ID-KD vaccine induced T-cell cytotoxicity

Fighting lethal cancer with a one-two punch

The immune system is the ultimate yin and yang, explains Anthony D. Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National in Washington, D.C. With an ineffective immune system, infections such as the flu or diarrheal illness can run unchecked, causing devastating destruction. But on the other hand, excess immune activity leads to autoimmune diseases, such as lupus or multiple sclerosis. Thus, the immune system has “checks and balances” to stay controlled.

Cancer takes advantage of “the checks and balances,” harnessing the natural brakes that the immune system puts in place to avoid overactivity. As the cancer advances, molecular signals from tumor cells themselves turn on these natural checkpoints, allowing cancers to evade immune attack.

Several years ago, a breakthrough in pharmaceutical science led to a new class of drugs called checkpoint inhibitors. These medicines take those proverbial brakes off the immune system, allowing it to vigorously attack malignancies. However, Dr. Sandler says, these drugs have not worked uniformly and in some cancers, they barely work at all against the cancer.

One of these non-responders is high risk neuroblastoma, a common solid tumor found outside the skull in children. About 800 U.S. children are diagnosed with this cancer every year. And kids who have the high-risk form of neuroblastoma have poor prognoses, regardless of which treatments doctors use.

However, new research could lead to promising ways to fight high-risk neuroblastoma by enabling the immune system to recognize these tumors and spark an immune response. Dr. Sandler and colleagues recently reported on these results in the Jan. 29, 2018, PLOS Medicine using an experimental model of the disease.

The researchers created this model by injecting the preclinical models with cancer cells from an experimental version of neuroblastoma. The researchers then waited several days for the tumors to grow. Samples of these tumors showed that they expressed a protein on their cell surfaces known as PD-L1, a protein that is also expressed in many other types of human cancers to evade immune system detection.

To thwart this protective feature, the researchers made a cancer vaccine by removing cells from the experimental model’s tumors and selectively turning off a gene known as Id2. Then, they irradiated them, a treatment that made these cells visible to the immune system but blocked the cells from dividing to avoid new tumors from developing.

They delivered these cells back to the experimental models, along with two different checkpoint inhibitor drugs – antibodies for proteins known as CLTA-4 and PD-L1 – over the course of three treatments, delivered every three days. Although most checkpoint inhibitors are administered over months to years, this treatment was short-term for the experimental models, Dr. Sandler explains. The preclinical models were completely finished with cancer treatment after just three doses.

Over the next few weeks, the researchers witnessed an astounding turnaround: While experimental models that hadn’t received any treatment uniformly died within 20 days, those that received the combined vaccine and checkpoint inhibitors were all cured of their disease. Furthermore, when the researchers challenged these preclinical models with new cancer cells six months later, no new tumors developed. In essence, Dr. Sandler says, the preclinical models had become immune to neuroblastoma.

Further studies on human patient tumors suggest that this could prove to be a promising treatment for children with high-risk neuroblastoma. The patient samples examined show that while tumors with a low risk profile are typically infiltrated with numerous immune cells, tumors that are high-risk are generally barren of immune cells. That means they’re unlikely to respond to checkpoint inhibiting drugs alone, which require a significant immune presence in the tumor microenvironment. However, Dr. Sandler says, activating an immune response with a custom-made vaccine from tumor cells could spur the immune response necessary to make these stubborn cancers respond to checkpoint inhibitors.

Dr. Sandler cautions that the exact vaccine treatment used in the study won’t be feasible for people. The protocol to make the tumor cells immunogenic is cumbersome and may not be applicable to gene targeting in human patients. However, he and his team are currently working on developing more feasible methods for crafting cancer vaccines for kids. They also have discovered a new immune checkpoint molecule that could make this approach even more effective.

“By letting immune cells do all the work we may eventually be able to provide hope for patients where there was little before,” Dr. Sandler says.

In addition to Dr. Sandler, study co-authors include Priya Srinivasan, Xiaofang Wu, Mousumi Basu and Christopher Rossi, all of the Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI), at Children’s National in Washington, D.C.

Financial support for research described in this post was provided by the EVAN Foundation, the Catherine Blair foundation, the Michael Sandler Research Fund and SZI.

ID-KD vaccine induced T-cell cytotoxicity

Mechanism of Id2kd Neuro2a vaccination combined with α-CTLA-4 and α-PD-L1 immunotherapy in a neuroblastoma model. During a vaccine priming phase, CTLA-4 blockade enhances activation and proliferation of T-cells that express programmed cell death 1 (PD1) and migrate to the tumor. Programmed cell death-ligand 1 (PD-L1) is up-regulated on the tumor cells, inducing adaptive resistance. Blocking PD-L1 allows for enhanced cytotoxic effector function of the CD8+ tumor-infiltrating lymphocytes. Artist: Olivia Abbate

Children’s National ranked No. 6 overall and No. 1 for newborn care by U.S. News

Children’s National in Washington, D.C., is the nation’s No. 6 children’s hospital and, for the third year in a row, its neonatology program is No.1 among all children’s hospitals providing newborn intensive care, according to the U.S. News Best Children’s Hospitals annual rankings for 2019-20.

This is also the third year in a row that Children’s National has been in the top 10 of these national rankings. It is the ninth straight year it has ranked in all 10 specialty services, with five specialty service areas ranked among the top 10.

“I’m proud that our rankings continue to cement our standing as among the best children’s hospitals in the nation,” says Kurt Newman, M.D., President and CEO for Children’s National. “In addition to these service lines, today’s recognition honors countless specialists and support staff who provide unparalleled, multidisciplinary patient care. Quality care is a function of every team member performing their role well, so I credit every member of the Children’s National team for this continued high performance.”

The annual rankings recognize the nation’s top 50 pediatric facilities based on a scoring system developed by U.S. News. The top 10 scorers are awarded a distinction called the Honor Roll.

“The top 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver outstanding care across a range of specialties and deserve to be nationally recognized,” says Ben Harder, chief of health analysis at U.S. News. “According to our analysis, these Honor Roll hospitals provide state-of-the-art medical expertise to children with rare or complex conditions. Their rankings reflect U.S. News’ assessment of their commitment to providing high-quality, compassionate care to young patients and their families day in and day out.”

The bulk of the score for each specialty is based on quality and outcomes data. The process also includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with challenging conditions.

Below are links to the five specialty services that U.S. News ranked in the top 10 nationally:

The other five specialties ranked among the top 50 were cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastro-intestinal surgery, orthopedics, and urology.

T cell

Clinical Trial Spotlight: Is more really better? Dose escalation of multi-antigen targeted T cells to illicit a more robust response

T cell

As the promise of immunotherapy in treating patients with cancer becomes more evident, physician researchers at Children’s National are pushing the needle further along. Holly Meany, M.D., is leading a Phase 1 dose-escalation trial to determine the safety and efficacy of administering rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA CTL) to patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) or traditional therapy for a high-risk solid tumor due to the presence of refractory, relapsed and/or residual detectable disease.

“In the escalation portion of our trial, we found that the highest dose evaluated did not have unfavorable toxicity in these patients and is our recommended dose,” Dr. Meany said. “Our next step is an expansion of the trial in five distinct disease categories – Wilms tumor, neuroblastoma, rhabdomyosarcoma, adenocarcinoma and esophageal carcinoma – to examine efficacy on a broader level at the recommended dose.”

Dr. Meany and fellow research clinicians at Children’s National will evaluate not only what happens to the patients when given the additional dosage, but also what happens to the cells – How long will they last? Will they remain targeted against the same antigens or will they shift to target other proteins?

This novel trial is currently enrolling patients at Children’s National Health System in Washington, D.C.

  • PI: Holly Meany, M.D.
  • Title: Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors (REST)
  • Status: Currently enrolling

For more information about this trial, contact:

Holly Meany, M.D.
202-476-5697
hmeany@childrensnational.org 

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Billie Lou Short and Kurt Newman at Research and Education Week

Research and Education Week honors innovative science

Billie Lou Short and Kurt Newman at Research and Education Week

Billie Lou Short, M.D., received the Ninth Annual Mentorship Award in Clinical Science.

People joke that Billie Lou Short, M.D., chief of Children’s Division of Neonatology, invented extracorporeal membrane oxygenation, known as ECMO for short. While Dr. Short did not invent ECMO, under her leadership Children’s National was the first pediatric hospital to use it. And over decades Children’s staff have perfected its use to save the lives of tiny, vulnerable newborns by temporarily taking over for their struggling hearts and lungs. For two consecutive years, Children’s neonatal intensive care unit has been named the nation’s No. 1 for newborns by U.S. News & World Report. “Despite all of these accomplishments, Dr. Short’s best legacy is what she has done as a mentor to countless trainees, nurses and faculty she’s touched during their careers. She touches every type of clinical staff member who has come through our neonatal intensive care unit,” says An Massaro, M.D., director of residency research.

For these achievements, Dr. Short received the Ninth Annual Mentorship Award in Clinical Science.

Anna Penn, M.D., Ph.D., has provided new insights into the central role that the placental hormone allopregnanolone plays in orderly fetal brain development, and her research team has created novel experimental models that mimic some of the brain injuries often seen in very preterm babies – an essential step that informs future neuroprotective strategies. Dr. Penn, a clinical neonatologist and developmental neuroscientist, “has been a primary adviser for 40 mentees throughout their careers and embodies Children’s core values of Compassion, Commitment and Connection,” says Claire-Marie Vacher, Ph.D.

For these achievements, Dr. Penn was selected to receive the Ninth Annual Mentorship Award in Basic and Translational Science.

The mentorship awards for Drs. Short and Penn were among dozens of honors given in conjunction with “Frontiers in Innovation,” the Ninth Annual Research and Education Week (REW) at Children’s National. In addition to seven keynote lectures, more than 350 posters were submitted from researchers – from high-school students to full-time faculty – about basic and translational science, clinical research, community-based research, education, training and quality improvement; five poster presenters were showcased via Facebook Live events hosted by Children’s Hospital Foundation.

Two faculty members won twice: Vicki Freedenberg, Ph.D., APRN, for research about mindfulness-based stress reduction and Adeline (Wei Li) Koay, MBBS, MSc, for research related to HIV. So many women at every stage of their research careers took to the stage to accept honors that Naomi L.C. Luban, M.D., Vice Chair of Academic Affairs, quipped that “this day is power to women.”

Here are the 2019 REW award winners:

2019 Elda Y. Arce Teaching Scholars Award
Barbara Jantausch, M.D.
Lowell Frank, M.D.

Suzanne Feetham, Ph.D., FAA, Nursing Research Support Award
Vicki Freedenberg, Ph.D., APRN, for “Psychosocial and biological effects of mindfulness-based stress reduction intervention in adolescents with CHD/CIEDs: a randomized control trial”
Renee’ Roberts Turner for “Peak and nadir experiences of mid-level nurse leaders”

2019-2020 Global Health Initiative Exploration in Global Health Awards
Nathalie Quion, M.D., for “Latino youth and families need assessment,” conducted in Washington
Sonia Voleti for “Handheld ultrasound machine task shifting,” conducted in Micronesia
Tania Ahluwalia, M.D., for “Simulation curriculum for emergency medicine,” conducted in India
Yvonne Yui for “Designated resuscitation teams in NICUs,” conducted in Ghana
Xiaoyan Song, Ph.D., MBBS, MSc, “Prevention of hospital-onset infections in PICUs,” conducted in China

Ninth Annual Research and Education Week Poster Session Awards

Basic and Translational Science
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Differences in the gut microbiome of HIV-infected versus HIV-exposed, uninfected infants”
Faculty: Hayk Barseghyan, Ph.D., for “Composite de novo Armenian human genome assembly and haplotyping via optical mapping and ultra-long read sequencing”
Staff: Damon K. McCullough, BS, for “Brain slicer: 3D-printed tissue processing tool for pediatric neuroscience research”
Staff: Antonio R. Porras, Ph.D., for “Integrated deep-learning method for genetic syndrome screening using facial photographs”
Post docs/fellows/residents: Lung Lau, M.D., for “A novel, sprayable and bio-absorbable sealant for wound dressings”
Post docs/fellows/residents:
Kelsey F. Sugrue, Ph.D., for “HECTD1 is required for growth of the myocardium secondary to placental insufficiency”
Graduate students:
Erin R. Bonner, BA, for “Comprehensive mutation profiling of pediatric diffuse midline gliomas using liquid biopsy”
High school/undergraduate students: Ali Sarhan for “Parental somato-gonadal mosaic genetic variants are a source of recurrent risk for de novo disorders and parental health concerns: a systematic review of the literature and meta-analysis”

Clinical Research
Faculty:
Amy Hont, M.D., for “Ex vivo expanded multi-tumor antigen specific T-cells for the treatment of solid tumors”
Faculty: Lauren McLaughlin, M.D., for “EBV/LMP-specific T-cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation”

Staff: Iman A. Abdikarim, BA, for “Timing of allergenic food introduction among African American and Caucasian children with food allergy in the FORWARD study”
Staff: Gelina M. Sani, BS, for “Quantifying hematopoietic stem cells towards in utero gene therapy for treatment of sickle cell disease in fetal cord blood”
Post docs/fellows/residents: Amy H. Jones, M.D., for “To trach or not trach: exploration of parental conflict, regret and impacts on quality of life in tracheostomy decision-making”
Graduate students: Alyssa Dewyer, BS, for “Telemedicine support of cardiac care in Northern Uganda: leveraging hand-held echocardiography and task-shifting”
Graduate students: Natalie Pudalov, BA, “Cortical thickness asymmetries in MRI-abnormal pediatric epilepsy patients: a potential metric for surgery outcome”
High school/undergraduate students:
Kia Yoshinaga for “Time to rhythm detection during pediatric cardiac arrest in a pediatric emergency department”

Community-Based Research
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Recent trends in the prevention of mother-to-child transmission (PMTCT) of HIV in the Washington, D.C., metropolitan area”
Staff: Gia M. Badolato, MPH, for “STI screening in an urban ED based on chief complaint”
Post docs/fellows/residents:
Christina P. Ho, M.D., for “Pediatric urinary tract infection resistance patterns in the Washington, D.C., metropolitan area”
Graduate students:
Noushine Sadeghi, BS, “Racial/ethnic disparities in receipt of sexual health services among adolescent females”

Education, Training and Program Development
Faculty:
Cara Lichtenstein, M.D., MPH, for “Using a community bus trip to increase knowledge of health disparities”
Staff:
Iana Y. Clarence, MPH, for “TEACHing residents to address child poverty: an innovative multimodal curriculum”
Post docs/fellows/residents:
Johanna Kaufman, M.D., for “Inpatient consultation in pediatrics: a learning tool to improve communication”
High school/undergraduate students:
Brett E. Pearson for “Analysis of unanticipated problems in CNMC human subjects research studies and implications for process improvement”

Quality and Performance Improvement
Faculty:
Vicki Freedenberg, Ph.D., APRN, for “Implementing a mindfulness-based stress reduction curriculum in a congenital heart disease program”
Staff:
Caleb Griffith, MPH, for “Assessing the sustainability of point-of-care HIV screening of adolescents in pediatric emergency departments”
Post docs/fellows/residents:
Rebecca S. Zee, M.D., Ph.D., for “Implementation of the Accelerated Care of Torsion (ACT) pathway: a quality improvement initiative for testicular torsion”
Graduate students:
Alysia Wiener, BS, for “Latency period in image-guided needle bone biopsy in children: a single center experience”

View images from the REW2019 award ceremony.

Beth Tarini

Getting to know SPR’s future President, Beth Tarini, M.D., MS

Beth Tarini

Quick. Name four pillar pediatric organizations on the vanguard of advancing pediatric research.

Most researchers and clinicians can rattle off the names of the Academic Pediatric Association, the American Academy of Pediatrics and the American Pediatric Society. But that fourth one, the Society for Pediatric Research (SPR), is a little trickier. While many know SPR, a lot of research-clinicians simply do not.

Over the next few years, Beth A. Tarini, M.D., MS, will make it her personal mission to ensure that more pediatric researchers get to know SPR and are so excited about the organization that they become active members. In May 2019 Dr. Tarini becomes Vice President of the society that aims to stitch together an international network of interdisciplinary researchers to improve kids’ health. Four-year SPR leadership terms begin with Vice President before transitioning to President-Elect, President and Past-President, each for one year.

Dr. Tarini says she looks forward to working with other SPR leaders to find ways to build more productive, collaborative professional networks among faculty, especially emerging junior faculty. “Facilitating ways to network for research and professional reasons across pediatric research is vital – albeit easier said than done. I have been told I’m a connector, so I hope to leverage that skill in this new role,” says Dr. Tarini, associate director for Children’s Center for Translational Research.

“I’m delighted that Dr. Tarini was elected to this leadership position, and I am impressed by her vision of improving SPR’s outreach efforts,” says Mark Batshaw, M.D., Executive Vice President, Chief Academic Officer and Physician-in-Chief at Children’s National. “Her goal of engaging potential members in networking through a variety of ways – face-to-face as well as leveraging digital platforms like Twitter, Facebook and LinkedIn – and her focus on engaging junior faculty will help strengthen SPR membership in the near term and long term.”

Dr. Tarini adds: “Success to me would be leaving after four years with more faculty – especially junior faculty – approaching membership in SPR with the knowledge and enthusiasm that they bring to membership in other pediatric societies.”

SPR requires that its members not simply conduct research, but move the needle in their chosen discipline. In her research, Dr. Tarini has focused on ensuring that population-based newborn screening programs function efficiently and effectively with fewer hiccups at any place along the process.

Thanks to a heel stick to draw blood, an oxygen measurement, and a hearing test, U.S. babies are screened for select inherited health conditions, expediting treatment for infants and reducing the chances they’ll experience long-term health consequences.

“The complexity of this program that is able to test nearly all 4 million babies in the U.S. each year is nothing short of astounding. You have to know the child is born – anywhere in the state – and then between 24 and 48 hours of birth you have to do testing onsite, obtain a specific type of blood sample, send the blood sample to an off-site lab quickly, test the sample, find the child if the test is out of range, get the child evaluated and tested for the condition, then send them for treatment. Given the time pressures as well as the coordination of numerous people and organizations, the fact that this happens routinely is amazing. And like any complex process, there is always room for improvement,” she says.

Dr. Tarini’s research efforts have focused on those process improvements.

As just one example, the Advisory Committee on Heritable Disorders in Newborns and Children, a federal advisory committee on which she serves, was discussing how to eliminate delays in specimen processing to provide speedier results to families. One possible solution floated was to open labs all seven days, rather than just five days a week. Dr. Tarini advocated for partnering with health care engineers who could help model ways to make the specimen transport process more efficient, just like airlines and mail delivery services. A more efficient and effective solution was to match the specimen pick-up and delivery times more closely with the lab’s operational times – which maximizes lab resources and shortens wait times for parents.

Conceptual modeling comes so easily for her that she often leaps out of her seat mid-sentence, underscoring a point by jotting thoughts on a white board, doing it so often that her pens have run dry.

“It’s like a bus schedule: You want to find a bus that not only takes you to your destination but gets you there on time,” she says.

Dr. Tarini’s current observational study looks for opportunities to improve how parents in Minnesota and Iowa are given out-of-range newborn screening test results – especially false positives – and how that experience might shake their confidence in their child’s health as well as heighten their own stress level.

“After a false positive test result, are there parents who walk away from newborn screening with lingering stress about their child’s health? Can we predict who those parents might be and help them?” she asks.

Among the challenges is the newborn screening occurs so quickly after delivery that some emotionally and physically exhausted parents may not remember it was done. Then they get a call from the state with ominous results. Another challenge is standardizing communication approaches across dozens of birthing centers and hospitals.

“We know parents are concerned after receiving a false positive result, and some worry their infant remains vulnerable,” she says. “Can we change how we communicate – not just what we say, but how we say it – to alleviate those concerns?”

Assorted foods

Tamp down food allergy anxieties with this quiz


Eugene Hwang in an exam room

Clinical Trial Spotlight: Creating a super army to target CNS tumors

Eugene Hwang in an exam room

Following the noted success of CAR-T cells in treating leukemia, Eugene Hwang, M.D., and a team of physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors.

Following the noted success of CAR-T cells in treating leukemia, physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors. Employing a strategy of “supertraining” the cells to target and attack three tumor targets as opposed to just one, Eugene Hwang, M.D., and the team at Children’s are optimistic about using this immunotherapy technique on a patient population that hasn’t previously seen much promise for treatment or cure. The therapy is built on the backbone of T cell technology championed by Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research, which is only available at Children’s National. Hwang sees this trial as an exciting start to using T cells to recognize resistant brain cancer. “We have never before been able to pick out markers on brain cancer and use the immune system to help us attack the cancer cells. This strategy promises to help us find treatments that are better at killing cancer and lessening side effects,” he says.

This Phase 1 dose-escalation is designed to determine the safety and feasibility of rapidly generated tumor multiantigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) or recurrent, progressive or refractory non-brainstem CNS malignancies. Pediatric and adult patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or surviving) will be enrolled in one of two groups: Group A includes patients with newly diagnosed DIPGs who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from a patient’s peripheral blood mononuclear cells (PBMCs) or by apheresis. This protocol is designed as a phase 1 dose-escalation study. Group A patients: TAA-T will be infused any time >2 weeks after completion of radiotherapy. Group B patients: TAA-T will be infused any time >2 after completing the most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

For more information about this trial, contact:

Eugene Hwang, M.D.
202-476-5046
ehwang@childrensnational.org

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Assorted foods

Food allergies: a research update

Assorted foods

Promising new therapies for food allergies are on the horizon, including an experimental immunotherapy awaiting federal approval that enables people who are very allergic to eat peanut protein without suffering serious side effects.

Good news, right?

As it turns out, the idea of a child who is highly allergic to a specific food eating that same food item makes kids with lifelong food allergies and their parents a bit queasy.

“It’s a very big paradigm shift. From diagnosis, children are told to avoid their food triggers at all cost. But now they may be counseled to approach the very thing that scares them, put it in their body and see what happens,” says Linda Herbert, Ph.D., an assistant professor in Children’s Division of Psychology and Behavioral Health.

“On the flip side, these new protections could reduce long-term anxieties, replacing daily anxiety about accidental exposure with a newfound sense of empowerment. Either way, a lot of families will need support as they try these new treatments that enable them to ingest a food allergen daily or wear a patch that administers a controlled dose of that food allergen,” Herbert says.

She will discuss food allergy treatments in the pipeline and families’ psychosocial concerns related to daily life as she presents a research update during the American Academy of Allergy, Asthma & Immunology (AAAAI) 2019 Annual Meeting. A select group, including Herbert, has been recognized with an AAAAI Foundation Heritage Lectureship, which honors distinguished AAAAI members with a special lecture and plaque.

Herbert’s symposium targets allied health professionals at the annual meeting, including psychologists, dietitians and nurse practitioners who attend to a host of psychosocial concerns felt by families affected by allergies to foods like eggs, nuts and cow’s milk.

“When patients arrive for outpatient therapy, they feel anxious about being safe when they’re out in public. They have anxieties about their children feeling safe at school as well as managing restaurant meals. They explain difficulties being included in social events like birthday parties, field trips and shared vacations,” Herbert says. “Some families restrict social activities due to stress and anxiety.”

Children’s National Health System takes a multidisciplinary approach for complex conditions like food allergies, she says, combining the expertise of psychologists, medical providers, research nurses, clinical nurses, registered dietitians and other allied health professionals.

“When we all communicate, we can see the complete picture. It strengthens the care that the child receives, and it’s especially powerful that it can happen all at once – rather than going to multiple appointments,” she adds.

During such group huddles, the team agrees on a plan together that is communicated to the family. One ongoing challenge is that one-third of school children with food allergies are bullied or teased.

“A lot of parents don’t necessarily know to ask or how to ask. I frequently suggest that clinicians discuss peer concerns more in clinic.”

American Academy of Allergy, Asthma & Immunology 2019 Annual Meeting presentation

  • “Allied Health Plenary – Food Allergy Updates.”

Friday, Feb. 22, 2019, 4:15-5:30 p.m. (PST)

Linda Herbert, Ph.D., director of Children’s Division of Allergy and Immunology’s psychosocial clinical program.

Making the grade: Children’s National is nation’s Top 5 children’s hospital

Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.

Children’s National also ranked in the Top 10 in six additional services:

For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.

“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”

The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.

“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”

The 12th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.

This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.

Michael Keller

Virus-specific t-cells show promise before transplant in SCID patients

Michael Keller

“Today, we know that virus-specific T-cells can help protect patients from dangerous viruses after stem cell transplants,” says Michael Keller, M.D. “Through this research, we used the same therapy and approach, but applied it pre-transplant with the hope of providing the same benefit of protection against life-threatening viruses to patients who need it the most.”

Experts at Children’s National Health System have been successfully studying the use of virus-specific T-cells (VST) to help protect immunocompromised patients from life-threatening viruses after bone marrow transplants. Research published recently in the Biology of Blood and Marrow Transplantation presents promising new findings from testing the use of these same VSTs before transplant to help give patients with severe combined immunodeficiency (SCID) a better chance at long-term survival.

Babies born with SCID are highly susceptible to severe infections that are often fatal if not treated with immune-restoring treatments, like hematopoietic stem cell transplants (HSCT). However, undergoing an HSCT with an infection present has shown to lead to a decrease in survival at two years old for SCID patients when compared to those who start the HSCT infection-free. The study lead, Michael Keller, M.D., hypothesized that the success of HSCTs in SCID patients may be improved by controlling severe viral infections before the patient undergoes the transplant.

“Today, we know that virus-specific T-cells can help protect patients from dangerous viruses after stem cell transplants,” says Dr. Keller. “Through this research, we used the same therapy and approach, but applied it pre-transplant with the hope of providing the same benefit of protection against life-threatening viruses to patients who need it the most.”

Dr. Keller administered the VSTs from a healthy third-party donor in a five-month-old infant fighting adenovirus before undergoing a HSCT to cure him of SCID. Today, the baby is healthy and has a normal immune system. Ultimately, this research shows that the use of VSTs is likely safe in the pre-HSCT period in patients with SCID and may be an effective therapy for viral infections when they are resistant to antiviral therapy.

“I believe this VST therapy could make a real and lasting impact for patients with SCID,” said Dr. Keller. “It gives them a real chance at a long life.”

Kirsten-M.-Williams

Helpful, hopeful news for bone marrow transplant patients

Kirsten-M.-Williams

Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Kirsten M. Williams, M.D., suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

Leukemia can be a terrifying diagnosis for the more than 60,000 U.S. patients who are told they have this blood cancer every year. But the treatment for this disease can be just as frightening. For patients with certain forms of leukemia, the only chance they have for a cure is to receive a massive dose of radiation and chemotherapy that kills their hematopoietic stem cells (HSCs), the cells responsible for making new blood, and then receive new HSCs from a healthy donor.

While patients are waiting for these new cells to go to the bone marrow factory and begin churning out new blood cells, patients are left without an immune system. Devoid of working HSCs for two to four weeks – or longer, if a first transplant doesn’t take – patients are vulnerable to infections that can be just as deadly as their original cancer diagnosis.

As they wait in the protected confines of a hospital, patients who undergo HSC transplants receive blood tests every day to gauge successful engraftment, searching for the presence of immune cells called neutrophils, explains Kirsten M. Williams, M.D., blood and bone marrow transplant specialist at Children’s National Health System.

“As you head into week three post-transplant and a patient’s cell counts remain at zero, everyone starts to get nervous,” Dr. Williams says. The longer a patient goes without an immune system, the higher the chance that they’ll develop a life-threatening infection. Until recently, Dr. Williams says, there has been no way beyond those daily blood tests to assess whether the newly infused cells have survived and started to grow early healthy cells in the bone marrow, a process called engraftment.

A new study could change that paradigm. Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Dr. Williams suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

The study evaluated an investigational imaging test called 18F-fluorothymidine (18F-FLT). It’s a radio-labeled analogue of thymidine, a natural component of DNA. Studies have shown that this compound is incorporated into just three white blood cell types, including HSCs. Because it’s radioactive, it can be seen on various types of common clinical imaging exams, such as positron emission tomography (PET) and computed tomography (CT) scans. Thus, after infusion, the newly infused developing immune system and marrow is readily visible.

To see whether this compound can readily and safely visualize transplanted HSCs, Dr. Williams and colleagues tested it on 23 patients with various forms of high-risk leukemia.

After these patients received total-body irradiation to destroy their own HSCs, they received donor HSCs from relatives or strangers. One day before they were infused with these donor cells, and then at five or nine days, 28 days, and one year after transplantation, the patients underwent imaging with the novel PET/and CT scan imaging platform.

Each of these patients had successful engraftment, reflected in blood tests two to four weeks after their HSC transplants. However, the results of the imaging exams revealed a far more complicated and robust story.

With 18F-FLT clearly visible in the scans, the researchers saw that the cells took a complex journey as they engrafted. First, they migrated to the patients’ livers and spleens. Next, they went to the thoracic spine, the axial spine, the sternum, and the arms and legs. By one year, most of the new HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.

Interestingly, notes Dr. Williams, this pathway is the same one that HSCs take in the fetus when they first form. Although experimental model research had previously suggested that transplanted HSCs travel the same route, little was known about whether HSCs in human patients followed suit.

The study also demonstrated that the radiation in 18F-FLT did not adversely affect engraftment. Additionally, images could identify success of their engraftments potentially weeks faster than they would have through traditional blood tests – a definite advantage to this technique.

“Through the images we took, these patients could see the new cells growing in their bodies,” Dr. Williams says. “They loved that.”

Besides providing an early heads up about engraftment status, she adds, this technique also could help patients avoid painful bone marrow biopsies to make sure donor cells have taken residence in the bones or at the very least help target those biopsies. It also could be helpful for taking stock of HSCs in other conditions, such as aplastic anemia, in which the body’s own HSCs fade away. And importantly, if the new healthy cells don’t grow, this test could signal this failure to doctors, enabling rapid mobilization of new cells to avert life-threatening infections and help us save lives after transplants at high risk of graft failure.

“What happens with HSCs always has been a mystery,” Dr. Williams says. “Now we can start to open that black box.”

Dr. Williams’ co-authors include co-lead author Jennifer Holter-Chakrabarty, M.D., Quyen Duong, M.S., Sara K. Vesely, Ph.D., Chuong T. Nguyen, Ph.D., Joseph P. Havlicek, Ph.D., George Selby, M.D., Shibo Li, M.D., and Teresa Scordino, M.D., University of Oklahoma; Liza Lindenberg, M.D., Karen Kurdziel, M.D., Frank I. Lin, M.D., Daniele N. Avila, N.P., Christopher G. Kanakry, M.D., Stephen Adler, Ph.D., Peter Choyke, M.D., and senior author Ronald E. Gress, M.D., National Cancer Institute; Juan Gea-Banacloche, M.D., Mayo Clinic Arizona; and Catherine “Cath” M. Bollard, M.D., MB.Ch.B., Children’s National.

Research reported in this story was supported by the National Institutes of Health, Ben’s Run/Ben’s Gift, Albert and Elizabeth Tucker Foundation, Mex Frates Leukemia Fund, Jones Family fund and Oklahoma Center for Adult Stem Cell Research.

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.”

Doctors working together to find treatments for autoimmune encephalitis

Shining light on autoimmune encephalitis

Doctors working together to find treatments for autoimmune encephalitis

Experts at Children’s National Health System brought together over 40 specialists from around the world to talk about autoimmune encephalitis (AE) and how the present institutions can better align their research priorities with the goal of finding more effective treatment for children with AE.

About autoimmune encephalitis

AE is a serious and rare medical condition in which the immune system attacks the brain, significantly impairing function and causing the loss of the ability to perform basic actions such as walking, talking or eating. If diagnosed quickly and treated appropriately, many patients recover most or all functions within a few years. However, not all patients will fully recover, or even survive, if the condition is not diagnosed early. AE is mainly seen in female young adults, but is increasingly being seen more in males and females of all ages.

The condition is often difficult to diagnose. Symptoms can vary and include psychosis, tremors, multiple seizures, and uncontrollable bodily movements. Once diagnosed, AE is treated by steroids and neuro-immunology treatments such as plasmapheresis, the removal and exchange of infected plasma with healthy plasma.

The Neuro-Immunology Clinic at Children’s National treats infants, children, and adolescents with several neurologic autoimmune conditions including AE. The multidisciplinary team consists of neurologists, neuropsychologists, physical and rehabilitation medicine experts, and complex care physicians.

A look at the pediatric autoimmune encephalitis treatment consensus meeting

Children’s National, along with Autoimmune Encephalitis Alliance and the Childhood Arthritis and Rheumatology Research Alliance, hosted the first International Pediatric Autoimmune Encephalitis Treatment Consensus Meeting at the Carnegie Endowment for International Peace in Washington, DC, this month. Several leading children’s hospitals and health institutions including Duke University Medical Center, Texas Children’s Hospital, and Alberta Children’s Hospital also co-hosted the event with Children’s National.

“This meeting gathered experts from around the world to discuss our current efforts to standardize approaches to diagnosis, treatment, and research for pediatric autoimmune encephalitis with the common goal of discovering new ways to provide more effective care to children and adolescents with AE,” says Elizabeth Wells, MD, director of the Neuro-Immunology Clinic at Children’s National.

The following were the three main objectives of the meeting:

  • Beginning the formation of treatment roadmaps for initial treatment and maintenance therapy for pediatric AE
  • Discussing current work to standardize approaches to diagnosis, initial treatment, maintenance immunotherapy, disease surveillance, biomarker discovery, supportive care, and multidisciplinary coordination
  • Aligning research priorities and planning future collaborative work

Three families who have children with AE also shared their stories of diagnosis and journeys to recovery, putting the need for more research into perspective for the experts in the room.

“We are very hopeful for the future of autoimmune encephalitis research and are proud to be at the forefront of it so we are able to provide the best possible care to our patients,” says Dr. Wells.

New research shows success training t-cells to recognize and fight life-threatening viruses

Children's is the only U.S. pediatric hospital that manufactures specialized T-cells from native cord blood

Patients with leukemia, lymphoma, other cancers, and genetic disorders who receive stem cell or cord blood transplants face the post-transplant risk of developing a life-threatening infection with adenovirus, cytomegalovirus (CMV), or Epstein-Barr virus (EBV).

The study reports the results of a head-to-head comparison of two powerful immunotherapeutic strategies to thwart such viral infections. Both therapeutic approaches leverage the power of multivirus-specific, donor-derived T-cells (mCTL), which are highly skilled at recognizing foreign invaders and, in the case of the peripheral blood cells, have long memories of past battles.

The award-winning paper, “Multivirus-Specific T Cells From Both Cord Blood and Bone Marrow Transplant Donors” was presented during the International Society for Cellular Therapy (ISCT) 2016 Annual Meeting, held from May 25 through May 28, in Singapore. The abstract’s lead author, Patrick J. Hanley, PhD, Laboratory Facility Director of Children’s Cellular Therapy and Stem Cell Processing facility, was recognized by ISCT with a Young Investigator award during the meeting.

Nine research scientists and clinicians affiliated with Children’s National Health System are co-authors of a paper, including Michael D. Keller, MD, the lead clinical investigator of the peripheral blood T-cell study, and Catherine M. Bollard, MBChB, MD, the study’s sponsor and Director of Children’s National Program for Cell Enhancement and Technologies for Immunotherapy.

After certain treatments, some cancer patients’ bodies are stripped of their natural ability to fight infection. The stem cell or the cord blood transplant restores the body’s ability to produce a full complement of blood cells, including infection-fighting white blood cells. As a further boost to these patients, the T-cells are trained to spot and neutralize all three potentially lethal viruses (CMV, EBV, and adenovirus) simultaneously. The personalized cell therapy can be accomplished in a single infusion and administered in the outpatient setting.

In the phase I perspective study, the personalized T-cells were grown from peripheral blood (PB) of adult donors who were seropositive for CMV, a relative of the virus that causes chickenpox, and were also coaxed to grow from naïve cord blood (CB). These naïve cells need additional training since they have never been to battle.

Since the mid-1990s, PB has been shown to be effective for such use. Hanley says that fewer than one dozen facilities in the United States perform PB antiviral T-cell infusions. Of that selective group, Children’s National is the only U.S. location that also grows the specialized T-cells from naïve CB, a procedure that takes a bit longer to accomplish but can help patients whose blood type is in short supply.

Thirteen patients were infused with PB mCTL, and 12 patients were infused with the T-cells derived from cord blood. Patients received their transfusions from 35 to 384 days after their stem cell or cord blood transplant. Within four weeks, the research team saw up to a 160-fold increase in virus-specific T-cells, a development that coincided with patients’ response to therapy. “The overall … response rate in both groups was 81 percent,” writes Hanley and colleagues.

Eight patients had a complete response. Five had a partial response. Nine remain free of infection/reactivation. What’s more, the patients’ restored immunity was durable with at least one patient remaining free of infection two years after treatment – without the need for pharmaceuticals administered in a hospital setting, which exacts a higher overall cost to the healthcare system.

“This study demonstrates that mCTL derived from the PB of seropositive donors, as well as the CB of virus naïve donors, expand in vivo and are active against multiple viruses. Furthermore, by restoring immunity to multiple viruses simultaneously, the need for continued prophylaxis with pharmacotherapy is eliminated, thus, improving the efficiency and cost-effectiveness of protecting SCT and CBT recipients from these potentially lethal viruses,” Hanley and co-authors conclude.

Related Resources: Research at a Glance