Clinical Trial Spotlight: Creating a super army to target 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.
- PI: Eugene Hwang, M.D.
- Title: Phase 1 Research on Multi-antigen T Cell Infusion Against Neuro-oncologic Disease
- Status: Currently enrolling
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.
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.
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.
Food allergies: a research update
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:
- Neurology and Neurosurgery (No. 5), led by Roger Packer, M.D., and Robert Keating, M.D.
- Nephrology (No.6), led by Marva Moxey-Mims, M.D., FASN
- Cancer (No. 7), led by Jeffrey Dome, M.D., Ph.D.
- Orthopedics (No. 8), led by Matthew Oetgen, M.D.
- Pulmonary (No. 9), led by Anastassios Koumbourlis, M.D., M.P.H., and
- Diabetes and Endocrinology (a tie for No. 10), led by Fran Cogen, M.D., acting division co-chief
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.
Virus-specific t-cells show promise before transplant in SCID patients
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.”
Helpful, hopeful news for bone marrow transplant patients
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.
Combined FACT accreditation related to cellular immunotherapy spotlights Children’s ongoing commitment to revolutionary cancer therapies
As new immunotherapy treatments are starting to hit the market, care-delivery must adapt so that facilities are prepared to deliver these novel treatments to patients. Children’s National is proud to announce that it became the first pediatric medical institution in the United States to receive accreditations for both immune effector cells and more than minimal manipulation from the Foundation for the Accreditation of Cellular Therapy (FACT). Considered the threshold for excellence in cellular therapy, FACT establishes standards for high-quality medical and laboratory practice in the field.
“We are proud to receive these critically important seals of approval,” said David Jacobsohn, M.D., ScM, division chief of the Division of Blood and Marrow Transplantation at Children’s National. “Our patients are our highest priority and having these accreditations only further demonstrates our commitment to providing the most innovative care.”
The first new designation, FACT Accreditation for Immune Effector Cells, certifies that Children’s National is able to safely administer cutting-edge cellular therapies and monitor and report patient outcomes. The designation applies to CAR-T cells and therapeutic vaccines, among other therapies.
“We continuously set high standards for cellular therapy within the walls of Children’s National, and we are thrilled to be recognized for our leadership in this field,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research within the Children’s Research Institute. “Cell therapies represent the next generation of cancer treatment, and we are excited to continue our journey in revolutionizing patient care.”
Children’s National also received FACT Accreditation for More than Minimal Manipulation,
a designation that is unique to only a few pediatric institutions in the United States. This accreditation certifies that Children’s National is prepared to safely manufacture its own cellular therapies.
“Being accredited for More than Minimal Manipulation is a tremendous achievement for us as a stand-alone pediatric institution; it exemplifies our ability to manufacture our own innovative cellular therapy products for patients in need,” said Patrick Hanley, Ph.D., director of the Cellular Therapy Laboratory where the cells are manufactured for clinical use. “These two accreditations allow Children’s National to serve as a complex immunotherapy center that is capable of providing immunotherapies and gene therapies from external groups and companies.”
Nationally recognized immunotherapy and pathology experts take on new leading roles at Children’s National
Children’s National Health System recently made several exciting leadership announcements in the allergy, immunology and laboratory medicine fields, furthering the hospital’s ongoing commitment to providing the most comprehensive, innovative care for children.
Award-winning hematologist and immunotherapist Catherine Bollard, M.D., M.B.Ch.B., currently chief of the Division of Allergy and Immunology, has been chosen to serve as director of the Children’s Research Institute’s (CRI) Center for Cancer and Immunology Research (CCIR). CCIR includes more than 50 clinicians and scientists performing groundbreaking clinical and translational research in understanding the origins of, and developing and testing novel therapies for childhood cancers and immunologic disorders. The center receives more than $10 million annually from the National Institutes of Health and other external entities. In her new role on the leadership team of CCIR, Dr. Bollard will lead the advancement and oversight of cancer and immunology research performed at Children’s National.
“All of the progress made in cellular immunotherapy here at Children’s National can be attributed to Catherine and her leadership,” says Mark L. Batshaw, M.D., chief academic officer and director of CRI. “We are confident her impact will extend even further in her new role.”
Hemant Sharma, M.D., M.H.S., will assume the role of chief of the Division of Allergy and Immunology. In 2008, he joined the faculty at Children’s National and started the Food Allergy Program, which he directs today. His areas of interest include health disparities and community-based management of food allergy. He is also site principal investigator of novel clinical trials of immunotherapy for peanut allergy. He serves on the Medical Advisory Board of Food Allergy Research and Education (FARE), and was the recipient of the 2016 FARE Vision Award for his contributions to the national food allergy community. Dr. Sharma also serves as the site director of the allergy immunology fellowship program with the National Institutes of Health and has won various teaching awards.
In addition, nationally recognized laboratory medicine expert Meghan Delaney, D.O., M.P.H., has joined Children’s National as chief of pathology and lab medicine. An expert in the field of transfusion medicine, Dr. Delaney will lead efforts to unify Anatomic Pathology and Laboratory Medicine into a single division, while advancing cutting-edge practices in the lab to ensure the highest standard of quality and safety for patients. Dr. Delaney joins Children’s National from Seattle, where she held many leadership positions including serving as medical director at the Pediatric Apheresis Program at Seattle Children’s Hospital & Seattle Cancer Care Alliance, the blood bank at Seattle Children’s Hospital and the Immunohematology & Red Blood Cell Genomics Reference Laboratory at Bloodworks Northwest.
“Dr. Delaney brings extensive experience in laboratory medicine innovation and program-building, and we are confident she will make a lasting impact on our patients,” said Jeffrey Dome, M.D., Ph.D., vice president for the Center for Cancer and Blood Disorders at Children’s National. “Her leadership will bolster our commitment to providing top quality care for our patients through advancement of lab medicine research and treatments.”
Advancing pediatric cancer research by easing access to data
Speeding research into pediatric cancers and other diseases relies not only on collecting good data, but making them accessible to research teams around the world to analyze and build on. Both efforts take time, hard work and a significant amount of financial resources – the latter which can often be difficult to attain.
In a move that could considerably advance the field of pediatric cancer, the National Institutes of Health (NIH), a body that funds biomedical research in the United States, recently awarded a public-private research collective that includes Children’s National Health System up to $14.8 million to launch a data resource center for cancer researchers around the world in order to accelerate the discovery of novel treatments for childhood tumors. Contingent on available funds, five years of funding will be provided by the NIH Common Fund Gabriella Miller Kids First Pediatric Research Program, named after Gabriella Miller, a 10-year-old child treated at Children’s National.
As principal investigators, researchers at Children’s Hospital of Philadelphia will lead the joint effort to build out the “Kids First” Data Resource Center. Children’s National in Washington, D.C., will spearhead specific projects, including the Open DIPG project, and as project ambassador will cultivate additional partnerships with public and private foundations and related research consortia to expand a growing trove of data about pediatric cancers and birth defects.
“This is a tremendous opportunity for children and families whose lives have been forever altered by pediatric cancers,” says Javad Nazarian, Ph.D., M.S.C., principal investigator in the Center for Genetic Medicine Research and scientific director of the Brain Tumor Institute at Children’s National. “From just a dozen samples seven years ago, Children’s National has amassed one of the nation’s largest tumor biorepositories funded, in large part, by small foundations. Meanwhile, research teams have been sequencing data from samples here and around the world. With this infusion of federal funding, we are poised to turn these data into insights and to translate those research findings into effective treatments.”
Today’s NIH grant builds on previous funding that Congress provided to the NIH Common Fund to underwrite research into structural birth defects and pediatric cancers. In the first phase, so-called X01 grantees—including Eric Vilain, M.D., Ph.D., newly named director of the Center for Genetic Medicine Research at Children’s National—received funding to sequence genetic data from thousands of patients and families affected by childhood cancer and structural birth defects.
This new phase of funding is aimed at opening access to those genetic sequences to a broader group of investigators around the globe by making hard-to-access data easily available on the cloud. The first project funded will be Open DIPG, run by Nazarian, a single disease prototype demonstrating how the new data resource center would work for multiple ailments.
DIPG stands for diffuse intrinsic pontine glioma, aggressive pediatric brain tumors that defy treatment and are almost always fatal. Just as crowd sourcing can unleash the collective brainpower of a large group to untangle a problem swiftly, open data sharing could accomplish the same for childhood cancers, including DIPG. In addition to teasing out molecular alterations responsible for making such cancers particularly lethal, pooling data that now sits in silos could help to identify beneficial mutations that allow some children to survive months or years longer than others.
“It’s a question of numbers,” Dr. Vilain says. “The bottom line is that making sense of the genomic information is significantly increased by working through large consortia because they provide access to many more patients with the disease. What is complicated about genetics is we all have genetic variations. The challenge we face is teasing apart regular genetic variations from those genetic variations that actually cause childhood cancers, including DIPG.”
Nazarian predicts some of the early steps for the research consortium will be deciding nuts-and-bolts questions faced by such a start-up venture, such as the best methods to provide data access, corralling the resources needed to store massive amounts of data, and providing data access and cross correlation.
“One of the major challenges that the data resource center will face is to rapidly establish physical data storage space to store all of the data,” Nazarian says. “We’re talking about several petabytes—1,000 terabytes— of data. The second challenge to address will be data dissemination and, specifically, correlation of data across platforms representing different molecular profiles (genome versus proteome, for example). This is just the beginning, and it is fantastic to see a combination of public and private resources in answering these challenges.”
Children’s welcomes hematology leaders, expands expertise
The Center for Cancer and Blood Disorders at Children’s National is emerging as a leader in Pediatric Hematology, and the recruitment of two prominent physician-scientists to our Division of Hematology and Sickle Cell Disease Program is evidence of that growth and presence on the national platform. Joining the faculty in June are:
Suvankar (Seve) Majumdar, M.D.
Division Chief, Hematology
Dr. Majumdar was born in Zambia, attended the University of Zimbabwe College of Health Sciences and conducted his postdoctoral medical education at the University of Mississippi. Dr. Majumdar is currently the director of the Comprehensive Pediatric Sickle Cell Program at the University of Mississippi Medical Center. He previously directed the Mississippi Hemophilia Treatment Center and is a recognized leader in hematology and sickle cell disease. In addition to his broad clinical expertise, Dr. Majumdar is an accomplished researcher, and a principal investigator of NIH-funded studies.
Andrew (Drew) Campbell, M.D.
Director, Sickle Cell Disease Program
Dr. Campbell’s distinguished training and career path began at Morehouse College. He continued medical school at Case Western Reserve University and completed post graduate training at Massachusetts General Hospital (Harvard) and Lurie Children’s Hospital (Northwestern University). He has been director of the Comprehensive Sickle Cell Center at the University of Michigan since 2005. His research interests span several topics in sickle cell disease including pulmonary complications, fetal hemoglobin switching in transgenic sickle cell mice, phenotype/genotype relationships and renal complications.
The Children’s National Division of Hematology includes the most comprehensive pediatric blood disorders team in the Washington, D.C., area. The Sickle Cell Disease Program is among the largest in the country, treating more than 1,400 children and young adults with all types of sickle cell disease.
Advances in T-cell immunotherapy at ISCT
T-cell immunotherapy, which has the potential to deliver safer, more effective treatments for cancer and life-threatening infections, is considered one of the most promising cell therapies today. Each year, medical experts from around the world – including leaders in the field at Children’s National Health System – gather at the International Society for Cellular Therapy (ISCT) Conference to move the needle on cell therapy through several days of innovation, collaboration and presentations.
Dr. Catherine Bollard, Children’s National chief of allergy and immunology and current president of ISCT, kicked off the week with a presentation on how specific approaches and strategies have contributed to the success of T-cell immunotherapy, a ground-breaking therapy in this fast-moving field.
Later in the week, Dr. Kirsten Williams, a blood and marrow transplant specialist, presented encouraging new findings, demonstrating that T-cell therapy could be an effective treatment for leukemia and lymphoma patients who relapse after undergoing a bone marrow transplant. Results from her phase 1 study showed that four out of nine patients achieved complete remission. Other medical options for the patients involved – those who relapsed between 2 and 12 months post-transplant – are very limited. Looking to the future, this developing therapy, while still in early stages, could be a promising solution.
Other highlights include:
- Both Allistair Abraham, blood and marrow transplantation specialist, and Dr. Michael Keller, immunologist, presented oral abstracts, the former titled “Successful Engraftment but High Viral Reactivation After Reduced Intensity Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease” and the latter “Adoptive T Cell Immunotherapy Restores Targeted Antiviral Immunity in Immunodeficient Patients.”
- Patrick Hanley engaged attendees with his talk, “Challenges of Incorporating T-Cell Potency Assays in Early Phase Clinical Trials,” and his poster presentation “Cost Effectiveness of Manufacturing Antigen-Specific T-Cells in an Academic GMP Facility.” He also co-chaired a session titled “Early Stage Professionals Session 1 – Advanced Strategic Innovations for Cell and Gene Therapies.”
- To round out this impressive group, Shabnum Piyush Patel gave a talk on genetically modifying HIV-specific T-cells to enhance their anti-viral capacity; the team plans to use these HIV-specific T-cells post-transplant in HIV-positive patients with hematologic malignancies to control their viral rebound.
This exciting team is leading the way in immunology and immunotherapy, as evidenced by the work they shared at the ISCT conference and their ongoing commitment to improving treatments and outcomes for patients at Children’s National and across the country. To learn more about the team, visit the Center for Cancer and Blood Disorders site.
Cell therapy virtuoso: Catherine Bollard
In the Medicine Maker piece, Cell Therapy Virtuoso, Children’s National Medical System’s Chief of Allergy and Immunology, Catherine Bollard M.D., discusses why she chose a career in medicine, the personal experience that ignited her interest in cell therapies, and her insights on the current state and future of the immunotherapy field. Highlights from the interview include:
- On the promise of T-cell therapy: “We’ve now developed several T-cell therapies that give complete remission rates of approximately 75% and two-year progression-free survival rates ranging from 50 percent to over 90 percent depending on the patient population.”
- Regarding the future of immunotherapy: “The field has expanded dramatically over the last 25 years. In particular, T-cell therapies for cancer have grown rapidly and now the field is expanding into other areas, such as regulatory T-cells for autoimmune disease and virus T-cells for HIV. Given what the immune system can do, the applications are almost limitless.”
Dr. Bollard was featured for her role as president of the International Society for Cellular Therapy.
Shining light on autoimmune encephalitis
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.
Surviving pediatric diffuse intrinsic pontine glioma
For more than four decades, clinicians around the nation have been giving the parents of pediatric patients diagnosed with diffuse intrinsic pontine glioma (DIPG) the same grim prognosis. In the past five years, there has been an explosion of innovative research at Children’s National Health System and elsewhere that promises to change that narrative. That’s because the black box that is DIPG is beginning to divulge its genetic secrets. The new-found research knowledge comes as a direct result of parents donating specimens, judicious shepherding of these scarce resources by researchers, development of pre-clinical models, and financing from small foundations.
From just 12 samples six years ago, Children’s National has amassed one of the nation’s largest tumor bio banks – 3,000 specimens donated by more than 900 patients with all types of pediatric brain tumors, including DIPG.
Such donated specimens have led to the identification of H3K27M mutations, a groundbreaking finding that has been described as the single-most important discovery in DIPG. Mutations in histone-encoding genes are associated with the vast majority of pediatric DIPG cases.
Histone mutations (also referred to as oncohistones) are sustained in the tumor throughout its molecular evolution, found a research team led by Javad Nazarian, Ph.D. Not only were H3K27M mutations nearly ubiquitous in all samples studied, the driver mutation maintained partnerships with other secondary mutations as DIPG tumor cells spread throughout the developing brain. Children’s National researchers have identified tumor driver mutations and obligate partner mutations in DIPG. They are examining what happens downstream from the histone mutation – changes in the genome that indicate locations they can target in their path toward personalized medicine. The value of that genomic knowledge is akin to emergency responders being told the specific house where their help is needed, rather than a ZIP code or city name, Dr. Nazarian says. While there is currently no effective treatment for DIPG, new research has identified a growing number of genomic targets for future therapeutics.“That changed the dynamic,” says Dr. Nazarian. “In DIPG clinical research, nothing had changed for 45 years. Now we know some of the genomic mutations, how the tumor was evolving – gaining new mutations, losing mutations. With precision medicine, we can target those mutations.”
Another study led by neuro-oncologist Eugene Hwang, M.D., reported the most comprehensive phenotypic analyses comparing multiple sites in a young girl’s primary and metastatic tumors. This study showed that despite being uniform, small molecules (mRNA) could be used to distinguish an evolved tumor from its primary original tumor mass.Key to this multidisciplinary work is collaboration across divisions and departments. Within the research lab, knowledge about DIPG is expanding.
Each member of the DIPG team – neurosurgery, neuro-oncology, immunology, genomics, proteomics – feeds insight back to the rest of the team, accelerating the pace of research discoveries being translated into clinical care. Among the challenges that the team will address in the coming months is outmaneuvering tumors that outsmart T-cells (immune cells).
“What is happening in the checkpoint inhibitor field is exciting,” says Catherine M. Bollard, MBChB, MD, Chief of Allergy and Immunology and Director of the Program for Cell Enhancement of Technologies for Immunotherapy. “The inhibitors work by reversing the ‘off’ switch – releasing the brake that has been placed on the T-cells so they can again attack multiple tumor proteins. The next exciting step, and novel to Children’s National, will be to combine this approach with T-cell therapies specifically designed to attack the DIPG tumors. Unlike the use of combination chemotherapy, which has had a limited impact, we hope that the novel combination of immunotherapeutic approaches will offer the hope of a potential cure.”
Dr. Hwang, another member of the multidisciplinary team, adds: “When you’re looking at the landscape – for me, at least – it starts and ends with how my patients are doing. There are kids for whom we have had great successes in improving survival rates in some cancers, like leukemia, and some where the needle has moved nowhere, like DIPG. We’re still trying to figure out the whole picture of who responds. The immune system is present in all kids. Its ability to attack is present in all kids.”
Children’s National is one of the few hospitals in the nation that conducts brainstem biopsies for DIPG and does so with very little chance of complications. The pons is like a superhighway through which nerves pass, making it instrumental in smooth operation of such vital functions as breathing, heart rate, sleeping, and consciousness. The ability of neurosurgeon Suresh Magge, MD, to perform such sensitive biopsies upends conventional wisdom that these procedures were inherently too dangerous. Within two weeks of diagnosis, genomics analyses are run to better understand the biology of that specific tumor. Within the following weeks, the tumor board occurs, and patients with DIPG are placed on therapy that best targets their tumor’s mutations.
Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of children with DIPG die within two years of diagnoses. Biomarkers that point to DIPG – like the copies of DNA that tumors shed and leave behind in the bloodstream – could enable creation of liquid biopsies, compared with today’s surgical approach.
Children’s also is making a concerted effort to create preclinical models of DIPG. Preclinical models will be used to winnow the field of potential therapeutics to the candidates most likely to help children survive DIPG. The preclinical tumor cells will be labeled with luciferase – enzymes that, like photoproteins, produce bioluminescence – permitting the researcher to visually see the formation, progression, and response of DIPG tumors to treatment in preclinical settings.
These preclinical models could be used to test multiple drug combinations in conjunction with radiation therapy. Molecular signatures and response to treatment could then be assessed to learn how the tumor resists therapy. Due to the obligate partnerships between driver mutations and secondary mutations, the research team already knows that effective DIPG medicines will need more than one target. If there were a single mutation, that would be like having a single master key to open many locks. Multiple mutations imply that more than one key will be needed. Thus, the search for cures for DIPG will necessitate taking a multi-pronged approach.
Combined drug regimens, including those created with proprietary technology, with or without radiation, will be keys to targeting myriad mutations in order to kill tumors where they are. Those drug combinations that demonstrate they can do their jobs – slowing tumor growth, increasing chances of survival, taming toxicity – will be selected for clinical application.
Immunotherapy leverages T-cells, the immune system’s most able fighters, to help in the overall goal of extending patients’ survival. One of the most challenging aspects of pediatric brain tumors is the body does a very good job of shielding the brain from potential pathogens. Precise drug delivery means finding innovative ways for therapeutics to cross the blood-brain barrier in order to reach the tumor. The team has identified one such potential target, the protein NG2, which may represent a good target for immune therapy. The protein is expressed in primitive cells that have not become specialized – meaning there may be an opportunity to intervene before it is driven to become a tumor cell.
Research at a Glance: Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape
Research at a Glance: The role of NG2 proteoglycan in glioma
Research at a Glance: Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Research at a Glance: Histological and molecular analysis of a progressive diffuse intrinsic pontine glioma: a case report
Expanding cytotoxic T lymphocytes from umbilical cord blood to target three viruses
Source: P.J. Hanley, J. J. Melenhors, S. Nikiforow, P. Scheinberg, J.W. Blaney, G. Demmler-Harrison, C.R. Cruz, S. Lam, R.A. Krance, K.S. Leung, C.A. Martinez, H. Liu, D.C. Douek, H.E. Heslop, C. M. Rooney, E.J. Shpall, A.J. Barrett, J.R. Rodgers, and C.M. Bollard. “CMV-Specific T-Cells Generated From Naïve T-Cells Recognize Atypical Epitopes and May Be Protective In Vivo.” Published by Science Translational Medicine on April 29, 2015
New research shows success training t-cells to recognize and fight life-threatening viruses
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
Analysis of a progressive diffuse intrinsic pontine glioma: a case report
Questions for Future Research
Source: “Histological and Molecular Analysis of a Progressive Diffuse Intrinsic Pontine Glioma and Synchronous Metastatic Lesions: A Case Report.” J. Nazarian, G.E. Mason, C.Y. Ho, E. Panditharatna, M. Kambhampati, L.G. Vezina, R.J. Packer, and E.I. Hwang. Published by Oncotarget on June 14, 2016.
Training t-cells, essential players in the immune system, to fight a trio of viruses
Questions for Future Research
Source: “A Phase 1 Perspective: Multivirus-Specific T Cells From Both Cord Blood and Bone Marrow Transplant Donors.” Hanley, P., M. D. Keller, M. Martin Manso, C. Martinez, K. Leung, C.R. Cruz, C. Barese, S. McCormack, M. Luo, R.A. Krance, D. Jacobsohn, C. Rooney, H. Heslop, E.J. Shpall, and C. Bollard. Presented during the International Society for Cellular Therapy 2016 Annual Meeting, Singapore. May 26, 2016.
Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Questions for Future Research
Source: “Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pontine Glioma.” H. Nikbakht, E. Panditharatna, L.G. Mikael, R. Li, T. Gayden, M. Osmond, C.Y. Ho, M. Kambhampati, E.I. Hwang, D. Faury, A. Siu, S. Papillon-Cavanagh, D. Bechet, K.L. Ligon, B. Ellezam, W.J. Ingram, C. Stinson, A.S. Moore, K.E. Warren, J. Karamchandani, R.J. Packer, N. Jabado, J. Majewski, and J. Nazarian. Published by Nature Communications on April 6, 2016.