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Vittorio Gallo and Mark Batshaw

Children’s National Research Institute releases annual report

Vittorio Gallo and Marc Batshaw

Children’s National Research Institute directors Vittorio Gallo, Ph.D., and Mark Batshaw, M.D.

The Children’s National Research Institute recently released its 2019-2020 academic annual report, titled 150 Years Stronger Through Discovery and Care to mark the hospital’s 150th birthday. Not only does the annual report give an overview of the institute’s research and education efforts, but it also gives a peek in to how the institute has mobilized to address the coronavirus pandemic.

“Our inaugural research program in 1947 began with a budget of less than $10,000 for the study of polio — a pressing health problem for Washington’s children at the time and a pandemic that many of us remember from our own childhoods,” says Vittorio Gallo, Ph.D., chief research officer at Children’s National Hospital and scientific director at Children’s National Research Institute. “Today, our research portfolio has grown to more than $75 million, and our 314 research faculty and their staff are dedicated to finding answers to many of the health challenges in childhood.”

Highlights from the Children’s National Research Institute annual report

  • In 2018, Children’s National began construction of its new Research & Innovation Campus (CNRIC) on 12 acres of land transferred by the U.S. Army as part of the decommissioning of the former Walter Reed Army Medical Center campus. In 2020, construction on the CNRIC will be complete, and in 2012, the Children’s National Research Institute will begin to transition to the campus.
  • In late 2019, a team of scientists led by Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, traveled to the Democratic Republic of Congo to collect samples from 60 individuals that will form the basis of a new reference genome data set. The researchers hope their project will generate better reference genome data for diverse populations, starting with those of Central African descent.
  • A gift of $5.7 million received by the Center for Translational Research’s director, Lisa Guay-Woodford, M.D., will reinforce close collaboration between research and clinical care to improve the care and treatment of children with polycystic kidney disease and other inherited renal disorders.
  • The Center for Neuroscience Research’s integration into the infrastructure of Children’s National Hospital has created a unique set of opportunities for scientists and clinicians to work together on pressing problems in children’s health.
  • Children’s National and the National Institute of Allergy and Infectious Diseases are tackling pediatric research across three main areas of mutual interest: primary immune deficiencies, food allergies and post-Lyme disease syndrome. Their shared goal is to conduct clinical and translational research that improves what we know about those conditions and how we care for children who have them.
  • An immunotherapy trial has allowed a little boy to be a kid again. In the two years since he received cellular immunotherapy, Matthew has shown no signs of a returning tumor — the longest span of time he’s been tumor-free since age 3.
  • In the past 6 years, the 104 device projects that came through the National Capital Consortium for Pediatric Device Innovation accelerator program raised $148,680,256 in follow-on funding.
  • Even though he’s watched more than 500 aspiring physicians pass through the Children’s National pediatric residency program, program director Dewesh Agrawal, M.D., still gets teary at every graduation.

Understanding and treating the novel coronavirus (COVID-19)

In a short period of time, Children’s National Research Institute has mobilized its scientists to address COVID-19, focusing on understanding the virus and advancing solutions to ameliorate the impact today and for future generations. Children’s National Research Institute Director Mark Batshaw, M.D., highlighted some of these efforts in the annual report:

  • Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research, is looking at whether or not the microbiome of bacteria in the human nasal tract acts as a defensive shield against COVID-19.
  • Catherine Bollard, M.D., MBChB, director of the Center for Cancer and Immunology Research, and her team are seeing if they can “train” T cells to attack the invading coronavirus.
  • Sarah Mulkey, M.D., Ph.D., an investigator in the Center for Neuroscience Research and the Fetal Medicine Institute, is studying the effects of, and possible interventions for, coronavirus on the developing brain.

You can view the entire Children’s National Research Institute academic annual report online.

T cell

Clinical Trial Spotlight: Is more really better? Dose escalation of multi-antigen targeted T cells to illicit a more robust response

T cell

As the promise of immunotherapy in treating patients with cancer becomes more evident, physician researchers at Children’s National are pushing the needle further along. Holly Meany, M.D., is leading a Phase 1 dose-escalation trial to determine the safety and efficacy of administering rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA CTL) to patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) or traditional therapy for a high-risk solid tumor due to the presence of refractory, relapsed and/or residual detectable disease.

“In the escalation portion of our trial, we found that the highest dose evaluated did not have unfavorable toxicity in these patients and is our recommended dose,” Dr. Meany said. “Our next step is an expansion of the trial in five distinct disease categories – Wilms tumor, neuroblastoma, rhabdomyosarcoma, adenocarcinoma and esophageal carcinoma – to examine efficacy on a broader level at the recommended dose.”

Dr. Meany and fellow research clinicians at Children’s National will evaluate not only what happens to the patients when given the additional dosage, but also what happens to the cells – How long will they last? Will they remain targeted against the same antigens or will they shift to target other proteins?

This novel trial is currently enrolling patients at Children’s National Health System in Washington, D.C.

  • PI: Holly Meany, M.D.
  • Title: Research Study Utilizing Expanded Multi-antigen Specific Lymphocytes for the Treatment of Solid Tumors (REST)
  • Status: Currently enrolling

For more information about this trial, contact:

Holly Meany, M.D.
202-476-5697
hmeany@childrensnational.org 

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

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

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.

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.