal Medicine Institute.”

Children’s National is dedicated to improving the lives of children through innovative research, expert care and advocacy on behalf of children’s needs. In addition to being recognized among the “best of the best” by U.S. News & World Report, Children’s National is a Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. As a top NIH-funded pediatric health system, Children’s National marries cutting-edge research with the highest quality care, to deliver the best possible outcomes for children today and in the future.

Children’s welcomes hematology leaders, expands expertise

The Center for Cancer and Blood Disorders at Children’s National is emerging as a leader in Pediatric Hematology, and the recruitment of two prominent physician-scientists to our Division of Hematology and Sickle Cell Disease Program is evidence of that growth and presence on the national platform. Joining the faculty in June are:

Suvankar (Seve) Majumdar, M.D., Suvankar (Seve) Majumdar, M.D.
Division Chief, Hematology
Dr. Majumdar was born in Zambia, attended the University of Zimbabwe College of Health Sciences and conducted his postdoctoral medical education at the University of Mississippi. Dr. Majumdar is currently the director of the Comprehensive Pediatric Sickle Cell Program at the University of Mississippi Medical Center. He previously directed the Mississippi Hemophilia Treatment Center and is a recognized leader in hematology and sickle cell disease. In addition to his broad clinical expertise, Dr. Majumdar is an accomplished researcher, and a principal investigator of NIH-funded studies.

Andrew Campbell, M.D.Andrew (Drew) Campbell, M.D.
Director, Sickle Cell Disease Program
Dr. Campbell’s distinguished training and career path began at Morehouse College. He continued medical school at Case Western Reserve University and completed post graduate training at Massachusetts General Hospital (Harvard) and Lurie Children’s Hospital (Northwestern University). He has been director of the Comprehensive Sickle Cell Center at the University of Michigan since 2005. His research interests span several topics in sickle cell disease including pulmonary complications, fetal hemoglobin switching in transgenic sickle cell mice, phenotype/genotype relationships and renal complications.

The Children’s National Division of Hematology includes the most comprehensive pediatric blood disorders team in the Washington, D.C., area. The Sickle Cell Disease Program is among the largest in the country, treating more than 1,400 children and young adults with all types of sickle cell disease.

Pamela Hinds

Giving children a voice in clinical trials

Pamela Hinds

“When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children’s organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience,” says Pamela S. Hinds, Ph.D., R.N.

Children as young as 8 years old with incurable cancer can reliably characterize the impact an experimental therapy has on their symptoms and quality of life – even at the earliest stages of drug development – making self-reported patient outcomes a potential new clinical trial endpoint, according to a longitudinal validity study led by Children’s National Health System researchers.

Cancer is the No. 1 disease-related cause of death in U.S. children aged 1 to 19, and roughly 25 percent of the 12,400 children newly diagnosed with cancer will die of their disease, the study authors write.

“When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children’s organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience,” says Pamela S. Hinds, Ph.D., R.N., director of Nursing Research and Quality Outcomes at Children’s National and lead author of study published June 5, 2017 in the journal Cancer. “Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects.”

To demonstrate the feasibility of children self-reporting outcomes, Hinds and colleagues recruited children and adolescents aged 8 to 18 with incurable or refractory cancers who were enrolled in Phase 1 safety trials or Phase 2 efficacy trials at four cancer settings: Children’s National, Seattle Children’s Hospital, Children’s Hospital of Philadelphia and Boston Children’s Hospital. Using a validated instrument to measure symptoms, function and other aspects of quality of life reported by patients, as well as four open-ended interview questions, researchers were able to better understand what aspects of symptoms and quality of life were most important to patients at this point in their lives and cancer treatment.

Of the 20 study participants, most were male (60 percent), adolescents (65 percent) and white (70 percent). Thirteen (65 percent) had solid tumors. Patients could describe “a good day” as having fewer side effects from the experimental therapy and fewer interruptions to their lives. “Bad days” were marked by interruptions to their usual activities and missing out on spending time with family and friends due to being at the hospital. A few study participants suggested that researchers add questions related to being away from home, family and friends and the ripple effect of treatment on other family members.

“Only by measuring and understanding self-reported symptoms and function in children and adolescents with incurable cancer can we adequately address threats to their quality of life and improve symptom control and supportive care,” Hinds and co-authors conclude. “By giving children a voice in the process, clinicians will be able to better anticipate and manage symptoms and thereby improve life for patients and their families.”

EKG monitor

Protecting the hearts of pediatric cancer patients

EKG monitor

Children’s National has developed a cardio-oncology program to closely follow the heart health of oncology patients to detect and stop progression of heart disease.

The five-year survival rate for pediatric cancers has climbed to nearly 82 percent, but the damaging, long-term side effects of rigorous treatment are prevalent. Cardiac toxicity, specifically the association of several cancer therapy agents with the development of left ventricular dysfunction, cardiomyopathy, dysrhythmia, valve disease and hypertension, is an issue of growing concern. Cardiac complications are the third leading cause of death for childhood cancer survivors, only after cancer recurrence and secondary malignancy. Cardiac mortality is 10-fold higher among this population as compared with age-matched control subjects.

The American Heart Association released a statement in 2013 pointing to the need for closer monitoring of cardiac affects from cancer treatments. Craig Sable, M.D., Associate Division Chief of Cardiology at Children’s National, co-authored the statement titled “Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions.” The statement concluded that it is crucial to develop an optimal monitoring regimen for this specific subgroup of patients, affirming:  “As clinicians continue to learn about the cardiovascular effects of cancer treatment, the importance of primary prevention becomes abundantly clear. The objective of effective monitoring is to identify signs of cardiac disease early enough to potentially prevent, reverse, or slow the deterioration of the structure and function of the heart. We must tailor therapies to decrease the risk of cardiotoxicity while balancing the beneficial effects of the cancer therapy.”

The American College of Cardiology also launched a Cardio-Oncology section dedicated to the subspecialty and noting the need for increased and closer cardiac monitoring for cancer patients. Cardiologists and oncologists at Children’s National came together to address this issue by formalizing a multidisciplinary path of care for patients with malignancies as they enter the care system.

Multidisciplinary care from point of diagnosis

Niti Dham

“It is tremendously important that we care for the whole child, including each individual health anomaly. Working closely with the oncology team, we try to balance how we treat their cancer at the same time as managing their heart disease,” says Niti Dham, M.D.

In response to the outstanding need for cardiac observation and follow-up care for cancer patients, Children’s National developed a Cardio-Oncology Program in 2011 to closely follow the heart health of oncology patients to detect and stop progression of heart disease. Led by Niti Dham, M.D., the cardio-oncology program within the Division of Cardiology includes the Cardiology Oncology Blood (COB) Clinic, a special clinic dedicated to pediatric cancer patients. The clinic assesses cancer patients, including bone marrow transplant (BMT) patients, who have been exposed to certain medications or radiation that have shown potential long-term, negative cardiac outcomes.  Patients are monitored for any early signs of cardiac changes in hopes to halt or even reverse the disease.

When a child is diagnosed with cancer that requires certain chemotherapies and radiation for treatment, Children’s National oncologists coordinate with Dr. Dham and her team for a cardiac evaluation prior to beginning treatment. Appropriate cardiac screening tests are administered based on the planned cancer treatment regimen. Cardiac health is evaluated regularly throughout the treatment course as well as after completion to continue monitoring for early signs of changes.

“The frequent, close monitoring allows Children’s experts to notice even the slightest differences in the heart, with a goal of preventing progression of cardiac disease,” says Dr. Dham.

The cardiology team works closely with the oncology team through the whole process, alerting them immediately of any changes noted. Together, the subspecialists develop a plan that is safe for each individual patient.

The program also sees patients that have pre-existing cardiac conditions prior to cancer treatments.

“It is tremendously important that we care for the whole child, including each individual health anomaly. Working closely with the oncology team, we try to balance how we treat their cancer at the same time as managing their heart disease,” says Dr. Dham.

Advances in T-cell immunotherapy at ISCT

Healthy Human T Cell

T-cell immunotherapy, which has the potential to deliver safer, more effective treatments for cancer and life-threatening infections, is considered one of the most promising cell therapies today. Each year, medical experts from around the world – including leaders in the field at Children’s National Health System – gather at the International Society for Cellular Therapy (ISCT) Conference to move the needle on cell therapy through several days of innovation, collaboration and presentations.

Dr. Catherine Bollard, Children’s National chief of allergy and immunology and current president of ISCT, kicked off the week with a presentation on how specific approaches and strategies have contributed to the success of T-cell immunotherapy, a ground-breaking therapy in this fast-moving field.

Later in the week, Dr. Kirsten Williams, a blood and marrow transplant specialist, presented encouraging new findings, demonstrating that T-cell therapy could be an effective treatment for leukemia and lymphoma patients who relapse after undergoing a bone marrow transplant. Results from her phase 1 study showed that four out of nine patients achieved complete remission. Other medical options for the patients involved – those who relapsed between 2 and 12 months post-transplant – are very limited. Looking to the future, this developing therapy, while still in early stages, could be a promising solution.

Other highlights include:

  • Both Allistair Abraham, blood and marrow transplantation specialist, and Dr. Michael Keller, immunologist, presented oral abstracts, the former titled “Successful Engraftment but High Viral Reactivation After Reduced Intensity Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease” and the latter “Adoptive T Cell Immunotherapy Restores Targeted Antiviral Immunity in Immunodeficient Patients.
  • Patrick Hanley engaged attendees with his talk, “Challenges of Incorporating T-Cell Potency Assays in Early Phase Clinical Trials,” and his poster presentation “Cost Effectiveness of Manufacturing Antigen-Specific T-Cells in an Academic GMP Facility.” He also co-chaired a session titled “Early Stage Professionals Session 1 – Advanced Strategic Innovations for Cell and Gene Therapies.”
  • To round out this impressive group, Shabnum Piyush Patel gave a talk on genetically modifying HIV-specific T-cells to enhance their anti-viral capacity; the team plans to use these HIV-specific T-cells post-transplant in HIV-positive patients with hematologic malignancies to control their viral rebound.

This exciting team is leading the way in immunology and immunotherapy, as evidenced by the work they shared at the ISCT conference and their ongoing commitment to improving treatments and outcomes for patients at Children’s National and across the country. To learn more about the team, visit the Center for Cancer and Blood Disorders site.

Catherine Bollard named to Medicine Maker’s Annual Power List

Catherine Bollard

Children’s National Health System’s Chief of Allergy and Immunology, Catherine Bollard M.D., has been named to The Medicine Maker’s 2017 Power List, which honors the top 100 most influential people in the world of drug development. Dr. Bollard is featured as a ”Champion of Change,” a category that highlights experts striving to make the world a better place by getting medicines to those who need them the most. She joins notable scientists Frances Collins, director of the U.S. National Institutes of Health, and Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

In the Medicine Maker feature, Dr. Bollard describes the inspiration behind her dedication to cellular immunotherapy and how that led to her team’s breakthrough T-cell therapy that gives complete remissions in over 50 percent of some patient groups. Read the full piece here.

Cell therapy virtuoso: Catherine Bollard

Catherine Bollard

In the Medicine Maker piece, Cell Therapy Virtuoso, Children’s National Medical System’s Chief of Allergy and Immunology, Catherine Bollard M.D., discusses why she chose a career in medicine, the personal experience that ignited her interest in cell therapies, and her insights on the current state and future of the immunotherapy field. Highlights from the interview include:

  • On the promise of T-cell therapy: “We’ve now developed several T-cell therapies that give complete remission rates of approximately 75% and two-year progression-free survival rates ranging from 50 percent to over 90 percent depending on the patient population.”
  • Regarding the future of immunotherapy: “The field has expanded dramatically over the last 25 years. In particular, T-cell therapies for cancer have grown rapidly and now the field is expanding into other areas, such as regulatory T-cells for autoimmune disease and virus T-cells for HIV. Given what the immune system can do, the applications are almost limitless.”

Dr. Bollard was featured for her role as president of the International Society for Cellular Therapy.

A vaccine approach to tumor cure

Anthony Sandler

Anthony Sandler, M.D, is trying to understand how cancer cells can change their behavior and activate the immune system – enlisting the patients’ own defenses to fight the tumor.

Building on their groundbreaking research that found a method to cure neuroblastoma tumors in mice, researchers at Children’s National have been working in recent months on a personalized tumor-specific vaccine approach for neuroblastoma and other solid tumors.

The possibility that such a vaccine could non-invasively cure one of the most common childhood cancers is part of Children’s innovative efforts to address some of the most critical medical research challenges facing the field. Anthony Sandler, M.D., Senior Vice President, the Joseph E. Robert, Jr. Center for Surgical Care, and the Diane and Norman Bernstein Professor in Pediatric Surgery, is leading the research that followed an initial publication in PLOS ONE. Sandler’s team seeks to understand how cancer cells can change their behavior and activate the immune system – enlisting the patients’ own defenses to fight the tumor.

Their research is particularly significant because neuroblastoma, most commonly centered in the adrenal glands, is the third most common tumor in childhood, and the most common cancer in babies younger than one year old. It accounts for six percent of all childhood cancers in the United States, with about 700 children younger than 15 diagnosed each year.

“Historically, tumor vaccines held much promise, but demonstrated little clinical success,” Dr. Sandler and his team wrote in their study. “Thus, the task of establishing an effective anti-tumor response in neuroblastoma has been daunting.” However, with this most recent study finding, Dr. Sandler says this failed promise is changing.

The study revealed that “knockdown’” of a DNA-protein inhibitor, known as ID-2, in aggressive high-risk solid tumors resulted in activation of T-cells, which are white blood cells that have figured significantly in immunity research. Gene knockdown refers to a technique in which the expression of one or more of a cell’s genes is reduced.

The research also focused on using “checkpoint blockade,” a therapy in clinical use that allows for expansion of the immune response against tumors. “The combination of selective gene knock-down in tumor cells and checkpoint blockade produced a novel, potent T-cell triggered tumor vaccine strategy,” Dr. Sandler says.

As Children’s researchers examined the impact of the knockdown of ID-2 protein on a tumor, they implanted N2a, a fast growing mouse neuroblastoma cell line, in the mice. Unexpectedly, Sandler said, “Most of the mice rejected the tumor cells and subsequently were protected against further tumor challenges.”

The researchers also noted that a “massive influx” of T-cells infiltrated the shrinking tumor, indicating that T-cells are necessary for antitumor immunity in this vaccination protocol.

The ultimate goal for Sandler’s team is to work toward potential clinical trials to make further progress in neuroblastoma research, with immunotherapy playing a key role.

Dr. Sandler is the Principal Investigator of the Immunology initiative of the Sheikh Zayed Institute for Pediatric Surgical Innovation, and has worked in immunology research related to childhood cancers for more than 20 years.

cord blood

T-cell therapy success for relapsing blood cancer

cord blood

A unique immunotherapeutic approach that expands the pool of donor-derived lymphocytes (T-cells) that react and target three key tumor-associated antigens (TAA) is demonstrating success at reducing or eliminating acute leukemias and lymphomas when these cancers have relapsed following hematopoietic stem cell transplant (HSCT).

“There’s currently a less than 10 percent chance of survival for a child who relapses leukemia or lymphoma after a bone marrow transplant—in part because these patients are in a fragile medical condition and can’t tolerate additional intense therapy,” says Kirsten Williams, M.D., a blood and marrow transplant specialist in the Division of Hematology at Children’s National Health System, and principal investigator of the Research of Expanded multi-antigen Specifically Oriented Lymphocytes for the treatment of VEry High Risk Hematopoietic Malignancies (RESOLVE) clinical trial.

The unique manufactured donor-derived lymphocytes used in this multi-institutional Phase 1 dose-ranging study are receptive to multiple tumor-associated antigens within the cell, including WT1, PRAME, and Survivin, which have been found to be over-expressed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), B-cell AML/MDS, B-cell acute lymphoblastic leukemia (ALL), and Hodgkins lymphoma. Modifying the lymphocytes for several antigens, rather than a single target, broadens the ability of the T-cells to accurately target and eradicate cancerous cells.

Preliminary results demonstrate a 78 percent response rate to treatment, and a 44 percent rate of total remission for participating patients. To date, nine evaluable patients with refractory and relapsed AML/MDS, B-cell ALL, or Hodgkins lymphoma have received 1-3 infusions of the expanded T-cells, and of those, seven have responded to the treatment, showing reduction in cancer cells after infusion with little or no toxicity. All of these patients had relapse of their cancer after hematopoietic cell transplantation. The study continues to recruit eligible patients, with the goal of publishing the full study results within the next 12 months.

“Our preliminary data also shows that this new approach has few if any side effects for the patient, in part because the infused T-cells target antigens that are found only in cancer cells and not found in healthy tissues,” Dr. Williams notes.

The approach used to expand existing donor-derived TAA-lymphocytes, rather than using unselected T cells or genetically modified T-cells as in other trials, also seems to reduce the incidence of post infusion graft versus host disease and other severe inflammatory side effects. Those side effects typically occur when the infused lymphocytes recognize healthy tissues as foreign and reject them or when the immune system reacts to the modified elements of the lymphocytes, she adds.

“These results are exciting because they may present a truly viable option for the 30 to 40 percent of children who will relapse post-transplant,” Dr. Williams concludes. “Many of the patients who participated were given two options: palliative care or this trial. To see significant success and fewer side effects gives us, and families with children facing relapsing leukemia, some hope for this new treatment.”

Dr. Williams discussed the early outcomes of the RESOLVE trial during an oral presentation at the American Society for Blood and Marrow Transplantation meeting on February 22, 2017.

“The early indicators are very promising for this patient population,” says Catherine Bollard, M.D., M.B.Ch.B., Chief of the Division of Allergy and Immunology, Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, and senior author of the study. “If we can achieve this, and continue to see good responses with few side effects, it’s possible these methods could become a viable alternative to HSCT for patients with no donor match or who aren’t likely to tolerate transplant.”

This is one of the first immunotherapeutic approaches to successfully capitalize on the natural ability of human T-cells to kill cancer, though previous research has shown significant success for this approach in reducing the deadly impact of several viruses, including Epstein-Barr virus, adenovirus, and cytomegalovirus, post HSCT. These new findings have led to the development of additional clinical trials to investigate applications of this method of TAA-lymphocyte manufacture and infusion for pre-HSCT MDS/AML, B-cell ALL, Hodgkins Lymphoma, and even some solid tumors.