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Tailored T-cell therapies neutralize viruses that threaten kids with PID

November 18, 2019

t-cells

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children’s National Hospital faculty.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National and the study’s senior author, presented the teams’ findings Nov. 8, 2019, during a second-annual symposium jointly held by Children’s National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children’s National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings.

According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person’s immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person’s missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body’s infection-fighting white blood cells, the Children’s National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3).

Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

Three patients were treated for active CMV, and the T-cells resolved their viremia.
Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.
Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses.

“These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections,” says Michael Keller, M.D., a pediatric immunologist at Children’s National and the lead study author. “Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients.”

In addition to Drs. Bollard and Keller, additional study authors include Katherine Harris M.D.; Patrick J. Hanley Ph.D., assistant research professor in the Center for Cancer and Immunology; Allistair Abraham, M.D., a blood and marrow transplantation specialist; Blachy J. Dávila Saldaña, M.D., Division of Blood and Marrow Transplantation; Nan Zhang Ph.D.; Gelina Sani BS; Haili Lang MS; Richard Childs M.D.; and Richard Jones M.D.

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Children’s National-NIAID 2019 symposium presentations

“Welcome and introduction”
H. Clifford Lane, M.D., director of NIAID’s Division of Clinical Research

“Lessons and benefits from collaboration between the NIH and a free-standing children’s hospital”
Marshall L. Summar, M.D., director, Rare Disease Institute, Children’s National

“The hereditary disorders of PropionylCoA and Cobalamin Metabolism – past, present and future”
Charles P. Venditti, M.D., Ph.D., National Human Genome Research Institute Collaboration

“The road(s) to genetic precision therapeutics in pediatric neuromuscular disease: opportunities and challenges”
Carsten G. Bönnemann, M.D., National Institute of Neurological Disorders and Stroke

“Genomic diagnostics in immunologic diseases”
Helen Su, M.D., Ph.D., National Institute of Allergy and Infectious Diseases

“Update on outcomes of gene therapy clinical trials for X-SCID and X-CGD and plans for future trials”
Harry Malech, M.D., National Institute of Allergy and Infectious Diseases

“Virus-specific T-cell therapies: broadening applicability for PID patients”
Catherine Bollard, M.D., Children’s National

“Using genetic testing to guide therapeutic decisions in Primary Immune Deficiency Disease”
Vanessa Bundy, M.D., Ph.D., Children’s National

Panel discussion moderated by Lisa M. Guay-Woodford, M.D.
Drs. Su, Malech, Bollard and Bundy
Morgan Similuk, S.C.M., NIAID
Maren Chamorro, Parent Advocate

“Underlying mechanisms of pediatric food allergy: focus on B cells
Adora Lin, M.D., Ph.D., Children’s National

“Pediatric Lyme outcomes study – interim update”
Roberta L. DeBiasi, M.D., MS, Children’s National

“Molecular drivers and opportunities in neuroimmune conditions of pediatric onset”
Elizabeth Wells, M.D., Children’s National

Fighting lymphoma with targeted T-cells

August 28, 2019

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

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

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

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

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

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

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

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

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

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

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

Research and Education Week honors innovative science

April 19, 2019

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

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

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

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

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

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

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

Here are the 2019 REW award winners:

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

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

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

Ninth Annual Research and Education Week Poster Session Awards

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

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

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

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

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

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

View images from the REW2019 award ceremony.