Cancer

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.

Javad Nazarian named scientific director of the Brain Tumor Institute

Javad Nazarian

Javad Nazarian, Ph.D., has been named scientific director of the Brain Tumor Institute of the Children’s National Health System. Since 2006, Dr. Nazarian has been an active member of the Brain Tumor Institute, contributing to the advancement in understanding pediatric brain tumors.

He has been instrumental in his role as a Principal Investigator in the Center for Cancer and Immunology Research where his laboratory actively investigates the molecular mechanisms of diffuse intrinsic pontine gilomas (DIPGs) and establishes preclinical models of pediatric brain tumors.

Dr. Nazarian has also contributed to the expansion of the comprehensive biorepository at Children’s National, growing from 12 samples six years ago to more than 3,000 specimens donated by more than 900 patients with all types of pediatric brain tumors, including DIPG. Recently he was appointed Scientific Co-chair of the Children’s Brain Tumor Tissue Consortium.

Vittorio Gallo

Vittorio Gallo named Chief Research Officer

Vittorio Gallo

As chief research officer, Vittorio Gallo, Ph.D., will be instrumental in developing and realizing Children’s Research Institute’s long-term strategic vision.

Children’s National Health System has appointed the longtime director of its Center for Neuroscience Research, Vittorio Gallo, Ph.D., as Chief Research Officer. Gallo’s appointment comes at a pivotal time for the institution’s research strategic plan, as significant growth and expansion will occur in the next few years. Gallo is a neuroscientist who studies white matter disorders, with particular focus on white matter growth and repair. He is also the Wolf-Pack Chair in Neuroscience at Children’s Research Institute, the academic arm of Children’s National.

As Chief Research Officer, Gallo will be instrumental in developing and realizing Children’s Research Institute’s long-term strategic vision, which includes building out the nearly 12-acre property once occupied by Walter Reed National Military Medical Center to serve as a regional innovation hub and to support Children’s scientists conducting world-class pediatric research in neuroscience, genetics, clinical and translational science, cancer and immunology. He succeeds Mendel Tuchman, M.D., who has had a long and distinguished career as Children’s Chief Research Officer for the past 12 years and who will remain for one year in an emeritus role, continuing federally funded research projects and mentoring junior researchers.

“I am tremendously pleased that Vittorio has agreed to become Chief Research Officer as of July 1, 2017, at such a pivotal time in Children’s history,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “Since Mendel announced plans to retire last summer, I spent a great deal of time talking to Children’s Research Institute investigators and leaders and also asking colleagues around the nation about the type of person and unique skill sets needed to serve as Mendel’s successor. With each conversation, it became increasingly clear that the most outstanding candidate for the Chief Research Officer position already works within Children’s walls,” Dr. Batshaw adds.

“I am deeply honored by being selected as Children’s next Chief Research Officer and am excited about being able to play a leadership role in defining the major areas of research that will be based at the Walter Reed space. The project represents an incredible opportunity to maintain the core nucleus of our research strengths – genetics, immunology, neurodevelopmental disorders and disabilities – and to expand into new, exciting areas of research. What’s more, we have an unprecedented opportunity to form new partnerships with peers in academia and private industry, and forge new community partnerships,” Gallo says. “I am already referring to this as Walter Reed ‘Now,’ so that we are not waiting for construction to begin to establish these important partnerships.”

Gallo’s research focus has been on white matter development and injury, myelin and glial cells – which are involved in the brain’s response to injury. His past and current focus is also on neural stem cells. His work in developmental neuroscience has been seminal in deepening understanding of cerebral palsy and multiple sclerosis. He came to Children’s National from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) intramural program. His intimate knowledge of the workings of the National Institutes of Health (NIH) has helped him to establish meaningful collaborations between both institutions. During his tenure, he has transformed the Center for Neuroscience Research into one of the nation’s premier programs. The Center is home to the prestigious NIH/NICHD-funded District of Columbia Intellectual and Developmental Disabilities Research Center, which Gallo directs.

Children’s research scientists working under the auspices of Children’s Research Institute conduct and promote highly collaborative and multidisciplinary research within the hospital that aims to better understand, treat and, ultimately, prevent pediatric disease. As Chief Research Officer, Gallo will continue to establish and enhance collaborations between research and clinical programs. Such cross-cutting projects will be essential in defining new mechanisms that underlie pediatric disease. “We know, for instance, that various mechanisms contribute to many genetic and neurological pediatric diseases, and that co-morbidities add another layer of complexity. Tapping expertise across disciplines has the potential to unravel current mysteries, as well as to better characterize unknown and rare diseases,” he says.

“Children’s National is among the nation’s top seven pediatric hospitals in NIH research funding, and the extraordinary innovations that have been produced by our clinicians and scientists have been put into practice here and in hospitals around the world,” Dr. Batshaw adds. “Children’s leadership aspires to nudge the organization higher, to rank among the nation’s top five pediatric hospitals in NIH research funding.”

Gallo says the opportunity for Children’s research to expand beyond the existing buildings and the concurrent expansion into new areas of research will trigger more hiring. “We plan to grow our research enterprise through strategic hires and by attracting even more visiting investigators from around the world. By expanding our community of investigators, we aim to strengthen our status as one of the nation’s leading pediatric hospitals,” he says.

Study to evaluate heat-activated chemotherapy drug

Children’s National Health System and Celsion Corp., a leading oncology drug-development company, will be the first to launch a clinical study in the U.S. that evaluates the use of ThermoDox®, a heat-activated chemotherapy drug, in combination with noninvasive magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) to treat refractory or relapsed solid tumors in children and young adults.

The investigator-sponsored Phase I study, which is partially funded by an NIH R01 grant, will determine a safe and tolerable dose of ThermoDox, a lyso-thermosensitive liposomal doxorubicin (LTLD), which can be administered in combination with MR-HIFU. Under the guidance of an MRI, the high-intensity focused ultrasound directs soundwave energy to heat the tumor and the area around the tumor. When heated, the liposome rapidly changes structure and releases doxorubicin directly into and around the targeted tumor.

“There is currently no known cure for many patients with refractory recurring solid tumors, despite the use of intensive therapy, so we need to identify new, smarter therapies that can improve outcomes,” said AeRang Kim, M.D., Ph.D., oncologist and member of the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, who is also principal investigator for the study. “Recent advances in the use of noninvasive MR-HIFU coupled with novel therapies, such as LTLD, may provide us with a mechanism to noninvasively administer high concentrations of the drug directly to the site where it is most needed and avoid toxicity to other areas of the body.”

A First to Treat Childhood Cancer

This is the first time LTLD is being combined with MR-HIFU and the first time it is being evaluated in children.

“Celsion’s experience in combining ThermoDox with HIFU, a noninvasive next generation heating technology, supports this very important research in childhood cancers. From a safe dose, ThermoDox’s proven ability to deliver high concentrations of an effective chemotherapy directly to a heated tumor makes it an ideal candidate for a trial involving children and young adults,” said Michael H. Tardugno, Celsion’s chairman, president and CEO. “This study will further elucidate ThermoDox’s potential in combination with ultrasound-induced hyperthermia, and highlight potential applications of ThermoDox in combination with a broad range of heating technologies that could address an even larger population of patients.”

A Multidisciplinary Approach

The study targeting the treatment of childhood sarcomas will be carried out as a multidisciplinary collaboration between Children’s National, Celsion, and Dr. Bradford Wood’s team at the National Institutes of Health.

This is the latest study from the Image-Guided Non-Invasive Therapeutic Energy (IGNITE) program, a collaboration of the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National and the pediatric health system’s Divisions of Radiology, Oncology, Surgery, and Anesthesiology. 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. In 2015, doctors from Children’s National were the first in the U.S. to treat osteoid osteoma, a benign and painful bone tumor, using MR-HIFU.

ThermoDox is currently in late-stage clinical trials in primary liver cancer and recurrent chest wall breast cancer. It is positioned for use with multiple heating technologies, and has the potential for applications in the treatment of other forms of cancer including metastatic liver and nonmuscle invading bladder cancers.

Brain tumor expert from Children’s National speaks at Society for Neuro-Oncology’s scientific meeting and Education Day

Roger Packer

Roger Packer, M.D., Senior Vice President for the Center of Neuroscience and Behavioral Medicine and Director of the Brain Tumor Institute at Children’s National Health System, will be speaking at the 21st Annual Meeting and Education Day of the Society for Neuro-Oncology. From November 17-20, 2016, the conference will gather neuro-oncologists, medical oncologists, adult and pediatric neurosurgeons, pediatric neuro-oncologists, neuroradiologists, neuropathologists, radiation oncologists, neuropsychologists, and epidemiologists from across the country to discuss the future of neuro-oncology. Dr. Packer will be sharing his expertise in treating neurofibromatosis and pediatric brain tumors. He also will be part of a working group to discuss guidelines for response assessment in PDCT-13 medulloblastoma and other leptomeningeal seeding tumors.

Read more about the conference here.

Brain Tumor Institute Director Speaks at Coalition against Childhood Cancer Meeting

Roger Packer, MD, Senior Vice President for the Center of Neuroscience and Behavioral Medicine and Director of the Brain Tumor Institute at Children’s National Health System, was an invited speaker at the Coalition Against Childhood Cancer meeting at Cold Springs Harbor Laboratory on October 31 and November 1, 2016. This international conference was a unique collaborative effort between multiple foundations, the National Cancer Institute, and industry experts to develop a new path forward for the treatment of childhood cancer. Dr. Packer spoke on “Pediatric Brain Tumors: Where Are We Now” and shared his expertise in treating pediatric brain tumors and what he hopes the future of pediatric brain tumor research will look like. Pediatric brain tumors recently surpassed leukemia as the most deadly form of childhood cancer.

Read more about the conference here.

Pediatric research consortia unveil CAVATICA data platform

Javad Nazarian, PhD, MSC, joined peers from prestigious children’s hospitals from around the world.

Dr. Nazarian’s lab at Children’s is part of the CBTTC, which has helped in launching CAVATICA. Pictured (from left to right): Dr. Nazarian, Sabine Mueller, M.D., Ph.D. (PNOC Trial Director), Rishi Lulla, M.D. (CBTTC Executive Director), Francis Collins, M.D., Ph.D., (NIH Director), and Adam Resnick, PHD (CBTTC Scientific Director).

Earlier this week, The White House released the Cancer Moonshot report, which calls upon the public and private sectors to transform cancer research and care. Children’s National’s Javad Nazarian, Ph.D., M.S.C.,  joined peers from prestigious children’s hospitals from around the world at the news conference. Dr. Nazarian is a key player in the initiative, as his lab is part of the Children’s Brain Tumor Tissue Consortium (CBTTC) and is answering the call to action. The CBTTC and the Pacific Pediatric Neuro-Oncology Consortium, in partnership with Seven Bridges, announced the launch of CAVATICA, a data analysis platform that will help researchers to collaboratively access and share data about pediatric cancers, congenital disorders and rare diseases such as epilepsy and autism. More data will be connected than ever before—CAVATICA will interoperate with the Genomic Data Commons and other NIH data repositories. “It’s an exciting time for research,” says Dr. Nazarian.

Finding new ways to fight hemorrhagic cystitis for cancer patients

Michael Hsieh

Children diagnosed with cancer face fear and uncertainty, a series of medical appointments, and multiple diagnostic tests and treatments.

Children diagnosed with cancer face fear and uncertainty, a series of medical appointments, and multiple diagnostic tests and treatments. On top of these challenges, says Children’s National Health System urologist Michael Hsieh, M.D., Ph.D., many patients contend with additional issues: Treatment side effects, discomforts, and dangers that nearly eclipse that of the cancer itself. One of the most common side effects is hemorrhagic cystitis (HC), a problem marked by extreme inflammation in the bladder that can lead to tremendous pain and bleeding.

HC often results from administering two common chemotherapy drugs, cyclophosphamide and ifosfamide, used to treat a wide variety of pediatric cancers, including leukemias and cancers of the eye and nerves. In the United States alone, nearly 400,000 patients of all ages receive these drugs annually. Of these, up to 40 percent develop some form of HC, from symptomatic disease characterized by pain and bloody urine to cellular changes to the bladder detected by microscopic analysis.

“Having to deal with therapy complications makes the cancer ordeal so much worse for our patients,” says Dr. Hsieh, Director of the Clinic for Adolescent and Adult Pediatric Onset Urology at Children’s National. “Being able to eliminate this extremely detrimental side effect once and for all could have an enormous impact on patients at our hospital and around the world.”

Preventing complications with mesna

The severity of side effects from cyclophosphamide and ifosfamide can vary from mild and fleeting to bladder bleeding so extensive that patients require multiple transfusions and surgery to remove blood clots that can obstruct urinary release, says Dr. Hsieh, who frequently treats patients with this condition. But HC isn’t inevitable, he adds. A drug called mesna has the potential to prevent this complication when prescribed before a patient receives chemotherapy.

The problem is for a fraction of patients, mesna simply doesn’t work. For others, mesna can cause its own serious side effects, such as life-threatening malfunctions of the heart’s electrical system or allergic reactions.

“These kids are often already very sick from their cancers and treatments, and then you compound it with these complications,” says Dr. Hsieh. “There’s a desperate need for alternatives to mesna.”

Looking at alternative treatments

In a new review of the scientific literature, published August 24 by Urology, senior author Dr. Hsieh and a colleague detail all the substitutes for this drug that researchers have examined over several years.

One of these is hyperhydration, or delivering extra fluid intravenously to help flush the bladder and keep dangerous chemotherapy drug metabolites from accumulating and causing damage. Hyperhydration, however, isn’t an option for some patients with kidney, lung, or liver problems, who can’t tolerate excess fluid.

Researchers also have invested heavily in antioxidants as alternative treatments. Because much of the damage caused by these chemotherapy agents is thought to result from a cascade of oxidizing free radicals that cyclophosphamide and ifosfamide launch in the bladder, antioxidants might prevent injury by halting the free radical attack. Antioxidants that researchers have explored for this purpose include cytokines, or immune-signaling molecules, known as interleukin-1 and tumor necrosis factor, and a compound called reduced glutathione. Other studies have tested plant-based antioxidants, including a component of red wine known as resveratrol; a compound called diallyl disulfide isolated from garlic oil; and extracts from Uncaria tomentosa, a woody vine commonly known as “cat’s claw” that grows in the jungles of Central and South America.

Researchers also have tested options that focus on reducing the intense inflammation that cyclophosphamide and ifosfamide cause in the bladder, including the corticoid steroid drug dexamethasone as well as another cytokine known as interleukin-4.

However, Dr. Hsieh says, studies have shown that each of these treatments is inferior to mesna. To truly combat HC, researchers not only need to find new drugs and methods that outperform mesna but also new ways to reverse HC after other measures fail—problems he’s working to solve in his own lab.

Javad Nazarian

Surviving pediatric diffuse intrinsic pontine glioma

Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.

For more than four decades, clinicians around the nation have been giving the parents of pediatric patients diagnosed with diffuse intrinsic pontine glioma (DIPG) the same grim prognosis. In the past five years, there has been an explosion of innovative research at Children’s National Health System and elsewhere that promises to change that narrative. That’s because the black box that is DIPG is beginning to divulge its genetic secrets. The new-found research knowledge comes as a direct result of parents donating specimens, judicious shepherding of these scarce resources by researchers, development of pre-clinical models, and financing from small foundations.

From just 12 samples six years ago, Children’s National has amassed one of the nation’s largest tumor bio banks – 3,000 specimens donated by more than 900 patients with all types of pediatric brain tumors, including DIPG.

Such donated specimens have led to the identification of H3K27M mutations, a groundbreaking finding that has been described as the single-most important discovery in DIPG. Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.

Histone mutations (also referred to as oncohistones) are sustained in the tumor throughout its molecular evolution, found a research team led by Javad Nazarian, Ph.D. Not only were H3K27M mutations nearly ubiquitous in all samples studied, the driver mutation maintained partnerships with other secondary mutations as DIPG tumor cells spread throughout the developing brain. Children’s National researchers have identified tumor driver mutations and obligate partner mutations in DIPG. They are examining what happens downstream from the histone mutation – changes in the genome that indicate locations they can target in their path toward personalized medicine. The value of that genomic knowledge is akin to emergency responders being told the specific house where their help is needed, rather than a ZIP code or city name, Dr. Nazarian says. While there is currently no effective treatment for DIPG, new research has identified a growing number of genomic targets for future therapeutics.“That changed the dynamic,” says Dr. Nazarian. “In DIPG clinical research, nothing had changed for 45 years. Now we know some of the genomic mutations, how the tumor was evolving – gaining new mutations, losing mutations. With precision medicine, we can target those mutations.”

Another study led by neuro-oncologist Eugene Hwang, M.D., reported the most comprehensive phenotypic analyses comparing multiple sites in a young girl’s primary and metastatic tumors. This study showed that despite being uniform, small molecules (mRNA) could be used to distinguish an evolved tumor from its primary original tumor mass.Key to this multidisciplinary work is collaboration across divisions and departments. Within the research lab, knowledge about DIPG is expanding.

Each member of the DIPG team – neurosurgery, neuro-oncology, immunology, genomics, proteomics – feeds insight back to the rest of the team, accelerating the pace of research discoveries being translated into clinical care. Among the challenges that the team will address in the coming months is outmaneuvering tumors that outsmart T-cells (immune cells).

“What is happening in the checkpoint inhibitor field is exciting,” says Catherine M. Bollard, MBChB, MD, Chief of Allergy and Immunology and Director of the Program for Cell Enhancement of Technologies for Immunotherapy. “The inhibitors work by reversing the ‘off’ switch – releasing the brake that has been placed on the T-cells so they can again attack multiple tumor proteins. The next exciting step, and novel to Children’s National, will be to combine this approach with T-cell therapies specifically designed to attack the DIPG tumors. Unlike the use of combination chemotherapy, which has had a limited impact, we hope that the novel combination of immunotherapeutic approaches will offer the hope of a potential cure.”

Dr. Hwang, another member of the multidisciplinary team, adds: “When you’re looking at the landscape – for me, at least – it starts and ends with how my patients are doing. There are kids for whom we have had great successes in improving survival rates in some cancers, like leukemia, and some where the needle has moved nowhere, like DIPG. We’re still trying to figure out the whole picture of who responds. The immune system is present in all kids. Its ability to attack is present in all kids.”

Children’s National is one of the few hospitals in the nation that conducts brainstem biopsies for DIPG and does so with very little chance of complications. The pons is like a superhighway through which nerves pass, making it instrumental in smooth operation of such vital functions as breathing, heart rate, sleeping, and consciousness. The ability of neurosurgeon Suresh Magge, MD, to perform such sensitive biopsies upends conventional wisdom that these procedures were inherently too dangerous. Within two weeks of diagnosis, genomics analyses are run to better understand the biology of that specific tumor. Within the following weeks, the tumor board occurs, and patients with DIPG are placed on therapy that best targets their tumor’s mutations.

The black box that is diffuse intrinsic pontine glioma is beginning to divulge its genetic secrets.

Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of children with DIPG die within two years of diagnoses. Biomarkers that point to DIPG – like the copies of DNA that tumors shed and leave behind in the bloodstream – could enable creation of liquid biopsies, compared with today’s surgical approach.

Children’s also is making a concerted effort to create preclinical models of DIPG. Preclinical models will be used to winnow the field of potential therapeutics to the candidates most likely to help children survive DIPG. The preclinical tumor cells will be labeled with luciferase – enzymes that, like photoproteins, produce bioluminescence – permitting the researcher to visually see the formation, progression, and response of DIPG tumors to treatment in preclinical settings.

These preclinical models could be used to test multiple drug combinations in conjunction with radiation therapy. Molecular signatures and response to treatment could then be assessed to learn how the tumor resists therapy. Due to the obligate partnerships between driver mutations and secondary mutations, the research team already knows that effective DIPG medicines will need more than one target. If there were a single mutation, that would be like having a single master key to open many locks. Multiple mutations imply that more than one key will be needed. Thus, the search for cures for DIPG will necessitate taking a multi-pronged approach.

Combined drug regimens, including those created with proprietary technology, with or without radiation, will be keys to targeting myriad mutations in order to kill tumors where they are. Those drug combinations that demonstrate they can do their jobs – slowing tumor growth, increasing chances of survival, taming toxicity – will be selected for clinical application.

Immunotherapy leverages T-cells, the immune system’s most able fighters, to help in the overall goal of extending patients’ survival. One of the most challenging aspects of pediatric brain tumors is the body does a very good job of shielding the brain from potential pathogens. Precise drug delivery means finding innovative ways for therapeutics to cross the blood-brain barrier in order to reach the tumor. The team has identified one such potential target, the protein NG2, which may represent a good target for immune therapy. The protein is expressed in primitive cells that have not become specialized – meaning there may be an opportunity to intervene before it is driven to become a tumor cell.

Related resources
Research at a Glance: Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape
Research at a Glance: The role of NG2 proteoglycan in glioma
Research at a Glance: Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Research at a Glance: Histological and molecular analysis of a progressive diffuse intrinsic pontine glioma: a case report

Cancer update: tumor targeting, neurofibromatosis type 1 symptoms

June 6, 2016Targeting tumors more precisely, with fewer lasting side effects for kids
Pediatric patients with cancer are often treated with a cocktail of therapies to attack the disease through a variety of mechanisms. While this approach has been instrumental in saving children’s lives, the life-saving therapies can be accompanied by acute side effects, and the treatments may have lingering impacts as cancer survivors enter adulthood. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) holds the promise of surgically removing large tumors without exacting the same array of harsh side effects. Ultrasound relies on high-frequency sound waves to make diagnostic images, and those same sound waves can be used therapeutically to destroy tumors. Layering on MR imaging gives clinicians the ability to precisely guide the ultrasound therapy in real time. A study led by Children’s National Health System researchers and clinicians is using MR-HIFU for the first time in children to examine its safety and feasibility.

May 11, 2016 – Quantitative MRI criteria for optic pathway enlargement in neurofibromatosis type 1
Symptoms of neurofibromatosis type 1 (NF1) vary widely, but the condition is characterized by changes in skin pigmentation and growth of tumors along nerves. The research team sought to determine quantitative size thresholds for enlargement of the optic nerve, chiasm, and tract in children aged 0.5 to 18.6 years with NF1. The study, published in Neurology, found that quantitative reference values for anterior visual pathway enlargement will enhance development of objective diagnostic criteria for optic pathway gliomas secondary to NF1.