Cancer

tube labeled "CRISPR"

$2M from NIH to extract meaningful data from CRISPR screens

tube labeled "CRISPR"

Protein-coding genes comprise a mere 1% of DNA. While the other 99% of DNA was once derided as “junk,” it has become increasingly apparent that some non-coding genes enable essential cellular functions.

Wei Li, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National in Washington, D.C., proposes to develop statistical and computational methods that sidestep existing hurdles that currently complicate genome-wide CRISPR/Cas9 screening. The National Institutes of Health has granted him $2.23 million in funding over five years to facilitate the systematic study of genes, non-coding elements and genetic interactions in various biological systems and disease types.

Right now, a large volume of screening data resides in the public domain, however it is difficult to compare data that is stored in one library with data stored at a different library. Over the course of the five-year project, Li aims to:

  • Improve functional gene identification from CRISPR screens.
  • Develop new analyses algorithms for screens targeting non-coding elements.
  • Study genetic interactions from CRISPR screens targeting gene pairs.

Ultimately, Li’s work will examine a range of disease types. Take cancer.

“There is abundant information already available in the public domain, like the Project Achilles  from the Broad Institute. However, no one is looking to see what is going in inside these tumors,” Li says. “Cancer is a disease of uncontrolled cell growth that makes tumors grow faster.”

Li and colleagues are going to ask which genes control this process by looking at genes that hit the brakes on cell growth as well as genes that pump the gas.

“You knock out one gene and then look: Does the cell grow faster or does it grow more slowly? If the cell grows more slowly, you know you are knocking out a gene that has the potential to stop tumor growth. If cells are growing faster, you know that you’re hitting genes that suppress cancer cell growth.”

In a nutshell, CRISPR (clustered regularly interspaced short palindromic repeats) screens knock out different genes and monitor changes in corresponding cell populations. When CRISPR first became popular, Li decided he wanted to do something with the technology. So, as a Postdoc at Harvard, he developed comprehensive computational algorithms for functional screens using CRISPR/Cas9.

To reach as many people as possible, he offered that MAGeCK/MAGeCK-VISPR software free to as many researchers as possible, providing source code and offering internet tutorials.

“So far, I think there are quite a lot of people using this. There have been more than 40,000 software downloads,” he adds. “It’s really exciting and revolutionary technology and, eventually, we hope the outcomes also will be exciting. We hope to find something really helpful for cancer patients.”

Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under award number R01HG010753.

Epstein Barr virus

Fighting lymphoma with targeted T-cells

Epstein-Barr virus

The Epstein-Barr virus (EBV) is best known as the cause of mononucleosis, the ubiquitous “kissing disease” that most people contract at some point in their life. But in rare instances, this virus plays a more sinister role as the impetus of lymphomas, cancers that affect the white blood cells known as lymphocytes.

The Epstein-Barr virus (EBV) is best known as the cause of mononucleosis, the ubiquitous “kissing disease” that most people contract at some point in their life. But in rare instances, this virus plays a more sinister role as the impetus of lymphomas, cancers that affect the white blood cells known as lymphocytes. EBV-associated lymphomas account for about 40% of Hodgkin lymphomas, 20% of diffuse large B-cell lymphomas, and more than 90% of natural killer/T-cell lymphomas. This latter type of lymphoma typically has a very poor prognosis even with the “standard of care” lymphoma treatments such as chemotherapy and/or radiation.

When these interventions fail, the only curative approach is an allogeneic  hematopoietic stem cell transplant from a healthy donor, a treatment that’s tough on patients’ bodies and carries significant risks, says Lauren P. McLaughlin, M.D., a pediatrician specializing in hematology and oncology at Children’s National in Washington, D.C. Patients who receive these allogenic transplants are immune-compromised until the donor cells engraft; the grafts can attack patients’ healthy cells in a phenomenon called graft versus host disease; and if patients relapse or don’t respond to this treatment, few options remain.

To help improve outcomes, Dr. McLaughlin and colleagues tested an addition to the allogeneic hematopoietic stem cell transplant procedure for patients with EBV-associated lymphomas: infusion of a type of immune cell called T cells specifically trained to fight cells infected with EBV.

Dr. McLaughlin, along with Senior Author Catherine M. Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research and the Program for Cell Enhancement and Technologies for Immunotherapy at Children’s National, and colleagues tested this therapy in 26 patients treated at Children’s National or Baylor College of Medicine. They published these results online on Sept. 27, 2018, in the journal Blood. The study was a Phase I clinical trial, meaning that the therapy was tested primarily for safety, with efficacy as a secondary aim.

Seven patients who received the therapy had active disease that had not responded to conventional therapies. The other 19 were patients deemed to be at high risk for relapse.

Before each patient received their stem cell transplant, their donors gave an additional blood sample to generate the cancer-fighting T cells. Over the next 8 to 10 weeks, the researchers painstakingly manufactured the immune cells known as T-cells that specifically targeted EBV, growing these cells into numbers large enough for clinical use. Then, as early as 30 days after transplant, the researchers infused these T-cells into patients administering at least two doses, spaced two weeks apart.

Over the next several weeks, the researchers at CNMC and Baylor College of Medicine monitored patients with comprehensive exams to see how they fared after these transplants. The results showed that adverse effects from the treatment were exceedingly rare. There were no immediate infusion-related toxicities to the T-cell therapy and only one incident of dose-limiting toxicity.

This therapy may be efficacious, depending on the individual patients’ circumstances, Dr McLaughlin adds. For those in complete remission but at high risk of relapsing, the two-year survival rate was 78%, suggesting that the administration of this novel T-cell therapy may give the immune system a boost to prevent the lymphoma from returning after transplant. For patients with active T-cell lymphomas, two-year survival rates were 60%. However, even these lower rates are better than the historical norm of 30-50%, suggesting that the targeted T-cell therapies could help fight disease in patients with this poor prognosis lymphoma.

Dr. McLaughlin, the study’s lead author and a Lymphoma Research Foundation grantee, notes that researchers have more work to do before this treatment becomes mainstream. For example, this treatment will need to be tested in larger populations of patients with EBV-related lymphoma to determine who would derive the most benefit, the ideal dose and dose timing. It also may be possible to extend targeted T-cell treatments like this to other types of cancers. In the future, Dr. McLaughlin adds, it may be possible to develop T-cells that could be used “off the shelf”—in other words, they wouldn’t need to come from a matched donor and would be ready to use whenever a recipient needs them. Another future goal is using this therapy as one of the first lines of treatment rather than as a last resort.

“Our ultimate goal is to find a way to avoid chemotherapy and/or radiation therapy while still effectively treating a patient’s cancer,” she says. “Can you use the immune system to do that job? We’re working to answer that question.”

In addition to Drs. McLaughlin and Bollard, study co-authors include Rayne Rouce, Stephen Gottschalk, Vicky Torrano, George Carrum, Andrea M. Marcogliese, Bambi Grilley, Adrian P. Gee, Malcolm K. Brenner, Cliona M. Rooney and Helen E. Heslop, all of Baylor College of Medicine; Meng-Fen Wu from the Dan L. Duncan Comprehensive Cancer Center; and Fahmida Hoq and Patrick J. Hanley, Ph.D. from Children’s National in Washington, D.C.

Test tube with DNA

“Liquid biopsies” could track diffuse midline gliomas

Test tube with DNA

A multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of diffuse midline gliomas could reliably predict the tumors’ response to radiotherapy.

Diffuse midline gliomas are rare, diagnosed in fewer than 800 Americans every year, the majority of whom are children. These cancers arise in the cellular “glue” that holds the brain and spinal cord’s neurons together, grow swiftly and have no cure. About half of patients with these cancers, including diffuse intrinsic pontine glioma, die within one year of diagnosis.

Clinical trials are increasingly investigating new treatments that could offer hope for patients and their families. Yet, thus far, there have been few ways to track the progression of these conditions, offering little insight on whether a treatment is hitting its intended goal.

To solve this problem, a multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of these cancers could reliably predict the tumors’ response to radiotherapy. The scientists published their results online Oct. 15, 2018, in Clinical Cancer Research.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The team at Children’s National searches for the histone 3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M,” says Lindsay B. Kilburn, M.D., a neuro–oncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers children to not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients who had undergone a tumor biopsy.”

With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously, Nazarian adds.

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D., and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital;  John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Mathew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

2019 at a glance: Oncology at Children’s National

Oncology at Children's National
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

Holly Meany

TAA-Ts as therapy for tumors

Holly Meany

“The T cell immunotherapy regimen resulted in prolonged disease stabilization in patients who previously experienced rapid tumor progression,” says Holly Meany, M.D. “The therapy could prove to be an important component of immunotherapy for patients with solid tumor malignancies.”

In a study published in the Journal of Clinical Oncology, researchers from Children’s National Health System uncovered tumor-associated antigen cytotoxic T cells (TAA-Ts) that represent a new and potentially effective nontoxic therapeutic approach for patients with relapsed or refractory solid tumors.

The Phase 1 study led by Children’s National pediatric oncologists Holly Meany, M.D., and Amy B. Hont, M.D., represented the first in-human trial investigating the safety of administering TAA-Ts that target Wilms Tumor gene 1, a preferentially expressed antigen of melanoma and survivin in patients with relapsed/refractory solid tumors.

“These are exciting clinical results using a novel ‘first in-human’ T cell therapy,” said Catherine Bollard, MB.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s Research Institute. “This T cell therapy was safe and appeared to prolong patients’ time to progression which suggests that we can now use this novel treatment as a combination therapy to hopefully achieve long-term remissions in pediatrics and adults with relapsed/refractory solid tumors.”

During the Phase 1 trial, TAA-Ts products were generated from autologous peripheral blood and were infused over three dose levels. Patients were then eligible for up to eight infusions that were administered four to seven weeks apart.

Of the 15 evaluable patients, 11 were with stable disease or better at 45 days post-infusion and were defined as responders. Patients who were treated at the highest dose level showed the best clinical outcomes, with a 6-month progression-free survival rate of 73% after TAA-Ts infusion, an improvement as compared with prior therapy.

Overall, the Phase 1 trial of TAA-Ts resulted in safely induced disease stabilization and was associated with antigen spreading and a reduction in circulating tumor-associated antigen DNA levels in patients with relapsed/refractory solid tumors before infusion.

“The T cell immunotherapy regimen resulted in prolonged disease stabilization in patients who previously experienced rapid tumor progression,” said Dr. Meany. “The therapy could prove to be an important component of immunotherapy for patients with solid tumor malignancies,” she added.

The other researchers that contributed to this work are as follows: Amy B. Hont, M.D.; C. Russell Cruz, M.D., Ph.D.; Robert Ulrey, M.S.; Barbara O’Brien, B.S.; Maja Stanojevic, M.D.; Anushree Datar, M.S.; Shuroug Albihani, M.S.; Devin Saunders, B.A.; Ryo Hanajiri, M.D., Ph.D.; Karuna Panchapakesan, M.S.; Sam Darko, M.S.; Payal Banerjee, M.S.; Maria Fernanda Fortiz, B.S.; Fahmida Hoq, MBBS, M.S.; Haili Lang, M.D.; Yunfei Wang, Dr.PH.; Patrick J. Hanley, Ph.D.; Jeffrey S. Dome, M.D., Ph.D.; Catherine M. Bollard, M.D.; and Holly J. Meany, M.D.

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.

Vittorio Gallo Alpha Omega Alpha Award

Vittorio Gallo, Ph.D., inducted into Alpha Omega Alpha

Vittorio Gallo Alpha Omega Alpha Award

Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National, was inducted into Alpha Omega Alpha (AΩA), a national medical honor society that since 1902 has recognized excellence, leadership and research in the medical profession.

“I think it’s great to receive this recognition. I was very excited and surprised,” Gallo says of being nominated to join the honor society.

“Traditionally AΩA membership is based on professionalism, academic and clinical excellence, research, and community service – all in the name of ‘being worthy to serve the suffering,’ which is what the Greek letters AΩA stand for,” says Panagiotis Kratimenos, M.D., Ph.D., an ΑΩΑ member and attending neonatologist at Children’s National who conducts neuroscience research under Gallo’s mentorship. Dr. Kratimenos nominated his mentor for induction.

“Being his mentee, I thought Gallo was an excellent choice for AΩΑ faculty member,” Dr. Kratimenos says. “He is an outstanding scientist, an excellent mentor and his research is focused on improving the quality of life of children with brain injury and developmental disabilities – so he serves the suffering. He also has mentored numerous physicians over the course of his career.”

Gallo’s formal induction occurred in late May 2019, just prior to the medical school graduation at the George Washington University School of Medicine & Health Sciences (GWSMHS) and was strongly supported by Jeffrey S. Akman, Vice President for Health Affairs and Dean of the university’s medical school.

“I’ve been part of Children’s National and in the medical field for almost 18 years. That’s what I’m passionate about: being able to enhance translational research in a clinical environment,” Gallo says. “In a way, this recognition from the medical field is a perfect match for what I do. As Chief Research Officer at Children’s National, I am charged with continuing to expand our research program in one of the top U.S. children’s hospitals. And, as Associate Dean for Child Health Research at GWSMHS, I enhance research collaboration between the two institutions.”

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.

Suvankar Majumdar

Spotlight on Suvankar Majumdar, M.D.

Suvankar Majumdar

As a provider with international experience, Suvankar Majumdar, M.D., joined Children’s National in August 2017 as chief of Children’s Division of Hematology within the Center for Cancer and Blood Disorders. Dr. Majumdar is excited to be at Children’s National because of the opportunities for growth, cutting-edge research and continuing education that our diverse population of patients can provide clinicians.

Born in Zambia, in southern Africa, and educated in the United Kingdom, Dr. Majumdar moved to Zimbabwe to study medicine, which he considers the turning point of his career. While in medical school, Dr. Majumdar oversaw and managed the treatment of patients with HIV and other chronic illnesses and determined that blood disorders, particularly sickle cell, was where he wanted to place his focus. Since then, he has served as the Director of the Comprehensive Pediatric Sickle Cell Program as well as Director of the Hemophilia Treatment Center at the University of Mississippi and is a recognized leader in hematology and sickle cell disease. It is this expertise, as well as his dedication to research studies, that have already made him an asset to Children’s National.

Within the Division of Hematology, Children’s providers focus on treating patients with blood disorders, bleeding and clotting disorders, red blood cell disorders (such as sickle cell) and more. Since coming to Children’s National, Dr. Majumdar has experienced a tremendous amount of dedication and enthusiasm from his colleagues. “I’m excited to build on what our faculty has accomplished so far. We’re already well poised to become a national leader in hematology,” he says. “I have no doubt that we will continue to accomplish our goals through collaboration and working toward a common life-saving cause.”

One of his immediate goals for the division is to focus on bringing improved patient care and accessibility in the surrounding Washington area. Additionally, Dr. Majumdar is currently conducting two research studies for sickle cell disease. As one of his studies enters the second phase, he’s focused on seeing the impact of an intravenous citrulline, a nitric oxide booster, on patients with sickle cell disease. Another study has begun to determine if specific genetic mutations that cause prolonged QT, or irregular heartbeats in patients, cause mortality, as sickle cell patients are predisposed to cardiac episodes.

It is Dr. Majumdar’s hope that the hematology team at Children’s National will also continue training the next generation of providers to advance research, education and clinical aspects of the field. To those looking to join the specialty, Dr. Majumdar suggests keeping an open mind when it comes to collaborating with colleagues. “My dad always said to my siblings and I that ‘to break one stick is easy, but to break three sticks is harder’ and really impressed upon us that we’re stronger together,” he says. “By working together, we’re more likely to produce the results that we’re looking for.”

Being located in the nation’s capital, providers at Children’s National are accustomed to seeing a diverse array of patients. For Dr. Majumdar, this presents a unique opportunity. “Meeting and interacting with different patients and families was really appealing when I decided to come to Children’s National. The variety of cases we see in the Division of Hematology can definitely present new challenges, but it’s also more rewarding,” he says.

Working with the pediatric population is also a passion of his. “Children are resilient and tend to bounce back quickly,” Dr. Majumdar says. “As a parent, I try to empathize with treatment concerns and always treat every child as if they were my own. I’m always going to make sure it’s the best level of care possible.”

germ cells in testicular tissues

Experimental fertility preservation provides hope for young men

germ cells in testicular tissues

Confirming the presence of germ cells in testicular tissues obtained from patients. Undifferentiated embryonic cell transcription factor 1 (UTF1) is an established marker of undifferentiated spermatogonia as well as the pan-germ cell marker DEAD-box helicase 4 (DDX4). UTF1 (green) and/or DDX4 (red) immunostaining was confirmed in 132 out of 137 patient tissues available for research, including patients who had received previous non-alkylating (B, E, H, K) or alkylating (C, F, I, L) chemotherapy treatment. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Testicular tissue samples obtained from 189 males who were facing procedures that could imperil fertility were cryopreserved at one university, proving the feasibility of centralized processing and freezing of testicular tissue obtained from academic medical centers, including Children’s National, scattered around the world.

“It’s not surprising that the University of Pittsburgh would record the highest number of samples over the eight-year period (51 patients), given its role as the central processing facility for our recruiting network of academic medical centers,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National. “Children’s National recruited the third-highest number of patients, which really speaks to the level of collaboration I have with Jeff Dome’s team and their commitment to thinking about the whole patient and longer-term issues like fertility.”

An estimated 2,000 U.S. boys and young men each year receive treatments or have cancers or blood disorders that place them at risk for infertility. While older youths who have undergone puberty can bank their sperm prior to undergoing sterilizing doses of chemotherapy or radiation, there have been scant fertility preservation options for younger boys. However, some older adolescents and young men are too sick or stressed to bank sperm. For patients with no sperm to bank or who are too sick or stressed to bank sperm, the experimental procedure of freezing testicular tissue in anticipation that future cell- or tissue-based therapies can generate sperm is the only option.

Recent research in experimental models indicates that such testicular tissue biopsies contain stem cells, blank slate cells, hinting at the potential of generating sperm from biopsied tissue.

“This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of these spermatogonia was not tested,” writes lead author Hanna Valli-Pulaski, Ph.D., research assistant professor at the University of Pittsburgh, and colleagues in a study published online May 21, 2019, in Human Reproduction.

Right now, hematologists and oncologists discuss future treatment options with patients and families, as well as possible long-term side effects, including infertility. At Children’s National, they also mention the ongoing fertility preservation study and encourage families to speak with Dr. Hsieh. He meets with families, explains the study goals – which include determining better ways to freeze and thaw tissue and separating malignant cells from normal cells – what’s known about experimental fertility preservation and what remains unknown. Roughly half of patients decide to enroll.

“This study is unique in that there is definitely a potential direct patient benefit,” Dr. Hsieh adds. “One of the reasons the study is compelling is that it presents a message of hope to the families. It’s a message of survivorship: We’re optimistic we can help your child get through this and think about long-term issues, like having their own families.”

In this phase of the study, testicular tissue was collected from centers in the U.S. and Israel from January 2011 to November 2018 and cryopreserved. Patients designated 25% of the tissue sample to be used for the research study; 75 percent remains stored in liquid nitrogen at temperatures close to absolute zero for the patient’s future use. The fertility preservation patients ranged from 5 months old to 34 years old, with an average age of 7.9 years.

Thirty-nine percent of patients had started medical treatment prior requesting fertility preservation. Sixteen percent received non-alkylating chemotherapy while 23% received alkylating chemotherapy, which directly damages the DNA of cancer cells.

The research team found that the number of undifferentiated spermatogonia per seminiferous tubule increase steadily with age until about age 11, then rise sharply.

“We recommend that all patients be counseled and referred for fertility preservation before beginning medical treatments known to cause infertility. Because the decision to participate may be delayed, it is encouraging that we were able to recover undifferentiated spermatogonia from the testes of patients already in the early stages of chemotherapy treatments,” Dr. Hsieh says.

In addition to Dr. Hsieh, study co-authors include lead author, H. Valli-Pulaski, K.A. Peters, K. Gassei, S.R. Steimer, M. Sukhwani, B.P. Hermann, L. Dwomor, S. David, A.P. Fayomi, S.K. Munyoki, T. Chu, R. Chaudhry, G.M. Cannon, P.J. Fox, T.M. Jaffe, J.S. Sanfilippo, M.N. Menke and senior author, K.E. Orwig, all of University of Pittsburgh; E. Lunenfeld, M. Abofoul-Azab and M. Huleihel, Ben-Gurion University of the Negev; L.S. Sender, J. Messina and L.M. Klimpel, CHOC Children’s Hospital;  Y. Gosiengfiao, and E.E. Rowell, Ann & Robert H. Lurie Children’s Hospital of Chicago; C.F. Granberg, Mayo Clinic; P.P. Reddy, Cincinnati Children’s Hospital Medical Center; and J.I. Sandlow, Medical College of Wisconsin.

Financial support for the research covered in this post was provided by Eunice Kennedy Shriver National Institute for Child Health and Human Development under awards HD061289 and HD092084; Scaife Foundation; Richard King Mellon Foundation; University of Pittsburgh Medical Center; United States-Israel Binational Science Foundation and Kahn Foundation.

Catherine Bollard

Engineering TGFB receptor to enhance NK cells and fight neuroblastoma

Catherine Bollard

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Catherine Bollard, M.B.Ch.B., M.D.

Catherine Bollard, M.B.Ch.B., M.D., and her research team published results showing potential efficacy of a novel cell therapy for treatment of pediatric patients with relapsed/refractory neuroblastoma.

The research paper, entitled, “Engineering the TGFβ receptor to Enhance the Therapeutic Potential of Natural Killer Cell as an Immunotherapy for Neuroblastoma,” was published on April 29, 2019 by Clinical Cancer Research and is being recognized for the potential efficacy of the “off the shelf” treatment for patients with relapsed/refractory neuroblastoma.

The researcher’s approach allows them to manipulate Natural Killer (NK) cells, expand and reinfuse them within a patient so they can fight cancer and disease.

“In this study, we have genetically engineered cord blood derived NK cells so that they are not only resistant to the devastating effects of TGFb, but they are not able to become activated in the presence of TGFb,” said, Dr. Bollard, who is the senior corresponding author of the study and director of the Center for Cancer and Immunology Research at the Children’s Research Institute. “In other words, turning the negative effects of TGFb into positive effects enhances the persistence and anti-tumor activity of these tumor-killing NK cells in vivo.”

NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of human leukocyte antigen (HLA) expression on interacting target cells, as in the case for a majority of solid tumors, including neuroblastoma. With neuroblastoma being a leading cause of pediatric cancer-related deaths, it presents as an ideal candidate for NK cell therapy.

“This manuscript encompasses a significant portion of work, in which we generated genetically-modified NK cells as an enhanced form of immunotherapy for neuroblastoma,” said Rachel Burga, Ph.D., lead author and graduate of the Institute for Biomedical Sciences at George Washington and Children’s National Health System.  “We’re very excited to share our pre-clinical findings which demonstrate the efficacy of approaches to “hijack” the TGFb receptor and target TGFb in the tumor microenvironment.”

She added that the approach will allow for the NK cells to simultaneously resist the immune suppression in the microenvironment and initiate activation to increase their ability to target tumor cells.

Pre-clinical testing and research for this trial began in 2016 and ended in 2019. “The idea came from a Department of Defense award given to Dr. Bollard and Dr. Cruz and they took the idea and reduced it to practice and showed feasibility for pre-clinical trial,” said Rohan Fernandes, Ph.D., assistant professor in the Department of Medicine at George Washington University and senior author on the manuscript.

Fernandes added that the timeframe to start the clinical trial is within the next two to four years at Children’s National.

Additional authors include Rachel A. Burga, Ph.D., Eric Yvon, Rohan Fernandes, Conrad Russell Cruz, and Catherine M. Bollard, M.B.Ch.B., M.D.

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?”

Meghan Delaney

Pathology chief appointed to board of pathology advisory committee

Meghan Delaney

The American Board of Pathology (ABPath) has appointed the chief of Pathology and Laboratory Medicine at Children’s National Health System, Meghan Delaney, D.O., M.P.H., to its Test Development and Advisory Committee (TDAC) for blood banking and transfusion medicine. As a member of the committee, Dr. Delaney will play a role in the development and review of the American Board of Pathology certification exam questions. Physicians selected to serve on the TDAC are established subject matter experts in their subspecialty, with knowledge on the latest advances in the field of pathology and patient care.

“As TDAC members, these physicians play a critical role in the development of the exams and are entrusted with maintaining the integrity of the board-certified designation. The appointment to a TDAC indicates the physician is highly regarded in the field of pathology and exemplifies the utmost standards of care,” states Rebecca L. Johnson, M.D., CEO of the American Board of Pathology.

Dr. Delaney joined Children’s National as Chief of Pathology and Laboratory Medicine in 2017. A diplomate of the American Board of Pathology, with certification in transfusion medicine/blood banking and clinical pathology, she is an active member of several professional societies. She serves as chair of the AABB Transfusion Medicine Subsection Pediatric Subcommittee and as chair of the American Society of Apheresis Applications Committee Pediatric Subcommittee.  Dr. Delaney is also a scientific member of the BEST Collaborative, an associate editor for the journal Transfusion Medicine and a member of the editorial board of Transfusion.

The mission of the American Board of Pathology, as a member of the American Board of Medical Specialties, is to serve the public and advance the profession of pathology, by setting certification standards and promoting lifelong competency of pathologists. Founded in 1936, the ABPath accomplishes this mission by establishing certification and continuing certification standards, as well as, assessing the qualifications of those seeking to obtain voluntary certification in the specialty of pathology.  Since 1971, the ABPath has appointed test committees for each specialty area of pathology. The committee consists of ABPath trustees and other pathologists, or specialty physicians, who are recognized experts in their respective disciplines.

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.

ACC19 attendees from Children's National

ACC.19: A focus on pediatric cardiology

ACC19 attendees from Children's National

Dr. Gerard Martin, center, accepts an award before delivering the 2019 Dan G. McNamara Keynote lecture at ACC.19.

“Innovation meets tradition,” is how many attendees and journalists described the American College of Cardiology’s 68th Scientific Sessions (ACC.19), which took place March 16-18, 2019 in New Orleans, La.

Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., a pediatric cardiologist and the medical director of Global Services at Children’s National, supported this narrative by referencing both themes in his 2019 Dan G. McNamara keynote lecture, entitled “Improved Outcomes in Congenital Heart Disease through Advocacy and Collaboration.” Dr. Martin highlighted advancements in the field of pediatric cardiology that took place over the past 15 years, while touting modern advancements – such as pulse oximetry screenings for critical congenital heart disease – that were a result of physician-led advocacy and collaboration.

Dr. Martin’s message was to continue to invest in research and technology that leads to medical breakthroughs, but to remember the power of partnerships, such as those formed by the National Pediatric Cardiology Quality Improvement Collaborative. These alliances, which generated shared protocols and infrastructure among health systems, improved interstage mortality rates between surgeries for babies born with hypoplastic left heart syndrome.

A dozen cardiologists and clinicians from the Children’s National Heart Institute also participated in CME panel discussions or delivered poster presentations to support future versions of this template, touching on early-stage innovations and multi-institution research collaborations. The themes among Children’s National Heart Institute faculty, presented to a diverse crowd of 12,000-plus professional attendees representing 108 countries, included:

Personalized guidelines:

  • Sarah Clauss, M.D., F.A.C.C., a cardiologist, presented “Unique Pediatric Differences from Adult Cholesterol Guidelines: Lipids and Preventive Cardiology,” before Charles Berul, M.D., division chief of cardiology and co-director of the Children’s National Heart Institute, presented “Unique Pediatric Differences from Adult Guidelines: Arrhythmias in Adults with Congenital Heart Disease,” in a joint symposium with the American Heart Association and the American College of Cardiology.
  • Berul, who specializes in electrophysiology, co-chaired a congenital heart disease pathway session, entitled “Rhythm and Blues: Electrophysiology Progress and Controversies in Congenital Heart Disease,” featuring components of pediatric electrophysiology, including heart block, surgical treatment of arrhythmias and sudden death risk.

Early detection:

  • Anita Krishnan, M.D., associate director of the echocardiography lab, presented “Identifying Socioeconomic and Geographic Barriers to Prenatal Detection of Hypoplastic Left Heart Syndrome and Transposition of the Great Arteries” as a moderated poster in Fetal Cardiology: Quickening Discoveries.
  • Jennifer Romanowicz, M.D., a cardiology fellow, and Russell Cross, M.D., director of cardiac MRI, presented the “Neonatal Supraventricular Tachycardia as a Presentation of Critical Aortic Coarctation” poster in FIT Clinical Decision Making: Congenital Heart Disease 2.
  • Pranava Sinha, M.D., a cardiac surgeon, presented the poster “Neuroprotective Effects of Vitamin D Supplementation in Children with Cyanotic Heart Defects: Insights from a Rodent Hypoxia Model” in Congenital Heart Disease: Therapy 2.

Coordinated care:

  • Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P., a cardiologist with a focus on hyperlipidemia and preventive cardiology, co-presented an update about BMI quality improvement (Q1) activity from the American College of Cardiology’s Adult Congenital and Pediatric Quality Network – BMI Q1 leadership panel.
  • Niti Dham, M.D., director of the cardio-oncology program, and Deepa Mokshagundam, M.D., cardiology fellow, presented the poster “Cardiac Changes in Pediatric Cancer Survivors” in Heart Failure and Cardiomyopathies: Clinical 3.
  • Nancy Klein, B.S.N., R.N., C.P.N., clinical program coordinator of the Washington Adult Congenital Heart program at Children’s National, presented the poster “Improving Completion of Advanced Directives in Adults with Congenital Heart Disease” in Risks and Rewards in Adult Congenital Heart Disease.

Innovation:

  • Jai Nahar, M.D., a cardiologist, moderated “Future Hub: Augmented Cardiovascular Practitioner: Giving Doctors and Patients a New Voice.” The session focused on technical aspects of artificial intelligence, such as language processing and conversational artificial intelligence, as well as how applications are used in patient-physician interactions.
  • Nahar also participated in a key event on the Heart-to-Heart stage, entitled “Rise of Intelligent Machines: The Potential of Artificial Intelligence in Cardiovascular Care.”

“While I enjoyed the significant representation of Children’s National faculty at the meeting and all of the presentations this year, one research finding that I found particularly compelling was Dr. Krishnan’s poster about geographical disparities in detecting congenital heart disease,” says Dr. Berul. “Her research finds obstetricians providing care to women in the lowest quartile of socioeconomic areas were twice as likely to miss a diagnosis for a critical congenital heart defect during a fetal ultrasound, compared to obstetricians providing care for women in the highest quartiles.”

Dr. Krishnan’s study was the collaborative effort of 21 centers in the United States and Canada, and investigated how socioeconomic and geographic factors affect prenatal detection of hypoplastic left heart syndrome and transposition of the great arteries.

“We studied over 1,800 patients, and chose these diseases because they require early stabilization by a specialized team at a tertiary care center,” says Dr. Krishnan, who led the research in conjunction with the Fetal Heart Society Research Collaborative. “We hope that by understanding what the barriers are, we can reduce disparities in care through education and community-based outreach.”

Dr. Kurt Newman in front of the capitol building

Kurt Newman, M.D., shares journey as a pediatric surgeon in TEDx Talk

Kurt Newman, M.D., president and chief executive officer of Children’s National, shares his poignant journey as a pediatric surgeon, offering a new perspective for approaching the most chronic and debilitating health conditions. In this independently-organized TEDx event, Dr. Newman also shares his passion for Children’s National and the need to increase pediatric innovations in medicine.

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neuro–oncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

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In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Maureen E Lyon

Maureen E. Lyon receives American Cancer Society grant

Maureen E Lyon

Children’s Clinical Health Psychologist Maureen E. Lyon, Ph.D., has received the “Judy White Memorial Clinical Research Pilot Exploratory Projects in Palliative Care of Cancer Patients and their Families” grant from the American Cancer Society (ACS).

Over two years, Lyon will be allotted $144,000 to translate Children’s evidence-based Family-Centered (FACE) pediatric advance care planning (ACP) protocol into Spanish through a process of community-based participatory research for teens with cancer.

Lyon’s research focuses on enabling families to understand their adolescents’ treatment preferences and describing patient-reported palliative care needs for teens with cancer. Ultimately, the research will help identify the wants, values, goals and beliefs of teens with cancer.

Along with the ACS research grant, Lyon and Jessica Thompkins, BSN, R.N., CPN, research nurse coordinator at Children’s National, will present at the Annual Assembly of Hospice & Palliative Medicine conference, March 13-16, 2019 in Orlando, Fla. on data from the current multi-site, five-year randomized clinical trial funded by National Institute of Health/ National Institute of Nursing Research for English-speaking teens with cancer.

During the presentation, they will speak about the effect of FACE ACP on families’ appraisals of caregiving for their teens with cancer and describing advance care planning communication approaches.

Lyon and other researchers at Children’s National look forward to making significant contributions to the science of advance care planning aimed to minimize suffering and enhancing quality of life for young adults. Their contributions give teens a voice in their future medical care and help families “break the ice,” by providing an extra level of support to treating clinicians.