Center for Cancer and Immunology Research

In the past year, the Center for Cancer and Immunology Research (CCIR) has had a significant time of transition with the appointment of a new director and extensive restructuring of the leadership and management infrastructure. The center established an executive committee with members representing all the key components of research as well as center and business administration. The center has made major research advances pre-clinically and clinically. The center made key advances in the understanding of key signaling pathways involved with brain tumor development and major advances in translational research, with several key first-in-man studies open utilizing novel cell therapies for the treatment of cancer as well as life-threatening viral infections. The center was honored to be awarded a $1.5 million gift from the Board of Visitors to immunotherapy research at Children’s. In addition, a memorandum of understanding with George Washington University (GW) was signed to expand immune cell therapy research a joint Children’s-GW program.

Leadership

CCIR Executive Committee (EC)

EC Co-Chairs

EC Members

Center Research Programs

Neurooncology

The Neuro-Oncology Program continues to have robust translational and basic research components. Javad Nazarian, Ph.D. leads the basic research activities and was named scientific director of the Brain Tumor Institute in December 2017. Laboratory efforts underway include those focusing on systemic detections of intracranial lesions (liquid biopsies), the biology and the molecular therapeutic targets of high-grade gliomas, including pontine gliomas and new therapeutics for Group 3 medulloblastomas with MYC amplifications. Basic science efforts have expanded nationally and internationally with the program’s inclusion in the Childhood Brain Tumor Tissue Consortium (CBTTC), of which Dr. Nazarian was recently named the scientific director. The CBTTC has recently received National Cancer Institute (NCI) funding. The translational program remains robust as Children’s National remains an active member of the Pediatric Brain Tumor Consortium, the Pediatric (Pacific) Neuro-Oncology Consortium, the Sunshine Network and the newly opened CONNECT Consortium. All these consortia are focusing on novel means to treat childhood brain tumors with an emphasis on molecular-targeted therapy and immunologic approaches. Over the past year translational trials have been opened utilizing check-point inhibitors, vaccine studies for high-grade gliomas and diffuse intrinsic pontine gliomas and molecular-targeted trials for medulloblastomas, brainstem gliomas and low-grade gliomas. The low-grade glioma study utilizing a MEK inhibitor has progressed to the point that the MEK inhibitor studied will soon be part of a Phase III study for newly diagnosed patients with low-grade gliomas. Dr. Packer, director of the Brain Tumor Institute, has led multiple international consensus conferences on pediatric low-grade gliomas, which have resulted in new guidelines published for the evaluation and potential management of such tumors and has been named scientific director of the National Brain Tumor Society’s Defeat Pediatric Brain Tumor initiative.

Medulloblastoma

In 2014, CCIR established the Medulloblastoma Special Interest Group, which focuses on understanding the causative mechanism and improving the treatment of medulloblastoma. The group performs translational research to integrate advances in molecular biology with clinical trials, taking research from the “bench to the bedside.” The researchers are testing Hif1a inhibitors, such as echinomycin, for the treatment of medulloblastoma. Dr. Pei’s lab is interested in using mouse models to study the molecular and cellular mechanisms underlying the initiation, progression, and therapeutic resistance of Group 3 medulloblastoma (MB). Currently, there are two major research focuses in the lab. The first focus is to identify the cell of origin for Group 3 MB. Data demonstrate that the MYC oncogene alone is sufficient to induce medulloblastoma, and Sox2+ cells in the developing cerebellum with MYC overexpression can develop tumors upon transplantation into the cerebellum of immunodeficient mice. Characterization of these MYC-driven tumors reveals that they resemble human Group 3 MB at a histological, immunohistochemical, and molecular level, indicating that Group 3 MB may originate from the Sox2 lineage during cerebellar development. The lab is investigating why Sox2+ cells in the cerebellum are uniquely vulnerable to MYC- induced tumorgenesis, whereas other cell types are resistant. These studies may contribute to the development of novel therapeutic strategies for blocking tumor progression and possibly preventing tumor relapse. The second focus of the lab is to investigate the function of tumor-derived glial cells in the progression, maintenance, and recurrence of MYC- driven MB. Preliminary data demonstrate that MYC-driven MB cells create their own niche by giving rise to mature glial cells to maintain tumor growth. The investigators are interested in determining whether elimination of tumor- derived glial cells can induce tumor regression or increase the efficacy of standard chemotherapeutic drugs, thereby preventing tumor relapse.

Cancer Biology and Experimental Cancer Therapy

Brain Tumor Biomarkers

Dr. Rood has created a Labeled Atlas of Medulloblastoma Proteins (LAMP) using stable isotope-labeled amino acids in culture (SILAC) technology. The LAMP has been used to quantitatively characterize the proteome of medulloblastoma subgroups to identify the functional pathways driving the disease. In partnership with the Children’s Brain Tumor Tissue Collaboration, Dr. Rood is also applying proteomic techniques to identify novel genomic fusion events and disease specific protein isoforms creating tumor specific proteins. These proteins can serve as biomarkers, drug targets or neoantigens to be exploited for immunotherapy development. In collaboration with Harold Garner, Ph.D., of Virginia Tech, Dr. Rood has identified a panel of medulloblastoma-associated DNA microsatellite markers whose genotypes are non-randomly associated with tumor formation and can be used to differentiate those with the tumor based upon their germline DNA microsatellite variations.

Neurofibromatosis Program

The neurofibromatosis research group continues its work on the utility of MEK inhibitors (MEKi) in preventing the development of a variety of neurofibromatosis type 1 (NF1)-associated diseases. The team recently identified a therapeutic prospect in using a MEKi to prevent the formation of a developmental structural brain defect, an enlarged corpus callosum, which is also observed in a subset of NF1 patients with severe learning disabilities. Building on those results, the group has identified a similar therapeutic window during neonatal stages in which loss of NF1 leads to defects in both neuronal and glial precursors during cerebellar development. Importantly, MEKi treatment during the neonatal stage can rescue the developmental defects in the NF1-deficient cerebellum, providing a long- term benefit for motor function. Together, those studies provide strong preclinical evidence that a single MEKi agent used during the early postnatal period can prevent the formation of developmental brain defects, providing long-term benefits for developing brain structures and developmental behaviors. To translate those preclinical findings to the clinic, the team completed an analysis of the brain penetration of the three MEKi compounds presently in clinical trials and presented the information to one of the leading industry partners sponsoring a MEKi clinical trial. Based on the team’s preclinical work and the ongoing clinical work of Dr. Packer, the Gilbert Family Neurofibromatosis Institute has agreed to open a third MEKi study, trametinib (Novartis), for children with NF1 and progressive brain lesions. In addition, the team has used a series of genetic systems to identify the therapeutic window of NF1-related optic pathway gliomas (OPGs), which mainly occur in children younger than 7 years old with NF1.

Pleuropulmonary Blastoma (PPB)

The Hill laboratory has been devoted to clinical and genetic characterization of a cancer predisposition syndrome that features organ-based, embryonal cancers of children and adolescents specifically the rare lung cancer pleuropulmonary blastoma (PPB). Through a linkage study, the team identified germline mutations in the DICER1 gene as the basis of this cancer susceptibility, which is now known as DICER1 syndrome.

The long-term goal of the research program is to develop safer and more effective management strategies and new, targeted therapeutics for DICER1 syndrome patients, and by extension, for childhood cancers more generally. In part, the lab accomplishes this through continuing education of pediatricians and pathologists, and through improved methods for mutation-based screening to recognize syndromic neoplasias in their earliest stages, when they are most curable (Schultz et al Clin Cancer Res 2018). For the most threatening DICER1 syndrome cancers, such as advanced pleuropulmonary blastomas that were not diagnosed early, current chemotherapies are too often ineffective; about half of children with this disease die. The team believes that new biologic or biomimetic therapies such as synthetic miRNA, other forms of oligonucleotide-mediated silencing for dysregulated oncofetal genes, and corrective gene therapy (e.g., for TP53), will be effective if they can be properly targeted to tumor cells. This is a challenging problem, but the team has now developed tumor-derived cell lines and patient-derived xenograft mouse models for some DICER1 syndrome cancers, in which new biologic agents and new methods for tumor-targeted delivery can be validated.

Finally, the Hill lab has a long-standing partnership with the International Pleuropulmonary Blastoma Registry (IPPBR), through which the lab strives to improve understanding of the molecular pathogenesis and clinical features of PPB, and to translate new knowledge into safer, more effective treatments. The IPPBR recently completed the first international prospective treatment study for PPB, which highlighted their capabilities for identifying and recruiting patients to clinical studies, and for establishing mutually beneficial relationships with pediatric oncologists around the world.

Program for Cell Enhancement and Technologies for Immunotherapy (CETI)

Immunotherapy represents the most exciting recent development in cancer therapy. Childrenís National faculty members are at the frontline in developing molecular and cellular therapeutic approaches to harness the power of the immune system to combat cancer. The researchers are developing novel therapeutic approaches to target cancer cells, with a major emphasis on identifying and generating tools to effectively target cancer antigens that are recognized by either T cell receptors or immunoglobulin. Investigators also are developing new monoclonal antibodies that rejuvenate cancer immunity by stimulating cancer-reactive T cells. The Cell Enhancement and Technologies for Immunotherapy (CETI) Program consists of two main programmatic areas: 1) targeting pathogens and 2) eliminating cancer.

Targeting Pathogens

T cell immunotherapies have shown great success in the prevention and treatment of viral infections (most particularly Epstein-Barr virus [EBV], adenovirus, and cytomegalovirus [CMV]) in post-hematopoietic stem cell transplant, with no major adverse events. The team recently published a novel study using CMV seronegative donors to prime virus-specific responses. The team discovered that: 1) naive T cells can be primed in vitro with specificity for multiple viruses; 2) the virus-specific T cell immune responses are not derived from contaminating maternal cells and are not affected by the serostatus of the mother; 3) CMV-specific T cells primed from cord blood recognize unique and novel CMV epitopes not typically seen in memory CMV-specific T cells; and 4) these observations are a direct consequence of the clonal diversity of T cells derived from naive T cells rather than memory-derived T cells. Efforts are now under way to expand the targeted viral antigens (e.g., extend to HPV, HHV6, BKV, HIV) and the immune-compromised patients eligible to receive those products (through third-party T cell banking and generating cells from naive donors). For example, the team recently has shown that it can generate HIV-specific T cells from HIV+ individuals and to date, two patients have been treated with this novel cell therapy. The team also plans to test viral targets in other pathogens, such as Ebola and influenza. In summary, this group is continuing with clinical trials targeting viruses in immune-compromised patients post stem cell transplant and patients with primary immune deficiency. The group was recently awarded the highly prestigious UM1 Martin Delaney Collaborative Grant through the National Institutes of Health (NIH), which supports research focused on an HIV cure. Titled BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication,î the grant is led by Drs. Doug Nixon, Catherine Bollard, Brad Jones and Alan Greenberg from the Department of Microbiology, Immunology and Tropical Medicine at GW. Finally, Dr. Keller is leading an effort with the PBMTC to use third- party, multivirus- specific T cells to treat viral infections in pediatric patients after blood and marrow transplant (BMT).

Eliminating Cancer

The CETI group has set up a bench-to-bedside translational research workflow at Children’s National that aims to : 1) evaluate the use of additional immune cells (e.g., natural killer [NK] cells and dendritic cells) and how they can be combined into potent antitumor therapies; 2) improve upon current manufacturing processes used in the generation of clinical grade antitumor T cells in the good manufacturing process (GMP); 3) target more antigens in a single culture platform; and 4) develop highly novel cellular therapies either in combination with other drugs (e.g., epigenetic modifying drugs or immunomodulatory drugs) or via genetic modification — increase targeting, resistance against immunosuppressive microenvironments, persistence and function. The team has shown that it can effectively prevent lymphoma relapse in the post-transplant setting, particularly for lymphomas that express EBV antigens on their surface. Now the group aims to extend this therapy for patients with solid tumors and non- virus-associated malignancies. In 2015, the team launched a first-in-human protocol led by Dr. Williams using multi-tumor-associated antigen (TAA)-specific T cells for leukemia and lymphoma and has treated 10 patients with a response rate of 75 percent in relapsed or refractory patients. This protocol is now also open at JHU as part of a joint P01 project between Dr. Bollard and Dr. Jones (JHU). Dr. Hwang is the principal investigator of Children’s-led study utilizing cytotoxic T-cells primed against tumor-associated antigens PRAME, WT1 and survivin, which have been documented to be present on a significant number of pediatric CNS malignancies. This trial has just been approved by the FDA and is actively enrolling patients. Dr. Meany is the PI of a similar study targeting non-CNS pediatric solid tumors and Dr. Williams who is the PI of a novel TAA-specific T cell study targeting hematologic cancers is now expanding this approach with Dr. Dave as a combination strategy with checkpoint inhibitors and nanoparticles (two grants funded by the Leukemia and Lymphoma Foundation). In addition, the team has Department of Defense (DOD) and Alex’s Lemonade Stand funding to develop cord-blood-derived TGFb-resistant NK cells for neuroblastoma and brain tumors. Finally, Children’s National (Drs. Bollard, McLaughlin and Hanley) is leading a Children’s Oncology Group (COG) study for patients with post-transplant lymphoproliferative disorders using rituxan in combination with third-party EBV/LMP- specific T cells.

Giving Children Everywhere Access to Novel Therapies

Children’s National is a national leader in developing novel T cell therapies, and in making sure these novel therapies are available to all children who need them, regardless of patient sex, demographics and ethnicity. The first is a Children’s Oncology Group (COG) study for patients with post-transplant lymphoproliferative disorders using rituxan in combination with third-party EBV/LMP- specific T cells. Drs. Bollard, McLaughlin and Hanley are the principal investigators.

Children’s is the manufacturing center for a nationwide clinical trial using allogeneic virus-specific T cells that are shipped from us to the requesting institution. The trial, Antiviral Cellular Therapy for Enhancing T-cell Reconstitution Before or After Hematopoietic Stem Cell Transplantation (ACES), is a partnership between the Pediatric Blood & Marrow Transplant Consortium (PBMTC) and the California Institute of Regenerative Medicine (CIRM) and is led by Dr. Keller at Children’s National.

CETI Laboratory at George Washington University

The Children’s National/GW CETI MIMETIC Program focuses on engineering lymphocytes to target HIV and malignancies. The goal of engineering these cells is to confer additional functionalities and resistance against immune suppressive environments. This modification would therefore allow the cells to both persist longer at the site of disease and recruit endogenous immune responses. Currently, the team is modifying HIV-specific T cells, tumor associated antigen specific T cells, and natural killer cells. The laboratory uses nanoparticles, retroviral and lentiviral vectors, and transfection/electroporation to modify these cells.

Cellular Therapy Laboratory

The cellular therapy laboratory (CTL) is responsible for manufacturing cellular therapy products for patients receiving a bone marrow transplant or other novel cell therapies on clinical trials and then using complex immunological assays to correlate treatment with response. To carry out this mission, the CTL is comprised of three parts: 1) The Good Manufacturing Practices (GMP) facility, which manufactures cell therapy products such as T cells for clinical trials; 2) the stem cell processing (SCP) team, which is responsible for standard of care bone marrow transplants; and 3) the Good Laboratory Practices laboratory which performs quality control testing of products manufactured in the GMP and also processes follow-up samples from patients who have been treated with novel therapies. The CTL handles products for more than 100 patients annually and supports over 15 clinical trials, including mesenchymal stromal cells (MSCs) for the treatment of inflammatory bowel disease as well as T cells to treat or prevent HIV, viral complications (CMV, EBV, adenovirus, HHV6, BK virus, and parainfluenza) after transplant from both cord blood and peripheral blood, as well as leukemia, lymphoma, and solid tumors; the GLP processes approximately 800 samples or tests per year.

Bone Marrow Transplantation

Graft-versus-host disease is the main complication of bone marrow transplantation. Developing effective therapy for GVHD, as well as effective ways to diagnose and grade GVHD, have been a formidable challenge. Children’s National investigators have designed and led a number of clinical trials investigating various therapeutic agents to treat GVHD as well as improving outcomes for patients with SCD and other non-malignant disorders such as primary immune deficiencies after transplant. In addition, cell therapy studies utilizing the immune suppressive mesenchymal stromal cells are underway initially in patients with inflammatory bowel disease (led by Dr. Conklin) but then ultimately to be transferred to the post BMT setting.

Clinical Oncology

Pediatric Brain Tumor Consortium

The Pediatric Brain Tumor Consortium (PBTC) was established by the NCI in 1999 to improve the treatment of primary brain tumors in children. The consortium brings together the most prominent pediatric brain tumor programs in the country to perform early phase developmental therapeutic clinical trials. Dr. Hwang serves as the Children’s PI for the PBTC as well as co-chair of the Immunotherapy Working Group; Dr. Kilburn is chair of the Quality Assurance Committee, and Dr. Packer is both on the Steering Committee and is the site co-PI of the PBTC (the latter along with Dr. Rood), as well as lead of the Low-grade Glioma Working Group. In the PBTC, Dr. Hwang is the PI and Dr. Kilburn is the co-PI of a trial utilizing checkpoint inhibition in high-grade pediatric cancers; Dr. Hwang is the PI of a project examining immunophenotypes in pediatric CNS tumors and the co-PI of a trial utilizing the Optune device for children with recurrent high-grade glioma and ependymoma.

COllaborative Network for NEuro-oncology Trials (CONNECT)

The COllaborative Network for NEuro-oncology Trials is a new clinical trials consortium that strives to be both biology-driven as well as fill the gap between preclinical work and Phase I trials. Established by a large foundation initiative in 2017, Children’s has been invited as an inaugural member. Dr. Hwang is the PI for Children’s and Dr. Packer is on the steering committee for this consortium.

National Pediatric Cancer Foundation (NPCF)

Children’s National has recently joined the NPCF in order to lead and participate in trials focused on pediatric brain tumors. This has included the ReMATCH trial, utilizing a dendritic cell vaccine and adoptive cellular therapy in order to target recurrent medulloblastomas.

Children’s Brian Tumor Tissue Consortium

Children’s National is a member of the Children’s Brain Tumor Tissue Consortium (CBTTC), a multi-institutional consortium that banks brain tumor specimens, including blood, buccal swabs, cerebrospinal fluid, and urine, to be accessed by the pediatric brain tumor research community. Each specimen is annotated with clinical data in a continuously updated database. In addition, large data sets resulting from genomic, epigenomic, and proteomic studies of those specimens are housed within the Consortium in a computing environment that allows native analysis in the cloud. The CBTTC data repository, called CAVATICA, is the largest such repository in the world.

Children’s Oncology Group

The clinical oncology research team at Children’s National specializes in treating patients with specific types of cancer, including leukemia, solid tumors, and brain tumors. The research provides innovative treatments and the highest quality of care for each child. Established in 2000, Children’s Oncology Group (COG)’s vision is to eliminate the personal, family, and societal burden of cancer in children and adolescents. Children’s National has a long history of leadership and scientific contributions to the COG. Gregory Reaman, M.D., chief of oncology, emeritus) served as the first chair of the NIH-funded COG until December 2010. Dr. Dome currently serves as the COG PI for Children’s National and served as chair of the COG Renal Tumor Committee for over a decade. He now serves on the COG Scientific Council and Executive Committee, study for standard-risk acute lymphoblastic leukemia (ALL), the largest therapeutic study within the COG. Dr. Bollard is chair of the COG Non-Hodgkin Lymphoma Committee and is co-chair of the ANHL1522 study of Rituximab (RTX) and Cytotoxic T-Lymphocytes in Pediatric Solid Organ Recipients (SOT) with EBV-Positive CD20-Positive Post-Transplant Lymphoproliferative Disease (PTLD). Dr. Meany is the study chair for the COG ANBL1232 study for non-high-risk neuroblastoma. Dr. Jacobs is on the steering committee of the COG Cancer Control Committee, and Dr. Kilburn serves on the Developmental Therapeutics Committee. Dr. Kim is the study chair for the COG APEC1621G study, Pediatric MATCH - Phase 2 subprotocol of Vemurafenib in patients with tumors harboring actionable BRAF V600 mutations. Children’s National is one of a select group of institutions in North America to be included in the COG Phase I Consortium, allowing patients with recurrent and refractory tumors access to the newest agents. Dr. Kim serves as PI in this consortium. Dr. Kim serves as the study chair for APEC1621G, Phase 2 Subprotocol of Vemurafenib in Patients with Solid Tumors, and serves on the Pediatric MATCH Target and Agent Prioritization Committee.

Investigational Lead Early Phase Trials

Dr. Kim serves as the PI of a Phase I study of MR-guided high intensity focused ultrasound (MR-HIFU) for the ablation of recurrent pediatric solid tumors including desmoid tumors. She is also leading a NIH funded Phase 1 Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox) combined with MR-guided high intensity focused ultrasound for relapsed solid tumors in children. These are the first clinical studies using this novel device alone and in combination with temperature sensitive chemotherapy in children. Children’s National is one of the few Children’s Hospitals to participate in the Sarcoma Alliance through Collaboration (SARC) consortium dedicated to achieving breakthroughs in sarcoma research. Dr. Kim serves as the Overall PI of DOD-funded multi-institutional trial of SARC031, phase II study of selumetinib and vistusertib in patients with unresectable malignant peripheral nerve sheath tumors. Dr. Hwang is the co-PI of an international study examining the utility of bevacizumab and vinblastine as front-line therapy for children with low-grade gliomas. He is also the PI of a Children’s-led study testing the use of a novel gene therapy, coupled with irradiation and chemotherapy, to restore p53 function in children with recurrent brain tumors.

Hematology

Investigators in this section are involved in the study of the hematological diseases including treatment of patients with bleeding and clotting disorders, understanding the varied phenotype and evaluating novel therapies for sickle cell disease, and improving the understanding of complications associated with blood transfusions. Dr. Luban leads a team to investigate the adverse consequences of transfusion through epidemiological, clinical, and device or laboratory methods development and evaluation. The multidisciplinary team works in concert with colleagues in the divisions of Hematology, Blood and Marrow transplantation, Critical Care Medicine, and Center for Genetic Medicine Research, the Sheikh Zayed Institute, and colleagues at the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases, the Division of Transfusion Medicine, the American Red Cross, and the FDA.

Sickle Cell Disease

Dr. Campbell focuses his research in understanding the varied phenotypic expression of sickle cell disease in different populations through multinational CASiRe (Consortium for the Advancement of Sickle Cell Disease Research) International Consortium which he directs comprised of:1) Europe -- Italy (University of Padova, University of Naples), and UK (Guys St Thomas) 2) North America -- six sites in the USA, and 3) Africa -- Ghana (Korle Bu Teaching Hospital). The focus of the CASIRE Sickle Cell Research is the “CASIRE Renal Cohort Study” where they are describing the risk factors associated with proteinuria in different sickle cell populations within different ethnic groups and studying the role of the environment on the phenotype of sickle cell disease. Dr. Campbell is also involved in industry sponsored clinical trials in sickle cell disease, including the Voxelotor trial evaluating a novel small molecule drug that prevents the sickling of red blood cells.

Dr. Darbari is studying pain in SCD which is the most common complication of SCD. She is evaluating brain network connectivity patterns and its association with burden of pain experienced by patients and investigating if these connectivity patterns can be used to evaluate therapies in sickle cell. She is also validating brain connectivity changes using electroencephalogram (EEG) in an NIH funded study with Dr. He’s group in Minnesota. Working with colleagues at NIH. Dr. Darbari has evaluated risk factors for persistent pain after reversal by hematopoietic stem cell transplant. Publication emerging from this work shows for the first time the importance of non-hematological SCD factors in maintenance of pain in sickle cell disease after hematologic cure. Working with a multidisciplinary team, including members of anesthesiology, pain psychology, palliative care and others at Children’s National, the team is testing feasibility of non-pharmacologic integrative therapies such as acupuncture in reducing pain burden in patients with SCD.

Dr. Allistair Abraham’s research focuses on improving curative hematopoietic stem cell transplantation for sickle cell disease (SCD). He has recently been awarded the highly competitive American Society of Hematology’s Harold Amos Medical Faculty Development Award, supporting his study of immune mechanisms of rejection in haploidentical transplantation for SCD and will evaluate virus-specific T cell (VST) recovery after transplantation and determine if VST infusions can speed this recovery. Altogether, this work will provide new data to determine how rapid viral protection can be restored for people with SCD undergoing transplantation.

Drs. Abraham, Abraham and Nickel, have recently been awarded the prestigious Doris Duke Charitable Foundation’s inaugural Sickle Cell Disease/AdvancingCuresAwards to forward curative approaches for sickle cell disease. The project is one of seven projects to win support for its potential to significantly improve the only current proven cure for sickle cell disease -- hematopoietic cell transplantation. While transplantation using a matched sibling donor today has a high cure rate (greater than 90 percent) for sickle cell disease, traditional transplant approaches have many risks and side effects in both the short and long term. The study will examine if a chemotherapy-free approach can lead to a successful transplant without resulting in graft-versus-host disease (GVHD). GVHD, in which the transplant immune cells attack the patient’s body, is one of the most challenging complications of a transplant. The researchers anticipate that this new transplant approach will be so well tolerated that patients’ quality of life will be maintained and improved throughout the process, with most of the care administered in a clinic setting.

In addition, Dr. Nickel is evaluating HLA antibody and platelet transfusions related to transplant for sickle cell disease with a Thrasher Research Fund Early Career Award. The primary aim of this study is to investigate if alloimmunization to class I HLA is associated with increased platelet transfusion requirements undergoing HLA-identical bone marrow transplant. He is also involved in a multi-center, NIH/NHLBI-funded grant to evaluate the real world implementation of the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol in which transcranial Doppler (TCD), a measure of cerebral blood vessel velocity, is used to screen for stroke risk in children ages 2-16 with sickle cell disease.

Dr. Majumdar is conducting research in electrocardiographic complications in sickle cell disease. This is an R01 funded joint PI project that evaluates the SCN5A gene and other genetic risk factors for prolonged QT and cardiac arrhythmias to understand why individuals with sickle cell disease are at higher risk of premature death. In addition, Dr. Majumdar is conducting an investigator initiated phase1/2 trial of intravenous citrulline, a powerful nitric oxide booster and vasodilator, as a novel intervention for the treatment of acute pain in sickle cell disease.

Dr. Luban continues her research on transfusion safety and methods to improve transfusion in sickle cell disease. She also chaired an NHLBI meeting whose publication in the journal Transfusion is serving as the benchmark for future NIH and other funding for translational and clinical trials in transfusion in neonatology and pediatrics.

Bleeding Disorders and Coagulopathy

Dr. Guerrera leads a multidisciplinary team that is part of the Mid-Atlantic Region III Federally-funded Hemophilia Treatment Centers working to improve the health of children and adolescents with bleeding disorders. The team is currently involved in a number of clinical trials studying new products to treat and prevent bleeding in patients with hemophilia. In addition, Dr. Guerrera and colleagues are involved in the American Thrombosis Hemostasis Network (ATHN) registries for bleeding and clotting disorders that is looking at inhibitor (antibody) risk from the newer agents. As part of the hemophilia regional network, investigators are looking at standardization and outcomes of surgery in patients with bleeding disorders and participating in the My Life Our Future project which involves genotyping patients and potential carriers with hemophilia A or B. Dr. Diab has established complex anticoagulation assays to assist in the diagnosis and therapy of patients with thrombosis and those with the implantable Berlin Heart. Drs. Diab and Guerrera hold multidisciplinary thrombosis clinics with the evaluation of demographic and outcome data on patients through a contract with the Centers for Disease Control and Prevention to improve therapy for children on Coumadin.

Allergy

The Food Allergy Program at Children’s National Hospital is recognized as a FARE (Food Allergy Research and Education) Clinical Network Center of Excellence. The program provides care to children with food allergies at three clinical sites throughout the Washington metro area. Six allergy faculty and three advanced practice providers deliver care to food allergy patients. In 2017, more than 1,100 new and 2,000 returning food-allergic patients were treated. Over 400 oral food challenges are performed annually.

Program faculty are engaged in various research protocols related to food allergy. Dr. Lin was recently awarded the prestigious American Academy of Allergy, Asthma & Immunology (AAAAI) Foundation Faculty Development Award. She is conducting translational research on the role of B cells and regulatory B cells on the development of food allergy, sensitization, and tolerance.

Dr. Sharma is the PI of four clinical trials of peanut oral immunotherapy, in which Drs. Coleman, Uygungil, Lin and Robbins serve as co-investigators. Drs. Coleman and Sharma are also studying racial differences in food allergy outcomes between African American and Caucasian children as part of a multicenter study funded by an R01 at Northwestern University. In that study, outcomes including health care utilization, allergic reaction frequency, and stool and skin microbiome are being assessed by race in a cohort of 1,000 children with food allergy. Dr. Coleman is also investigating access to specialty care among urban children with food-induced anaphylaxis.

Dr. Uygungil has assembled a cohort of infants with peanut sensitization who have undergone oral food challenges to peanut. She is analyzing demographic, clinical and laboratory predictors of tolerance among that population. She also studies food allergy knowledge among general pediatricians and pediatric residents, and change in knowledge after standardized educational interventions. Dr. Robbins is evaluating nutritional outcomes and growth among children with food allergy.

Immunology/Immunodeficiency

Clinical Immunology

The Clinical Immunology Program is led by Dr. Keller who is the director of the Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiency Disorders. In a notable first for Children’s National, investigators from the Division of Allergy and Immunology and Infectious Disease have begun a joint clinical research program with intramural investigators from the the National Institute for Allergy and Infectious Disease to study primary immunodeficiency disorders, allergic diseases, and Lyme disease. Funded by a grant from the National Center for Advancing Translational Sciences, the program involves direct partnering with NIH investigators to study the mechanistic biology and natural history of these disorders. The Primary Immunodeficiency program, co-lead by Drs. Keller (CCIR) and Luigi Notarangelo (NIAID) has received IRB approval at both institutions and had their first joint clinic at the Friendship Heights Outpatient Center in February 2018.

Clinical Research in Pediatric and Adolescent HIV Infection

Tapping into the strength of their translational and basic research, the faculty’s research collaborations are yielding exciting new insights into the pathogenesis and therapy of childhood cancer, hematological disorders, and immunological diseases. The District of Columbia has the highest rates of HIV infection and AIDS prevalence in the nation, particularly among children and youth. This is the result of an overall high HIV prevalence rate in the community, previous high rates of perinatal transmission, and a growing number of acquired cases of infection. Several investigators are involved in funded research on infection trends and responses to treatment. Dr. Rakhmanina collaborates with investigators at the MedStar Washington Hospital Center to look at the current algorithm used for maternal HIV testing during pregnancy and the use of antiretrovirals as an effective prophylaxis for perinatal HIV transmission. Specifically, Dr. Rakhmanina is interested in determining whether any differences exist in transmission rates between African American women and African immigrant mothers. Dr. Rakhmanina also leads a multidisciplinary team of clinical researchers studying the most efficient mechanism of screening youth in pediatric emergency departments. Finally, her team has also launched a citywide study on prevention of HIV infection in at-risk young women by using pre-exposure prophylaxis. Dr. D’Angelo is involved with ongoing studies with the restructured Adolescent Trials Network, collaborating with investigators in Florida, New York and Maryland to improve medication adherence and treatment outcomes in HIV infected youth. He also collaborates locally with members of the District of Columbia Center for AIDS research to improve the transition of HIV infected youth from pediatric to adult care.

Pathology and Laboratory Medicine

Investigators in this section are involved in technological advancement of testing and diagnosis as well as the pathological basis of disease. Dr. Delaney is an international leader in pediatric transfusion medicine who focuses on decreasing risks of transfusion and investigating the best approach to transfusion of patients who have, or are at risk for, alloimmunization as well as the use of antifibrinolytics to decrease bleeding. As a continued interest, she focuses on transfusion improvement and medical education in developing nations by leading courses and developing sustainable technology in developing nations. She also serves as the chair of the AABB’s the Transfusion Medicine Subsection Pediatric Subcommittee for AABB; and the American Society of Apheresis Applications Committee Pediatric Subcommittee. She is an associate editor for the journal Transfusion Medicine, and on the editorial board of Transfusion. She is an associate scientific member of the BEST Collaborative, an international research and science consortium focused on safer transfusion.

Selected Publications from 17/18