Posts

Epstein Barr virus

Fighting lymphoma with targeted T-cells

Epstein-Barr virus

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

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

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

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

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

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

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

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

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

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

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

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

Holly Meany

TAA-Ts as therapy for tumors

Holly Meany

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

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

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

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

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

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

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

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

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

baby cardioilogy patient

Researchers receive $2.5M grant to optimize brain development in babies with CHD

baby cardioilogy patient

Children’s National Health System researchers Richard Jonas, M.D., Catherine Bollard, M.B.Ch.B., M.D., and Nobuyuki Ishibashi, M.D., have been awarded a $2.5 million, three-year grant from the National Institutes of Health (NIH) to conduct a single-center clinical trial at Children’s National. The study will involve collaboration between the Children’s National Heart Institute, the Center for Cancer and Immunology Research, the Center for Neuroscience Research and the Sheikh Zayed Institute for Pediatric Surgical Innovation.

The goal of the study will be to optimize brain development in babies with congenital heart disease (CHD) who sometimes demonstrate delay in the development of cognitive and motor skills. This can be a result of multiple factors including altered prenatal oxygen delivery, brain blood flow and genetic factors associated with surgery including exposure to the heart lung machine.

The award will be used to complete three specific aims of a Phase 1 safety study as described in the NIH grant:

  • Aim 1: To determine the safety and feasibility of delivering allogeneic bone marrow derived mesenchymal stromal cell (BM-MSC) during heart surgery in young infants less than 3 months of age using the heart lung machine. The optimal safe dose will be determined.
  • Aim 2: To determine the impact of MSC infusion on brain structure using advanced neuroimaging and neurodevelopmental outcomes.
  • Aim 3: To determine differences in postoperative inflammatory and patho-physiological variables after MSC delivery in the infant with CHD.

“NIH supported studies in our laboratory have shown that MSC therapy may be extremely helpful in improving brain development in animal models after cardiac surgery,” says Dr. Ishibashi. “MSC infusion can help reduce inflammation including prolonged microglia activation that can occur during surgery that involves the heart lung machine.”

In addition the researchers’ studies have demonstrated that cell-based intervention can promote white matter regeneration through progenitor cells, restoring the neurogenic potential of the brain’s own stem cells that are highly important in early brain development.

The Phase 1 clinical trial is being implemented in two stages beginning with planning, regulatory documentation, training and product development. During the execution phase, the trial will focus on patient enrollment. Staff from the Cellular Therapy Laboratory, led by director Patrick Hanley, Ph.D., manufactured the BM-MSC at the Center for Cancer and Immunology Research, led by Dr. Bollard. The Advanced Pediatric Brain Imaging Laboratory, led by Catherine Limperopoulos, Ph.D., will perform MR imaging.

The phase 1 safety study will set the stage for a phase 2 effectiveness trial of this highly innovative MSC treatment aimed at reducing brain damage, minimizing neurodevelopmental disabilities and improving the postoperative course in children with CHD. The resulting improvement in developmental outcome and lessened behavioral impairment will be of enormous benefit to individuals with CHD.

Catherine Bollard

Engineering TGFB receptor to enhance NK cells and fight neuroblastoma

Catherine Bollard

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

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

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

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

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

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

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

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

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

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

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

Eugene Hwang in an exam room

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

Eugene Hwang in an exam room

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

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

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

For more information about this trial, contact:

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

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

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

tubes filled with pink liquid

Manufacturing technologies lag behind breakthroughs in CAR-T cancer treatment

tubes filled with pink liquid

Drug companies around the country are banking on the cutting-edge cancer treatments known as CAR-T, but many manufacturing processes are holding back the treatment from reaching the market. With the success of CAR-T, which essentially re-trains T Cells to identify and target the cancer-causing cells, many manufacturers still need to catch up in the development process.

Currently, there are nearly 700 CAR-T studies in the database ClinicalTrials.gov, including 152 industry-sponsored trials that are active, recruiting or enrolling by invitation. According to market research firm, Coherent Market Insights, they predict the CAR-T market will grow to $8 billion worldwide by 2028 from $168 million in 2018.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National Health System, was featured in a recent Bloomberg Law article stating that academics, industry participants and medical product regulators are trying to catch up with the technology and determine the best standards for developing these products. Although this is an exciting and positive time in the field of oncology, it also presents a big learning curve.

Making these cells requires extracting patients T cells. They are then genetically engineered in a laboratory to produce proteins that allow them to identify cancer-causing cells. The new cells are then multiplied and then reintroduced into the body to kill off the cancer cells. The entire process can take a few weeks to complete.

“This is not a drug,” Bollard said. “This is a living biologic, and it comes from the patient and individuals. There’s so much variability.”

Along with manufacturing challenges, the outlook on creating more therapies is looking good. The FDA predicts that it will be approving 10 to 20 gene therapy products a year by 2025. Other companies are working to develop a manufacturing platform that can help reduce the complexity of the current system and ultimately make CAR-T manufacturing easier to scale.

American Society of Hematology logo

Leading blood disorder experts from Children’s National convene in Atlanta for 59th American Society of Hematology annual meeting

In early December 2017, more than 25,000 attendees from around the world, including several experts from Children’s National Health System, convened in Atlanta for the American Society of Hematology’s annual meeting and exposition, the world’s premiere hematology event. For four days, physicians, nurses and other healthcare professionals attended sessions, listened to speakers and collaborated with each other, focusing on enhancing care and treatment options for patients with blood disorders and complications, including leukemia, sickle cell disease and transplants.

As nationally recognized leaders in the field, the Children’s National team led educational sessions and gave keynote speeches highlighting groundbreaking work underway at the hospital, which sparked engaging and productive conversations among attendees. Highlights from the team include:

  • Catherine Bollard, M.D., M.B.Ch.B., Director of the Center for Cancer and Immunology Research, educating global experts on cellular immunotherapy for non-Hodgkin lymphoma.
  • Kirsten Williams, M.D., bone and marrow transplant specialist, presenting novel work utilizing TAA-specific T cells for hematologic malignancies with Dr. Bollard, the sponsor of this first-in-man immunotherapy; moderating sessions on immunotherapy and late complications and survivorship after hematopoietic stem cell transplantation (HSCT).
  • Allistair Abraham, M.D., blood and marrow transplantation specialist, moderating a session on hemoglobinopathies.
  • David Jacobsohn, M.D., ScM, Division Chief of Blood and Marrow Transplantation, moderating a session on allogeneic transplantation results.
  • Naomi Luban, M.D., hematologist and laboratory medicine specialist, introducing a plenary speaker on the application of CRISPR/Cas 9 technology for development of diagnostic reagents for diagnosis of alloimmunization from stem cells.

Additional presentations from the Children’s National team included an oral abstract on the hospital’s work to improve hydroxyurea treatment for sickle cell disease by pediatric resident Sarah Kappa, M.D., who also received an ASH Abstract Achievement Award; another key session on hemoglobinopathies moderated by Andrew Campbell, M.D., director of the Comprehensive Sickle Cell Disease Program; an abstract on the clinical use of CMV- specific T-cells derived from CMV-native donors, presented by Patrick Hanley, Ph.D.; a leukemia study presented by Anne Angiolillo, M.D., oncologist; and a presentation about pain measurement tools in sickle cell disease by Deepika Darbari, M.D., hematologist.

Visit the ASH website to learn more about the conference attendees and their research.

Combined FACT accreditation related to cellular immunotherapy spotlights Children’s ongoing commitment to revolutionary cancer therapies

DNA strand and Cancer Cell

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.”

Catherine-Bollard-SIOP

Advancing cures for pediatric cancer: Highlights from leading Children’s National experts at SIOP 2017

In mid-October 2017, nearly 2,000 clinicians, scientists, nurses, health care professionals and cancer patients and survivors gathered in Washington, D.C., for SIOP 2017, the Annual Congress of the International Society of Paediatric Oncology. For four days, attendees heard from world-renowned experts while exchanging ideas and information, all in the name of advancing cures for childhood cancer.

Hosted in the hometown of Children’s National Health System and chaired by Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders and Chief of Oncology at Children’s National Health System, more than 20 doctors and nurses from Children’s National made an impact on participants through a series of widely attended sessions and addresses, including:

  • Symposium lecture on the latest approaches in anti-viral T-cell therapy to improve patient outcomes, given by Catherine Bollard, M.D., M.B.Ch.B.
  • Keynote lecture on DICER1 mutations in pediatric cancer, given by Ashley Hill, M.D., whose study of a rare childhood lung cancer and gene mutations set the stage for a better understanding of microRNA processing gene mutations in the development of pediatric cancer.
  • Education session on new therapies for sarcomas, led by AeRang Kim, M.D., Ph.D., and Karun Sharma, M.D., Ph.D., sharing research on new approaches for local control of sarcomas, such as surgery, radiation and other ablative measures.
  • Education session on new therapies for gliomas, led by Roger J. Packer, M.D., with presentations on immunotherapy from Eugene Hwang, M.D., and targeted therapy by Lindsay Kilburn, M.D.
  • Podium paper presentation on a new method to measure cancer treatment toxicities as reported by the child by Pamela Hinds, Ph.D., RN, FAAN, as well as an education session on advanced care planning, led by Hinds with a presentation from Maureen E. Lyon, Ph.D.

“These sessions and lectures provided a glimpse into the groundbreaking work by SIOP attendees from around the world,” says Dr. Dome. “Children’s National is proud to play an active role in the development of life-saving treatments for children with cancer and our clinicians look forward to another year of revolutionary developments.”

For more on this year’s SIOP, see the Children’s National press release.

  • Jeffrey Dome, M.D., Ph.D., addresses a group of international colleagues at a reception at Children’s National.

    Jeffrey Dome SIOP
  • Catherine Bollard, M.D., M.B.Ch.B., addresses a group of international colleagues at a reception at Children’s National.

    Catherine-Bollard-SIOP
  • Lindsay Kilburn, M.D., engages with peers from around the world at a reception at Children’s National.

    Lindsay-Kilburn-SIOP

Catherine Bollard and Hemant Sharma

Nationally recognized immunotherapy and pathology experts take on new leading roles at Children’s National

Catherine Bollard and Hemant Sharma

Catherine Bollard, M.D., M.B.Ch.B., has been chosen to serve as director of the Children’s Research Institute’s Center for Cancer and Immunology Research and Hemant Sharma, M.D., M.H.S., will assume the role of chief of the Division of Allergy and Immunology.

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.”

Meghan Delaney

Nationally recognized laboratory medicine expert Meghan Delaney, D.O., M.P.H., has joined Children’s National as chief of pathology and lab medicine.

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.”

Children’s National Chief of Allergy and Immunology helps move gene therapy forward

Catherine Bollard

Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology, recently shared her expertise on an FDA panel that unanimously expressed its support for a pediatric cancer T-cell therapy called CTL019.

On July 12, 2017, a U.S. Food and Drug Administration advisory committee unanimously expressed its support for CTL019 – a pediatric cancer T-cell therapy. If the FDA follows the advice from the 10-member Oncologic Drug Advisory Committee (ODAC) – which included Children’s National Health System’s Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology and Director of the Program for Cell Enhancement and Technologies for Immunotherapy – CTL019 will become the first gene therapy to hit the market.

“Many of these children with recurrent cancer are out of other options to treat their illness,” said Dr. Bollard. “We are encouraged by these findings and the potential for this therapy to improve outcomes and quality of life.”

CTL019 is a chimeric antigen receptor (CAR) T-cell therapy, comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells. Also known as tisagenlecleucel, the therapy targets a single type of cancer called acute lymphoblastic leukemia and was created by Novartis.

In clinical trials, CTL019 showed unparalleled effectiveness. Of the 68 patients who received the drug, 52 responded almost immediately, and their cancer disappeared within the first three months. Seventy-five percent of those patients remained cancer-free six months after treatment. The therapy has one main side effect: an immune reaction called cytokine release syndrome, which can be deadly, with extended spiking fevers and other symptoms.

However, because of CTL019’s high efficacy, FDA scientists asked the ODAC panel to focus on the therapy’s safety and manufacturing challenges rather than whether or not it works.

Several committee members, including Dr. Bollard, expressed apprehension about the T-cell subpopulations’ heterogeneity, which could affect safety and efficacy. Another issue for consideration by the ODAC panel was the long-term side effects of CTL019 and the possibility that the T-cell modification could go awry, causing secondary cancers in the future.

Despite these concerns, the committee concluded that the strong efficacy data and the near-term benefits of CAR-T therapy more than tipped the scales in favor of the therapy. ODAC members were also pleased with Novartis’ plan to minimize risk, which includes limiting CTL019 distribution to selected centers with CAR T-cell therapy experience, and extensive, long-term post-marketing surveillance plans.

The FDA is not required to follow the ODAC panel’s advice when making its final decision, but it often does so. A final decision by the FDA is anticipated by late September.

Read more about the story in the Philadelphia Inquirer, Medpage Today and Healio.com.

SIOP-Kim, Bollard, and Hill

17 Children’s doctors featured at SIOP

SIOP-Kim, Bollard, and Hill

AeRang Kim, M.D., Ph.D., Catherine Bollard, M.D., MBChB, and D. Ashley Hill, M.D. are among the Children’s National experts who will be speaking at the 49th Congress of the International Society of Pediatric Oncology.

This October, thousands of pediatric oncologists, researchers, nurses, allied health professionals, patients and survivors will gather in Washington, D.C., for the 49th Congress of the International Society of Pediatric Oncology (SIOP). Chaired by Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders and Chief of Oncology at Children’s National Health System, and Stephen P. Hunger, M.D., of the Children’s Hospital of Philadelphia, the meeting will feature talks by renowned experts in pediatric oncology, including 17 doctors from Children’s National.

Among these expert speakers are AeRang Kim, M.D., Ph.D., pediatric oncologist and Associate Professor of Pediatrics at the George Washington University School of Medicine & Health Sciences, who will present her latest research on new approaches to local control of sarcomas as part of the SIOP Education Day. Dr. Kim focuses on the development of novel agents and devices for pediatric cancer including pre-clinical testing of novel agents, pharmacokinetic analysis, developing innovative methods for toxicity monitoring and clinical trial design.

Also speaking is Catherine Bollard, M.D., MBChB, Chief of the Division of Allergy and Immunology at Children’s National, Professor of Pediatrics and of Microbiology, Immunology and Tropical Medicine at the George Washington University School of Medicine & Health Sciences and Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI). Dr. Bollard will present a talk as part of the SIOP-St. Baldrick’s Symposium on Cell Therapy for Viral Infections.  Her translational research focuses on developing and applying novel cell therapies to improve outcomes for patients with viral infections, cancer and immunologic disorders.

And, D. Ashley Hill, M.D., Chief of the Division of Anatomic Pathology and Professor of Pathology and Pediatrics at the George Washington University School of Medicine & Health Sciences, will be giving a keynote address on DICER1 mutations in pediatric cancer. Dr. Hill first reported the connection between pleuropulmonary blastoma, a rare childhood lung tumor, and mutations in DICER1, setting the stage for our understanding of microRNA processing gene mutations in the development of pediatric cancer.

Other speakers, session chairs and abstract presenters from Children’s National include:

  • Anne L. Angiolillo, M.D., M.Sc., Director of the Leukemia/Lymphoma Program at Children’s National Health System
  • Kristina K. Hardy, Ph.D., Pediatric Psychologist at Children’s National Health System
  • Pamela Hinds, R.N., Ph.D., F.A.A.N., Director of Nursing Research and Quality Outcomes at Children’s National Health System
  • Eugene Hwang, M.D., Director of the Clinical Neuro-oncology Immunotherapeutics Program at Children’s National Health System
  • Robert Keating, M.D., Chief of Neurosurgery at Children’s National Health System
  • Lindsay Kilburn, M.D., Neuro-oncologist at Children’s National Health System
  • Matthew Ladra, M.D., Pediatric Radiation Oncologist for the Johns Hopkins and Children’s National Pediatric Cancer Care collaborative program at Sibley Memorial Hospital
  • Maureen Lyon, Ph.D., Psychologist at Children’s National Health System
  • Holly Meany, M. D., Director of the Solid Tumor Program at Children’s National Health System
  • Marie Nelson, M.D., Oncologist at Children’s National Health System
  • Roger J. Packer, M.D., Senior Vice-President of the Center for Neuroscience and Behavioral Medicine, Director of the Gilbert Neurofibromatosis Institute and the Brain Tumor Institute at Children’s National Health System
  • Karun Sharma, M.D., Director of Interventional Radiology at Children’s National Health System
  • Carly Varela, M.D., Oncologist at Children’s National Health System

Advances in T-cell immunotherapy at ISCT

Healthy Human T Cell

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.

Catherine Bollard named to Medicine Maker’s Annual Power List

Catherine Bollard

Children’s National Health System’s Chief of Allergy and Immunology, Catherine Bollard M.D., has been named to The Medicine Maker’s 2017 Power List, which honors the top 100 most influential people in the world of drug development. Dr. Bollard is featured as a ”Champion of Change,” a category that highlights experts striving to make the world a better place by getting medicines to those who need them the most. She joins notable scientists Frances Collins, director of the U.S. National Institutes of Health, and Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

In the Medicine Maker feature, Dr. Bollard describes the inspiration behind her dedication to cellular immunotherapy and how that led to her team’s breakthrough T-cell therapy that gives complete remissions in over 50 percent of some patient groups. Read the full piece here.

Cell therapy virtuoso: Catherine Bollard

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.

cord blood

T-cell therapy success for relapsing blood cancer

cord blood

A unique immunotherapeutic approach that expands the pool of donor-derived lymphocytes (T-cells) that react and target three key tumor-associated antigens (TAA) is demonstrating success at reducing or eliminating acute leukemias and lymphomas when these cancers have relapsed following hematopoietic stem cell transplant (HSCT).

“There’s currently a less than 10 percent chance of survival for a child who relapses leukemia or lymphoma after a bone marrow transplant—in part because these patients are in a fragile medical condition and can’t tolerate additional intense therapy,” says Kirsten Williams, M.D., a blood and marrow transplant specialist in the Division of Hematology at Children’s National Health System, and principal investigator of the Research of Expanded multi-antigen Specifically Oriented Lymphocytes for the treatment of VEry High Risk Hematopoietic Malignancies (RESOLVE) clinical trial.

The unique manufactured donor-derived lymphocytes used in this multi-institutional Phase 1 dose-ranging study are receptive to multiple tumor-associated antigens within the cell, including WT1, PRAME, and Survivin, which have been found to be over-expressed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), B-cell AML/MDS, B-cell acute lymphoblastic leukemia (ALL), and Hodgkins lymphoma. Modifying the lymphocytes for several antigens, rather than a single target, broadens the ability of the T-cells to accurately target and eradicate cancerous cells.

Preliminary results demonstrate a 78 percent response rate to treatment, and a 44 percent rate of total remission for participating patients. To date, nine evaluable patients with refractory and relapsed AML/MDS, B-cell ALL, or Hodgkins lymphoma have received 1-3 infusions of the expanded T-cells, and of those, seven have responded to the treatment, showing reduction in cancer cells after infusion with little or no toxicity. All of these patients had relapse of their cancer after hematopoietic cell transplantation. The study continues to recruit eligible patients, with the goal of publishing the full study results within the next 12 months.

“Our preliminary data also shows that this new approach has few if any side effects for the patient, in part because the infused T-cells target antigens that are found only in cancer cells and not found in healthy tissues,” Dr. Williams notes.

The approach used to expand existing donor-derived TAA-lymphocytes, rather than using unselected T cells or genetically modified T-cells as in other trials, also seems to reduce the incidence of post infusion graft versus host disease and other severe inflammatory side effects. Those side effects typically occur when the infused lymphocytes recognize healthy tissues as foreign and reject them or when the immune system reacts to the modified elements of the lymphocytes, she adds.

“These results are exciting because they may present a truly viable option for the 30 to 40 percent of children who will relapse post-transplant,” Dr. Williams concludes. “Many of the patients who participated were given two options: palliative care or this trial. To see significant success and fewer side effects gives us, and families with children facing relapsing leukemia, some hope for this new treatment.”

Dr. Williams discussed the early outcomes of the RESOLVE trial during an oral presentation at the American Society for Blood and Marrow Transplantation meeting on February 22, 2017.

“The early indicators are very promising for this patient population,” says Catherine Bollard, M.D., M.B.Ch.B., Chief of the Division of Allergy and Immunology, Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, and senior author of the study. “If we can achieve this, and continue to see good responses with few side effects, it’s possible these methods could become a viable alternative to HSCT for patients with no donor match or who aren’t likely to tolerate transplant.”

This is one of the first immunotherapeutic approaches to successfully capitalize on the natural ability of human T-cells to kill cancer, though previous research has shown significant success for this approach in reducing the deadly impact of several viruses, including Epstein-Barr virus, adenovirus, and cytomegalovirus, post HSCT. These new findings have led to the development of additional clinical trials to investigate applications of this method of TAA-lymphocyte manufacture and infusion for pre-HSCT MDS/AML, B-cell ALL, Hodgkins Lymphoma, and even some solid tumors.

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

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

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

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

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

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

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

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

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

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

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

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

Related Resources: Research at a Glance

Training t-cells, essential players in the immune system, to fight a trio of viruses

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

What’s Known
Following treatment, patients with leukemia, lymphoma, and other cancers may receive a transplant in order to restore their body’s natural ability to fight infection and, sometimes, such transplants are a component of leukemia treatment. (Leukemia is the second most common blood cancer, after lymphoma, and its incidence rate has increased by 0.2 percent annually from 2002 to 2011.) A stem cell or cord blood transplant restores the body’s ability to produce infection-fighting white blood cells. After such transplants, however, patients can face heightened risk of developing a life-threatening infection with such viruses as adenovirus, cytomegalovirus, or Epstein-Barr virus.

What’s New
A head-to-head comparison of two strategies to thwart such viral infections shows that both approaches leverage the power of multivirus-specific, donor-derived T-cells (mCTL), which are highly skilled at recognizing foreign invaders. The research team, made up of nine scientists and clinicians affiliated with Children’s National Health System, grew personalized T-cells from peripheral blood (PB) of adult donors who were seropositive for CMV and also coaxed T-cells to grow from naïve cord blood (CB). PB-derived cells have long memories of past battles; naïve CB-derived cells need additional training to acquire such skills. From 35 to 384 days after their stem cell or cord blood transplant, 13 patients were infused with PB mCTL and 12 patients were infused with CB mCTL. Within four weeks, patients experienced up to a 160-fold increase in virus-specific T-cells, which coincided with their response to therapy. Overall response rate was 81 percent.

Questions for Future Research
Q: Could T-cells be personalized to attack other viruses that infect patients post-transplant, such as human parainfluenza virus and BK polyomavirus, providing the potential to target five viruses in a single infusion?
Q: Could the proteins that are used to train T-cells to attack certain viruses also be used to create a personalized approach to tumor suppression?

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.