Tag Archive for: Bollard

teenager receiving an intravenous infusion

Novel cell therapy treatments offer promise to immune-compromised children

teenager receiving an intravenous infusion

In a first-of-its-kind clinical trial, researchers found that intravenous therapies made from virus-specific T-cells (VST) can effectively treat immunocompromised pediatric patients, far surpassing the current standard of care, according to new research published in Nature Communications.

More than 60% of patients in the phase 2 clinical trial led by investigators from Children’s National Hospital and Huntsman Cancer Institute responded to the innovative VST therapy. This new treatment uses blood from healthy donors to manufacture a highly specialized immune therapy that, when given to immune-compromised patients, prompts their immune system to fight off potentially life-threatening viruses, including cytomegalovirus, Epstein-Barr and adenovirus. Without this therapy, estimates suggest that less than 30% of patients would recover, using standard protocols.

“A vast majority of our patients not only responded to the therapy, but they were able to come off their antivirals, which come with extensive side effects,” said Michael Keller, M.D., the paper’s first author and the Translational Research Laboratory director at the Children’s National Cell Enhancement and Technologies for Immunotherapy (CETI) program. “This promising data suggests hope for patients with rare immune-compromising diseases that leave them vulnerable to so much in the world.”

The study brings together experts from the Pediatric Transplantation and Cell Therapy Consortium (PTCTC) and the Primary Immune Deficiency Treatment Consortium (PIDTC) to create the first multi-center, pediatric-consortium trial of adoptive T-cell therapies for viruses. It also represents one of the first to include critically ill patients, who are often excluded from research.

Children’s National leads the way

Working alongside Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research (CCIR), Dr. Keller and the CCIR team helped build an internationally recognized program, pioneering therapies to prevent complications from viral infections in immunocompromised patients. This includes patients with congenital immune deficiency and others who have undergone bone marrow transplantation for malignancies or non-malignant conditions, such as sickle cell disease.

While doctors can treat some immune-compromised patients for infections with standard antivirals, a small fraction don’t respond. Children’s National is one of a handful of hospitals in the country that has options. Over the last several decades, researchers have found ways to develop VST therapies made from banked T-cells, a more advanced application of how donated red blood cells are used to treat anemia.

In 2017, Drs. Keller and Bollard started collaborating with Michael Pulsipher, M.D.—now with Intermountain Primary Children’s Hospital and the Huntsman Cancer Institute at the University of Utah—to create a multi-institute clinical study. They combined the expertise at Children’s National in producing and banking cell therapy products with the community built around the PTCTC. Ultimately, they launched a clinical trial that was open to 35 centers in the U.S., enrolling 51 patients at 22 hospitals from 2018-2022.

“We wanted to prove that this potentially life-saving therapy could be given safely at regional pediatric centers that had never been able to use this approach before,” said Dr. Pulsipher, who served as the study’s co-principal investigator with Dr. Keller. “We united top experts in this area from the PTCTC and PIDTC and successfully treated some of the most challenging patients ever treated with this approach. Our findings helped define who can benefit the most from this therapy, paving the way for commercial development.”

The Good Manufacturing Practices (GMP) laboratory at Children’s National, led by Patrick Hanley, Ph.D., provided suitable VST therapies for 75 of 77 patients who requested to join the study. Clinical responses were achieved in 62% of patients who underwent stem cell transplants and in 73% of patients who were treated with VST and evaluated one month after their infusion. The paper laid out risks and clinical factors impacting outcomes when third-party donors are used to manufacture the VST therapies.

What’s ahead

Given that researchers are only beginning to develop cell therapies, work remains to understand the many ways they interact with the immune system. In a separate paper also recently published in Nature Communications, members of the multi-institute team documented a case of an infant with severe combined immune deficiency, who faced extremely rare side effects when the VST treatment interfered with her donor bone marrow graft. The case led the team to work with the Food and Drug Administration to identify criteria for VST donors enrolled in this study to mitigate complications.

In the decade ahead, Dr. Bollard sees promise in cell therapies for patients with cancer, immune deficiencies after transplant and dozens of other disorders, including genetic and autoimmune diseases. “Future studies will continue to look at ways to optimize the manufacturing, the administration and the long-term outcomes for these therapies—and to enhance the lifelong impact on our patients,” she said. “When we pair human ingenuity with the power of technology, I see tremendous potential.”

Acknowledgments: This study was funded with a nearly $5 million grant from the California Institute of Regenerative Medicine and was run through the operations center at the Children’s Hospital of Los Angeles, where Dr. Pulsipher was formerly on faculty.

The international NexTGen team

NexTGen team assembles to delve into progress on CAR T-cell therapies

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The international NexTGen team assembled at the Children’s National Research & Innovation Campus for their annual meeting to share progress made in their first full year of work on the $25-million Cancer Grand Challenge, focused on creating a CAR T-cell therapy for pediatric solid tumors.

“It was invigorating to bring the whole team together from our eight institutions in the U.S., U.K. and France, as we uncover opportunities in our research and share the headway that we have made,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research and interim chief academic officer at Children’s National Hospital. “Breakthroughs happen when Team Science collaborates, and that is exactly what is happening here with the NexTGen team.”

Why we’re excited

Over the course of two days, more than 85 team members met to discuss the six work packages that are coming together, with the ambitious goal of making CAR T-cell therapies the standard of care for solid tumors within the next decade:

  • Discovery of new targets
  • The tumor microenvironment
  • Component engineering
  • Integration and modeling
  • Clinical studies
  • Data integration

Each work package includes a patient advocate – individuals with a personal connection to cancer as a family member or survivor – who offers their invaluable perspectives on the research and treatment process. Many attended the meeting, sitting alongside the oncologists, immunologists, mathematicians, molecular biologists and other leading experts.

The big picture

The Cancer Grand Challenges are funded by grants from the National Cancer Institute, Cancer Research U.K. and the Mark Foundation for Cancer Research. Their goal is to drive progress against cancer by empowering global leaders in the research community to take on tough challenges and think differently.

“They call it a ‘grand challenge’ for a reason,” Dr. Bollard said. “It’s going to take the effort and expertise of all these individuals to make a new therapy a reality. I have confidence that we can do it.”

Winners of the International Conference on Medical Image Computing and Computer Assisted Intervention

AI team wins international competition to measure pediatric brain tumors

Winners of the International Conference on Medical Image Computing and Computer Assisted Intervention
Children’s National Hospital scientists won first place in a global competition to use artificial intelligence (AI) to analyze pediatric brain tumor volumes, demonstrating the team’s ground-breaking advances in imaging and machine learning.

During the International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI), the Children’s National team demonstrated the most accurate algorithm to study the volume of brain tumors – the most common solid tumors affecting children and adolescents and a leading cause of disease-related death at this young age. The technology could someday help oncologists understand the extent of a patient’s disease, quantify the efficacy of treatments and predict patient outcomes.

“The Brain Tumor Segmentation Challenge inspires leaders in medical imaging and deep learning to try to solve some of the most vexing problems facing radiologists, oncologists, computer engineers and data scientists,” said Marius George Linguraru, D.Phil., M.A., M.Sc., the Connor Family Professor in Research and Innovation and principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation. “I am honored that our team won, and I’m even more thrilled for our clinicians and their patients, who need us to keep moving forward to find new ways to treat pediatric brain tumors.”

Why we’re excited

With roughly 4,000 children diagnosed yearly, pediatric brain tumors are consistently the most common type of pediatric solid tumor, second only to leukemia in pediatric malignancies. At the urging of Linguraru and one of his peers at the Children’s Hospital of Philadelphia, pediatric data was included in the international competition for the first time, helping to ensure that children are represented in medical and technological advances.

The contest required participants to use data from multiple institutions and consortia to test competing methods fairly. The Children’s National team created a method to tap into the power of two types of imaging and machine learning: 3D convolutional neural network and 3D Vision Transformer-based deep learning models. They identified regions of the brain affected by tumors, made shrewd data-processing decisions driven by the team’s experience in AI for pediatric healthcare and achieved state-of-the-art results.

The competition drew 18 teams who are leaders from across the AI and machine learning community. The runner-up teams were from NVIDIA and the University of Electronic Science and Technology of China.

The big picture

“Children’s National has an all-star lineup, and I am thrilled to see our scientists recognized on an international stage,” said interim Executive Vice President and Chief Academic Officer Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer for Immunology Research. “As we work to attack brain tumors from multiple angles, we continue to show our exceptional ability to create new and better tools for diagnosing, imaging and treating these devastating tumors.”

Drs. Robert Keating, Brian Rood and Catherine Bollard

Children’s National announces new professorships

Drs. Robert Keating, Brian Rood and Catherine Bollard

Robert Keating, M.D., Brian Rood, M.D., and Catherine Bollard, M.D., M.B.Ch.B.

Children’s National Hospital named Robert Keating, M.D., as the McCullough Distinguished Professor of Neurosurgery. He serves as the chief of neurosurgery and co-director of the high-intensity focused ultrasound (HIFU) program at Children’s National.

Children’s National Hospital named Brian Rood, M.D., as the Kurt D. Newman, M.D., Professor of Neuro-Oncology. He serves as director of clinical neuro-oncology and medical director of the Brain Tumor Institute at Children’s National.

Children’s National Hospital elevated Catherine Bollard, M.D., M.B.Ch.B., to the Dr. Robert J. and Florence T. Bosworth Distinguished Professor of Cancer and Transplantation Biology Research. She is the Interim Executive Vice President and Chief Academic Officer and Interim Director, Children’s National Research Institute. She also serves as the director of the Center for Cancer and Immunology Research and director of the Program for Cell Enhancement and Technologies for Immunotherapy at Children’s National.

About the awards

Professorships at Children’s National support groundbreaking work on behalf of children and their families and foster new discoveries and innovations in pediatric medicine. These appointments carry prestige and honor that reflect the recipient’s achievements and donor’s forethought to advance and sustain knowledge. Children’s National is grateful for its generous donors, who have funded 47 professorships.

Dr. Keating is a longstanding leader in neurosurgery research and care. His areas of expertise include brain tumors, traumatic brain injuries, craniofacial anomalies, Chiari malformations and spinal dysraphism. With Dr. Keating’s leadership, the neurosurgery department is pioneering innovations such as HIFU, a non-invasive therapy using focused ultrasound waves to ablate a focal area of tissue. It can treat tumors located in difficult locations of the brain, movement disorders and epilepsy. Children’s National was one of the first pediatric hospitals in the nation to use HIFU for neuro-oncology patients.

“Our goal is to elevate our top-ranked program to even greater heights,” says Dr. Keating. “We will continue to use cutting-edge technology and non-invasive approaches to make the knife obsolete in pediatric neurosurgery and improve outcomes for children.”

Dr. Rood studies the biology of pediatric brain tumors. He focuses on protein signatures and biomarkers specific to different types of brain cancers. His study of neoantigens is informing the development of T-cell immunotherapies to target a tumor’s unique proteins.

“Immunotherapy is revolutionizing how we treat childhood brain tumors — safely, effectively and with the precision made possible by using a patient’s own cells,” says Dr. Rood. “This professorship enables our team to advance this revolution, which will save lives and improve lifetimes.”

Dr. Bollard received the Dr. Robert J. and Florence T. Bosworth Professor of Cancer and Transplantation Biology Research in 2018 to support her work to develop cell and gene therapies for patients with cancer and underlying immune deficiencies. Her professorship has been elevated to a distinguished professorship to amplify her research and celebrate her accomplishments in the field of immunotherapy.

About the donor

These appointments were made possible through an extraordinary $96 million investment from an anonymous donor family for rare pediatric brain tumor research and care. It is one of the hospital’s largest donations and will transform the hospital’s ability to give patients with rare brain cancer a better chance at healthy lifetimes.

The anonymous family brings a depth of compassion for children facing rare and often challenging diagnoses. Their partnership will immediately advance every aspect of our globally recognized leadership to create new, more effective treatments.

Their investment also endowed the Professorship in Molecular Neuropathology. We look forward to bestowing that honor on a Children’s National pediatric leader.

Dr. Catherine Bollard webinar screen grab

In the News: The challenges of pediatric clinical trials

Dr. Catherine Bollard webinar screen grab“Pediatric cancer is rare, when you compare it to other forms of cancer, especially adult solid tumors. Often pharma companies are not wanting to fund trials that are exclusively to support a pediatric cancer indication. This is a question that I get asked a lot: How to deal with the so-called ‘valley of death’? … You can successfully complete a phase 1/phase 2 trial, show a safety and efficacy signal, but then lack the funds to get FDA approval. Several of us in the field are looking at other strategies to fill this gap, like forming consortiums and using institutional support.”

Catherine Bollard, M.D., M.B.Ch.B, director of the Center for Cancer and Immunology Research, joined Nature to talk about clinical trials for children, including the significant challenges she and her colleagues face to ensure potentially successful treatments have the funding to make it through the approval process. Learn more about her thoughts on the current landscape for pediatric clinical trials and her work on CAR-T cell therapies in her webinar.

Catherine Bollard

In the news: Novel research to stop pediatric brain tumors

“The team is really bringing in very new ideas from mathematical modeling, engineering, all the way to cell therapy, immunotherapy and immunology…This is what really excites and energizes us to be part of this great team, to address the Cancer Grand Challenge, to better target pediatric solid tumors.”

The Cancer Letter connected with Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital, for a conversation about her work as a leader of the Cancer Grand Challenges NexTGen team. The $25 million effort is funded by Cancer Research U.K. and the National Institute of Health’s National Cancer Institute and the Mark Foundation for Cancer Research. Its ambitious goal: find novel therapies to break the stalemate in the treatment of pediatric solid brain tumors in the next 10 years. Bollard shared her work plan and the “secret sauce” that gives the team its edge with The Cancer Letter. Find out more about the hope behind this effort in the full interview here.

Catherine Bollard at People V. Cancer summit

In the news: People v. pediatric cancer

“I just want to hammer home the fact that, if you have a child with a pediatric solid tumor who relapses, most likely the chemotherapy that will be treating that child will be the same chemotherapy that a child diagnosed 20 years ago would have received. This is how little progress has been made…. This is what we are trying to change.”

Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital, pulled the curtain back on her work fighting pediatric brain tumors at The Atlantic’s People V. Cancer summit. This annual event brings together leading voices from the front lines for in-depth conversations about how to stop this complex and lethal disease. Dr. Bollard discussed the unique importance of collaboration among pediatric oncologists and the optimism she has for using a patient’s immune system to go after solid tumors with CAR T therapies.

Drs. Bollard and Hanley

Research into a new way to combat solid tumors earns part of a $25M award

Drs. Bollard and Hanley

Catherine Bollard, M.D., M.B.Ch.B., and Patrick Hanley, Ph.D.

Children’s National Hospital has developed multi-antigen specific T cells that have shown success in pre-clinical models in attacking pediatric solid tumors. Now the promising area of research earned a major boost from the Cancer Grand Challenges — founded in 2020 by the two largest funders of cancer research in the world – Cancer Research UK and the National Cancer Institute in the U.S.

This award supported the foundation of NexTGen, a team of scientists and clinicians with expertise in immunology, proteomics, mathematics and more, across eight institutions in the U.S., U.K. and France. Catherine Bollard, M.B.Ch.B, M.D., director of the Center for Cancer and Immunology Research at Children’s National, and Martin Pule, M.D., clinical associate professor at the University College of London are the co-leads of this effort.

The NexTGen team is one of four Cancer Grand Challenges’ new teams, representing a total investment of $100M to diverse, global teams to take on some of the toughest challenges in cancer research. NexTGen will create a new approach that performs clinical and basic research together to facilitate real-time knowledge exchange from the lab to the clinic and back again.

While the more widely known CAR T-cells have made tremendous progress for patients with B-cell leukemias, lymphomas and other blood cancers, the CAR T-cell field has not made the same impact for adult and pediatric solid tumors.

“A tumor cell is very clever because it tries to hide from the immune system by deleting or down regulating targets that the T cell is directed towards,” said Dr. Bollard.

Dr. Bollard further discusses the importance of having patient voices during the decision-making process in this quest, her hopes for their program and the concept of the combining tumor antigen-specific T cells with CAR-T cells that her team will develop.

Q: Can you explain the NexTGen vision?

A: The overall vision is that we will have developed the next generation of cell therapies to cure children with refractory solid tumors by the end of the five years. It is important to move the field forward, so we wanted to be innovative in our approach to this grand challenge for these children who have no other therapeutic options left.

Q: What are the most three important components of this project?

A: First, science and diplomacy played a significant role in bringing in the right set of investigators from diverse scientific backgrounds. What started as a conversation using the universal language of science, it quickly became an international project to address this complex issue. Second, we worked very hard with our patient advocates during the writing process, and they will be working side by side with the investigators at the bench and clinic. Third, we were the only group to have clinical trials in our proposal starting very early in the grant funding period, which is unprecedented.

Q: Can you describe NexTGen’s research model?

A: From our experience in leukemia, we know that progress is greatly accelerated if discovery occurs hand-in-hand with clinical development. Therefore, unlike classical programs where years of pre-clinical discovery and developmental work is required before the clinical translation, we will take a non-conventional non sequential approach.

Specifically, in the NexTGen Program, clinical development will start early with three cutting-edge clinical studies evaluating engineered T-cell technologies that we have recently developed understanding that there are some questions that can ONLY be answered in the clinic. To that end, clinical and translational data from these clinical trials will be able to feed into and enrich the discovery and pre-clinical science throughout the NexTGen Program in a circular fashion to promote this research program that goes from bedside to bench and back.

Q: How is Children’s National leading the way?

A: Children’s National is leading one of the three clinical trials that combine our non-gene engineered tumor antigen-specific T-cell platform with gene engineered T cells to generate a novel T-cell therapy against relapsed /refractory solid tumors. Combining tumor antigen specific T cells with the CAR T-cell platform represents a novel concept that may have more potency against these hardest to treat tumors in children.

Q: Why is it so important to include the patient voice during the discussion and decision making?

A: Because we are also physicians and scientists, we do not forget the patient and their families. Thus, we have a robust patient advocacy group embedded in this vision. The group will co-develop summaries explaining the challenges NextGen will address, how this will be achieved and how results will be used, with major input in clinical trial design and consent documents as well as key input into how patient tissue samples can be used to facilitate research discoveries. The patient advocacy team will also help find broad representation from multiple geographical locations of advocates with lived experience of different cancer types, including bereaved relatives and cancer survivors. These and many more strategies applied with patient advocacy groups will elevate the call for a broader and accelerated adoption of CAR-T clinical trials to broaden access to all patients.

Q: What excites you most about this?

A: What excites me the most is working with this incredible group of scientists, physicians and patient advocates all with rich and deep expertise who bring together an extensive and diverse knowledge base. The fact that we will be all working together toward a common goal of curing pediatric solid tumors in the next five to 10 years is extraordinarily energizing. This sizeable international collaboration comprises the right talent to get this done. It is also highly exciting to simultaneously have three clinical trials running in parallel with the discovery science and the pre-clinical work. I am extremely optimistic that we will realize NexTGen’s vision to bring next generation engineered T-cell therapies to the routine care of children with solid tumors within a decade.

Dr. Bollard and her laboratory

Catherine Bollard, M.D., M.B.Ch.B., selected to lead global Cancer Grand Challenges team

Dr. Bollard and her laboratory

Cancer Grand Challenges NexTGen team members (left to right): Amy Hont, M.D., AeRang Kim, M.D., Nitin Agrawal, Ph.D., Catherine Bollard, M.D., M.B.Ch.B., Conrad Russell Cruz, M.D., Ph.D., Patrick Hanley, Ph.D., and Anqing Zhang.

A world-class team of researchers co-led by Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital, has been selected to receive a $25m Cancer Grand Challenges award to tackle solid tumors in children. Cancer Grand Challenges is a global funding platform, co-founded by Cancer Research UK and the National Cancer Institute in the U.S., that supports a community of diverse, global teams to come together, think differently and take on some of cancer’s toughest challenges.

The Cancer Grand Challenges NexTGen team, co-led by University College London’s Martin Pule, M.D., will be working to develop next-generation cell therapies for children with solid cancers. Cancer is a leading cause of death by disease in children worldwide. Although survival has increased for some pediatric cancers, such as blood cancers, survival for some solid tumors has seen little improvement for more than 30 years. The team hopes to build a much deeper understanding of childhood cancers and develop and optimize novel therapies for children with solid tumors, ultimately hoping to improve survival and diminish the lifelong toxicities often experienced by survivors.

“With our Cancer Grand Challenge, we hope to bring next-generation CAR T-cell therapies to children with solid tumors,” said Dr. Bollard. “What excites me most is the energized, passionate group of people we’ve brought together to take this challenge on. Big problems remain to be addressed, but we believe they can be solved, and that we’re the team to solve them.”

“NexTGen represents crucial and overdue work. It has hope written all over,” said Sara Wakeling, patient advocate on the team and CEO and co-founder of Alice’s Arc, a children’s charity for rhabdomyosarcoma. “NexTGen hopes to transform the way these aggressive solid tumors are treated with less toxic side-effects, giving the children a real chance at growing up and realizing their potential. I’m so proud to be part of this exceptional team of scientists, clinicians and advocates who want to change the story for those diagnosed.”

The NexTGen team unites scientists and clinicians with expertise in immunology, proteomics, mathematics and more, across eight institutions throughout the U.S., U.K. and France. The Children’s National investigators that will also join are:

  • Nitin Agrawal, Ph.D., associate professor in the Center for Cancer and Immunology Research at Children’s National.
  • Conrad Russell Cruz, M.D., Ph.D.,principal investigator for the Program for Cell Enhancement and Technologies for Immunotherapies at Children’s National.
  • Patrick Hanley, Ph.D., chief and director of the cellular therapy program at Children’s National and leader of the Good Manufacturing Practices laboratory.
  • Amy Hont, M.D., oncologist in the Center for Cancer and Immunology Research at Children’s National.
  • AeRang Kim, M.D., oncologist in The Center for Cancer and Blood Disorders at Children’s National.
  • Holly Meany, M.D., oncologist in The Center for Cancer and Blood Disorders at Children’s National.
  • Anqing Zhang, biostatistician in the Biostatistics and Study Methodology Department at Children’s National.

The team, co-funded by Cancer Research UK, the National Cancer Institute and The Mark Foundation for Cancer Research, aims to bring much needed new treatments to children with solid cancers.

The NexTGen team is one of four new teams announced today as part of Cancer Grand Challenges, representing a total investment of $100m to diverse, global teams to take on some of the toughest challenges in cancer research.

“Cancer is a global issue that needs to be met with global collaboration. This investment in team science encourages diverse thinking to problems that have long hindered research progress,” said David Scott, Ph.D., director of Cancer Grand Challenges, Cancer Research UK. “Cancer Grand Challenges provides the multidisciplinary teams the time, space and funding to foster innovation and a transformative approach. NexTGen is one of four newly funded teams joining a scientific community addressing unmet clinical needs across cancer research.”

Find out more

Cancer Grand Challenges supports a global community of diverse, world-class research teams with awards of £20m/$25m to come together, think differently and take on cancer’s toughest challenges. These are the obstacles that continue to impede progress and no one scientist, institution or country will be able to solve them alone. Cancer Grand Challenges teams are empowered to rise above the traditional boundaries of geography and discipline.

Founded by the two largest funders of cancer research in the world – Cancer Research UK and the National Cancer Institute* in the U.S. – Cancer Grand Challenges aims to make the progress against cancer we urgently need. Cancer Grand Challenges currently supports more than 700 researchers and advocates across 10 countries, representing 11 teams are supported to take on 10 of the toughest challenges in cancer research.

The Cancer Grand Challenges NexTGen team, announced June 16, 2022, is taking on the initiative’s Solid Tumours in Children challenge. It is led by Dr. Bollard (Children’s National) and Dr. Pule (University College London), along with 23 co-investigators and 7 patient advocates, and is spread across eight institutions across the U.S., U.K. and France: Cardiff University; Children’s Hospital of Philadelphia; Children’s National Hospital; INSERM; the Institute of Cancer Research; Stanford Medicine; Stanford University; University College London. The Cancer Grand Challenges NexTGen team is funded by Cancer Research UK, the National Cancer Institute in the U.S. and The Mark Foundation for Cancer Research.

*The National Cancer Institute is part of the National Institutes of Health.

 

girl hugging stuffed animal

Developing next-generation T cells to fight cancer

girl hugging stuffed animal

In the last decade, researchers have witnessed significant advances in the immunotherapy field. Most recently, a study in Nature claimed a novel CAR T-cell therapy “cured” a patient.

In the last decade, researchers have witnessed significant advances in the immunotherapy field. Most recently, a study in Nature claimed a novel CAR T-cell therapy “cured” a patient. Given the landmark scientific achievement for patients with different types of leukemia and lymphoma, Children’s National Hospital experts chimed in on the technology they have developed beyond CAR T cells.

Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital, discusses the implications of this research, how it relates to the work she’s doing at Children’s National and the future of T-cell therapies.

Q: What did the research published in Nature find?

A: It reported a decade-long experience with this novel T-cell therapy called CD19 CAR T cells. These were used to treat patients with a type of leukemia or lymphoma that expresses the CD19 on its surface. While the article reported the experience of Children’s Hospital of Philadelphia and the University of Pennsylvania, multiple groups throughout the country did similar trials that have used these unique CD19 CAR T cells to treat children and adults with these refractory blood cancers.

Q: What are your thoughts on the implications of this research?

A: We now have three FDA-approved commercial CD19 CAR T-cell products developed by several academic institutions. This is revolutionary for our patients who have B-cell leukemias and lymphomas. It’s incredibly exciting for our T-cell therapy field in general because this was the first time the FDA approved a T-cell therapy. What it means now is the field is extremely excited to develop similar effective therapies for other patients with cancer.

Q: How does this relate to your work at Children’s National?

A: While CAR T cells have made tremendous progress for patients with B-cell leukemias, lymphomas and other blood cancers, the CAR T-cell field has not made the same impact for adult and pediatric solid tumors. We think the field is going to expand the type of T-cell therapies we’re generating beyond just CAR T cells. That’s where the work we’re doing comes in – not only by developing new T cells that don’t need gene engineering but also T cells that can be used as a platform for next-generation engineering approaches. We think the technology we’ve developed at Children’s National will help make an impact, especially in the solid tumor space. I hope in the next 10 years, we’ll be having a conversation not just about CAR T cells, but about other types of T cells that are now making an impact for solid tumors.

Q: How are the CAR T cells you develop different than those in the Nature article?

A: We think our multi-antigen specific T cells are complimentary and could have more potency than conventional CAR T cells for solid tumors especially when used in combination. This is in part because they can identify multiple targets on a tumor cell. Tumor cells are very clever and try to hide from T-cell therapies by down regulating the target that the T cell is directed towards. However, our novel T-cell therapies get around that escape by targeting multiple targets in a single product, making it much harder for the cancer cell to hide from the immune attack by the T cells.

Additionally, we’re excited by our approach because not all of our products require gene engineering, unlike CAR T cells. We have effectively used our T cells to target viruses in the “off-the-shelf” setting and we’re now about to start a first human clinical trial at Children’s National using an off the shelf T-cell product for children with solid tumors. It makes the T-cell therapy more like an “off-the-shelf” drug therapy that will allow us to treat many more children and adults nationally, as well as we hope, internationally.

doctor and cancer patient smiling

Manufactured leukemia-specific T cells may help increase survival rates

doctor and cancer patient smiling

Infusion of a novel, multi-targeted donor-derived T-cell therapy is safe and well-tolerated in patients with high-risk or relapsed leukemia after a donated bone marrow transplant, according to a new study published in Blood Advances.

Infusion of a novel, multi-targeted donor-derived T-cell therapy is safe and well-tolerated in patients with high-risk or relapsed leukemia after a donated bone marrow transplant, according to a new study published in Blood Advances. The findings suggest that this strategy may make a difference in these patients, as will be evaluated in later phase trials.

“A tumor cell is very clever because it tries to hide from T-cell therapies by deleting or down regulating targets that the T cell is directed towards,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital and co-senior author. “This novel cell therapy has the potential to get around that escape by targeting multiple proteins in a single product, making it much harder for the cancer cell to hide from the immune attack by the T cells.”

The tumor-associated antigen-specific T cell (TAA-T) product targets WT1, survivin and PRAME, which are proteins that play a role in cancer cell proliferation and survival. They are overexpressed in leukemia and many other human malignancies. The researchers chose to expand the T cells to target many malignancies through at least one expressed antigen. The manufactured TAA-T products are derived from peripheral blood mononuclear cells (PBMCs) obtained from the patient’s own BMT donor.

The hold-up in the field

Conventional therapies for patients with high-risk or relapsed malignancies often fail due to toxicity associated with additional chemotherapy and second transplant, particularly in those who relapse early after transplant. This novel cellular immunotherapy approach is shown to be safe and targets antigens that are found in CD19 positive and negative blood cancers, which may broaden the applicability to other cancer types, such as acute myeloid leukemia, that are currently lacking effective T cell therapy options.

What’s next

“Evaluation and tracking of unique T cell receptor clonotypes in patients following TAA-T cell infusion demonstrated expansion and persistence of some clonotypes up to 6 months to one-year post-infusion,” said Hannah Kinoshita, M.D., oncology fellow at Children’s National and co-lead author. “In future studies, we are hoping to identify and track unique target antigen-specific clonotypes from the T cell product infused to better understand the immunobiological effect of the infused T cells and how that can be translated into improved clinical outcomes.”

Children’s National Hospital leads the way

The Cell Enhancement and Technologies for Immunotherapy (CETI) program at Children’s National specializes in developing and analyzing novel cellular therapeutics such as this one.

You can read the full study “Outcome of Donor-derived TAA-T cell therapy in Patients with High-risk or Relapsed Acute Leukemia Post Allogeneic BMT,” in Blood Advances. Children’s National researchers worked in partnership with Rick Jones, M.D., co-senior author and Kenneth Cooke, M.D., Ph.D., co-lead author, both at Johns Hopkins Medicine.

Epstein-Barr virus

Study with largest cohort in the Western world sheds light on Epstein-Barr virus

Epstein-Barr virus

Epstein-Barr virus is a member of the herpes family and it spreads primarily through saliva.

Children’s National Hospital experts provided a contemporary description of the epidemiology, clinical presentation and management of chronic active Epstein-Barr virus (CAEBV), shedding light on this very rare disease. The paper, published in Blood Advances, assessed 57 patients outside of Asia — the biggest international retrospective cohort study published in the Western world.

Epstein-Barr virus is a member of the herpes family and it spreads primarily through saliva. Once a person is infected with Epstein-Barr virus, the immune system will control the infections, but the virus lies in a dormant state in the patient’s B Cells. However, in some patients, there is a failure of the body to control the infection, and the virus is found inside the patient’s T and/or NK cells. These rare patients are diagnosed with CAEBV. The hallmark of the disease is proliferation of Epstein-Barr virus-infected T or NK cells that infiltrate tissues, leading to end-organ damage. Patients most often experience fevers, hepatosplenomegaly, liver inflammation, cytopenias and lymphoproliferation that may progress to lymphoma.

Given it is most prevalent in Asia, little is known about the disease in the Western world. There has only been one published paper regarding the outcomes of patients in the U.S., which included 19 patients amassed over 28 years, and was published a decade ago.

Multiple treatments have been attempted to control the disease, but none have resulted in consistent remission. Historically, the consensus is to use steroids and/or antiviral drug in combination with proteasome inhibitor agents. In some cases, clinicians also use cytotoxic chemotherapy to reduce disease burden and improve the patient’s condition before HSCT. Still, this approach is limited because most patients die due to the progression of their disease despite these interventions.

Ultimately, most of these patients are referred for allogeneic hematopoietic stem cell transplantation (HSCT), which is the only known curative therapy for CAEBV. However, the best approach to control disease prior to HSCT, as well as the optimal conditioning regimen, are unknown.

“For the first time in many years, we provide insight on contemporary treatment options to consider for patients with CAEBV, as well as identifying risk factors for worse outcomes,” said Blachy Dávila Saldaña, M.D., blood and marrow transplant specialist at Children’s National and lead author of the study. “HSCT is curative, but patients need to be considered prior to the evolution of more advanced disease, particularly lymphoma. We also provide a new platform that will inform research on new interventions and therapies for this population.”

“CAEBV remains a challenging disorder to treat, especially once severe complications develop,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National. “However, our data suggests that T cell modulating therapies may enhance disease control, and future studies should address this question in a controlled setting.”

Future steps also include performing genetic studies to identify those at risk of developing the disease, and developing new platforms for treatment, including checkpoint inhibitors and cytotoxic lymphocyte therapies (CTL’s), which is a form of adoptive immunotherapy that employs virus-specific T cells.

The cohort includes patients treated in CNH and multiple institutions around the world, including Texas Children’s and the National Institutes of Health. “This work was only possible through our collaborative research in anti-EBV cellular therapies,” said Dr. Dávila.

t cells fighting cancer cell

Personalized T cell immunotherapy for brain tumors closer to becoming reality

t cells fighting cancer cell

Children’s National Hospital experts developed a new approach that discovered unique proteins in an individual tumor’s cells, which then helped scientists generate personalized T cells to target and kill tumors.

Children’s National Hospital experts developed a new approach that discovered unique proteins in an individual tumor’s cells, which then helped scientists generate personalized T cells to target and kill tumors, according to a pre-clinical study published in Nature Communications.

This effort is the first to create a new workflow for neoantigen identification that incorporates both genetic sequencing and protein identification to create a personalized treatment for medulloblastoma in children, a common malignant brain tumor. Given these promising findings, the researchers are now designing a phase I clinical trial slated to open in 12-18 months.

“This work is an incredibly exciting advancement in personalized medicine. It will allow us to treat patients with a novel T cell therapy that is developed for each individual patient to specifically attack and kill their tumor,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National and co-author on the paper. “This treatment will offer a potential option for children with hard-to-treat brain tumors for which all other therapeutic options have been exhausted.”

Catherine Bollard

Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National and co-senior author on the paper.

First, the researchers sequenced the DNA of small tissue samples while studying its complete set of proteins that influence cancer biology — also named a “low-input proteogenomic approach” by the authors. After analyzing the empirical data, which shies away from the commonly used predictive models, the researchers developed a T cell immunotherapy that targets the tumor’s unique proteins and allows the T cells to distinguish between healthy cells and tumor cells. This means that Rivero-Hinojosa et al. managed to merge two research fields, proteogenomics and immunotherapy, and lay the groundwork for personalized, targeted T cell therapies to treat children with brain tumors.

“Neoantigen discovery techniques have either been dependent upon in silico prediction algorithms or have required a significant amount of tumor tissue, making them inappropriate for most brain tumors,” said Brian Rood, M.D., medical director of Neuro-oncology and the Brain Tumor Institute at Children’s National. “This neoantigen identification pipeline creates a new opportunity to expand the repertoire of T cell-based immunotherapies.”

Tumor cells have damaged DNA that create mutations during the repair process because they do not do a good job at maintaining their DNA fidelity. The repairs therefore create aberrant DNA that codes for proteins that were never intended by the genetic code and, consequently, they are unique to the individual’s tumor cells.

Brian Rood

Brian Rood, M.D., medical director of Neuro-oncology and the Brain Tumor Institute at Children’s National and co-senior author on the paper.

“We developed a new filtering pipeline to remove non-annotated normal peptides. Targeting antigens that are completely specific to the tumor, and expressed nowhere else in the body, will potentially increase the strength of tumor antigen-specific T cell products while decreasing the toxicity,” said Samuel Rivero-Hinojosa, Ph.D., staff scientist at Children’s National and first author of the study.

Once the experts identified these unique peptides, they used them to select and expand T cells, which showed specificity for the tumor specific neoantigens and the ability to kill tumor cells. The next step is to conduct a clinical trial in which a patient’s own T cells are trained to recognize their tumor’s unique neoantigens and then reinfused back into the patient.

From an immunotherapy standpoint, tumor specificity is important because when clinicians treat patients with T cell therapies, they want to make sure that the T cells directly target and kill the tumor and will not cause devastating harm to healthy cells. This paper demonstrated that it may be possible to create a better efficacy and safety margin with this new approach.

In the past five years, under the leadership of Dr. Bollard, the Center for Cancer and Immunology Research at Children’s National has advanced the scientific knowledge in preclinical and clinical settings. The center discovered a signaling pathway that can be hijacked to prevent brain tumor development, and further advanced translational research with several key first-in-human studies that utilized novel cell therapies to treat cancer and life-threatening viral infections.

Hodgkin lymphoma cells

T-cell therapy alone or combined with nivolumab is safe and persistent in attacking Hodgkin’s lymphoma cells

Hodgkin lymphoma cells

Hodgkin’s lymphoma is a type of cancer that attacks part of the immune system and expresses tumor-associated antigens (TAA) that are potential targets for cellular therapies.

It is safe for patients with relapsed or refractory Hodgkin’s lymphoma (HL) to receive a novel tumor-associated antigen specific T-cell therapy (TAA-T) either alone or combined with a checkpoint inhibitor, nivolumab — a medication used to treat several types of cancer. The study, published in Blood Advances, further suggests that nivolumab aids in T-cell persistence and expansion to ultimately enhance anti-tumor activity. This offers a potential option for patients who do not have a durable remission with checkpoint inhibitors alone or are at a high risk of relapse after a transplant.

“The fact that this combination therapy is so safe was very encouraging for the treatment of patients with lymphomas,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital. “In addition, this data allows us to consider this combination immunotherapy for other patients, including those with solid tumors.”

HL is a type of cancer that attacks part of the immune system and expresses tumor-associated antigens (TAA) that are potential targets for cellular therapies. While it may affect children and adults, it is most common in those who are between 20 and 40 years old. The survival rate for this condition has improved due to scientific advances.

A new approach in cancer therapy is the use of “checkpoint inhibitors,” which are a class of drugs that block some of the inhibitory pathways of the immune system to unleash a powerful tumor killing immune response. Similarly, T-cell therapies have also shown to enhance anti-tumor immune response. Therefore, combining these novel immune therapies is an attractive and targeted alternative to conventional untargeted therapies – such as chemotherapy and radiation – which not only kill the tumor cells but also can kill healthy cells and tissues.

“In five to 10 years we can get rid of chemotherapy and radiation therapy and have an immunotherapy focused treatment for this disease,” said Dr. Bollard.

To determine the safety of infusing TAA-T with and without checkpoint inhibitors, eight patients were infused with TAA-specific T-cell products manufactured from their own blood. Two other patients received TAA-T generated from matched healthy donors as adjuvant therapy after hematopoietic stem cell transplant. According to Dave et al., the TAA-T infusions were safe and patients who received TAA-T as adjuvant therapy after transplant remained in continued remission for over two years.

Of the eight patients with active disease, one patient had a complete response, and seven had stable disease at three months, three of whom remained with stable disease during the first year.

“Treating Hodgkin’s lymphoma with cellular therapy has not yet achieved the same success that we have seen for other lymphoma subtypes,” said Keri Toner, M.D., attending physician at Children’s National. “This study brings us closer to overcoming some of the current barriers by developing methods to improve the persistence and function of the tumor-specific T-cells.”

This study builds upon the researchers’ latest findings in another study, which demonstrated that TAA-T manufactured from patients were safe and associated with prolonged time to progression in solid tumors.

“The addition of a checkpoint inhibitor like Nivolumab to the TAA-T treatment is a powerful next step, but previously, the safety of this combination was unknown,” said Patrick Hanley, Ph.D., chief and director of the Cellular Therapy Program at Children’s National, leader of the GMP laboratory and co-author of the study. “Now that we have demonstrated a safety profile, the next step will be to evaluate the efficacy of this combination in a larger subset of patients.”

T cell

Children’s National Hospital scientists shortlisted for Cancer Grand Challenges funding

T cell

If successful, the team would seek to tackle the challenge of solid tumors in children. The vision is to bring engineered T-cell therapies to the routine treatment of these children within a decade.

A diverse, global team of scientists, led by University College of London and Children’s National Hospital/George Washington University, has been selected for the final stages of Cancer Grand Challenges – and is in with a chance of securing a share of £80 million (c.$111 million) of funding to take on one of cancer’s toughest problems.

Nearly 170 teams submitted ideas for this round of awards, and the NGTC team, which stands for ‘Next Generation T-cell therapies for childhood cancers, led by Martin Pule, Ph.D., University College of London, and Catherine Bollard, M.B.Ch.B., M.D., Children’s National Hospital and George Washington University, is one of 11 shortlisted groups.

The team draws together a unique set of expertise, uniting researchers from the U.K., U.S. and France. Other team members from Children’s National include Conrad Russell Cruz, M.D., Ph.D., principal investigator for the Program for Cell Enhancement and Technologies for Immunotherapies, and Nitin Agrawal, Ph.D., associate professor in the Center for Cancer and Immunology Research (CCIR). Up to four winning teams will be announced in early 2022.

If successful, the NGTC team would seek to tackle the challenge of solid tumors in children. The team says that the scientific and medical communities are beginning to understand that solid tumors in children are very different from those in adults – if they could understand more about these differences and find new ways to target them, they could create new ways to better treat children’s cancers.

The NGTC team’s vision is to bring engineered T-cell therapies to the routine treatment of these children within a decade.

Through a series of ambitious studies, the team hopes to identify suitable, pediatric tumor-specific targets for engineered T-cells, including previously unexplored options like glycolipids or the immunopeptidome. They also hope to explore whether treatment effectiveness can be boosted by modulating the tumor microenvironment – which can inhibit T-cell therapies but is yet to be suitably studied in children’s cancers. The team has a strong translational focus and the most promising new treatment avenues would be explored in preclinical and early clinical studies.

“We’re tremendously excited to have this opportunity to work together and strive closer to our vision – to improve the lives of the patients we serve,” says joint team lead Dr. Bollard, who is also the director of the Center for Cancer and Immunology Research at Children’s National.

“This round of Cancer Grand Challenges has demonstrated the fresh thinking that can be sparked when global teams unite across disciplines to bring new perspectives to tough challenges,” says Dr. David Scott, Ph.D., director of Cancer Grand Challenges. “We were thrilled to receive such a strong response from the global research community.”

Find out more at cancergrandchallenges.org.

inside a GMP lab

Cell therapy manufacturing process ramps up to meet increased demand for T-cell products

inside a GMP lab

The new laboratory space includes floor-to-ceiling windows and brand new, state-of-the-art GMP lab suites.

Since Children’s National Hospital began its pediatric cellular therapy program in 2013, it has received more than $5 million in annual funding, treated over 200 patients, manufactured more than 400 cell-based products and supported over 25 clinical trials.

One of the in-house programs supporting this work is the Good Manufacturing Practices (GMP) facility. Patrick Hanley, Ph.D., chief and director of the cellular therapy program at Children’s National and leader of the GMP laboratory, explained that the first patient received a dose of less than 10 million cells in May 2014. Fast forward to now, the lab uses liters of media, automated bioreactors and multiple staff, making upwards of 12 billion cells per run — a growing production scale that enables many different options. Using cells as an off-the-shelf technology is one of those.

The cell therapy program exports these off-the-shelf products beyond Children’s National to make them available for kids across the country. Catherine Bollard, M.D., MBChB., director of the Center for Cancer and Immunology Research at Children’s National, and Michael Keller, M.D., director of the Translational Research Laboratory in the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, each led clinical trials with hospitals across the United States, including the first-ever cellular therapy clinical trial run through the Children’s Oncology Group.

To meet the high demand for cell therapy trials at Children’s National, the GMP lab moved to a larger space, doubling the team’s capacity to produce alternative treatment options for patients and facilitate the lab’s ability to support clinical divisions throughout the hospital.

The GMP lab is exploring how to make cell products more consistent — regardless of patient-to-patient variability. They are also hoping to delineate the characteristics that ensure quality cell products, educate other facilities, enhance the overall knowledge of how to safely manufacture these products and make these technologies more available and affordable to the patients who need them.

Among Hanley’s many goals for the GMP lab, one is to improve the transition from when an investigator discovers a product in the translational research lab to when it is manufactured for patients.

“To improve this transition, we have started a process development team that will learn the process alongside the research team, replicate it, and then train the staff who manufacture the product for patients,” said Hanley. “In addition to providing a better training opportunity for the manufacturing staff, it allows us to work with the investigators earlier on to identify changes that will need to be made to translate the products to patients, ultimately resulting in safer, more potent immunotherapy products.”

While cell therapy has seen increased interest in the last 10 years, there are still some challenges in the field, given that it is not as mature as other scientific areas. The lack of trained staff, scalability of cell and gene therapy, the variability between patients and products, delayed FDA approvals and rejection of licensing applications for cell therapy products — are barriers that scientists and companies often face.

“Each of us has a unique immune system, and that means that if we try and make a product from it, it will not behave like any other, so the number of cells, the potency the alloreactivity — it is all different,” said Hanley. “T-cells are a living drug that expand in the body at different rates, are composed of different types of T-cells, and release different cytokines and in different amounts.”

This all ties back to the process development and basic research. The better researchers can characterize the products under development, the more they will know about how the products work and the easier it will be to tie these products to patient outcomes.

Meet some of the Children’s National multidisciplinary experts who join forces to lead the cell therapy space.

Jay Tanna, M.S., quality assurance manager, has extensive experience with drug development at Children’s National as well as Sloan Kettering, another premier cell therapy institution. He has a Masters in Pharmaceutical Manufacturing and a Regulatory Affairs Certification (RAC) in U.S. FDA drugs and biologics regulations from the Regulatory Affairs Professional Society (RAPS).

Kathryn Bushnell, M.T. (ASCP), the cell therapy lab manager, oversees Stem Cell Processing. She has 20 years of experience with hematopoietic progenitor cells and cellular therapy, starting her career as a medical technologist at MD Anderson Cancer Center.

Nan Zhang, Ph.D., assistant director of manufacturing at Children’s National, has worked at Wake Forest and the National Institutes of Health developing various cellular therapies. Zhang chaired the cell processing session at the annual meeting of the American Society of Hematology in 2020.

Abeer Shibli, M.T., is a specialist in the cellular therapy laboratory with extensive experience in the processing of cellular therapy products. She has over 10 years of experience as a medical technologist, is specialized in blood banking and transfusion medicine and is one of the senior technologists in the lab.

Chase McCann, M.S.P.H., Ph.D., is the cell therapy lab lead for manufacturing at Children’s National Hospital. He recently completed his Ph.D. training in Immunology and Microbial Pathogenesis at Weill Cornell Medicine in New York. Much of his graduate research focused on developing and enhancing cellular therapies for HIV while identifying common mechanisms of escape, shared by both HIV and various cancers, which limit the efficacy of current cell therapies. Previously, McCann worked as the laboratory coordinator for the HIV Prevention Trials Network, and now oversees the manufacturing of many cell therapies supporting the many clinical trials currently underway at Children’s National.

Anushree Datar, M.S., the cell therapy lab lead for immune testing and characterization, oversees the release testing of products manufactured in the GMP for safety and function before they can be infused in patients. She also leads a part of the research team investigating the improvement in immune function after cell infusion.

Dr. Bollard is also the director of the Program for Cell Enhancement and Technologies for Immunotherapy and president of the Foundation for the Accreditation for Cellular Therapy (FACT). Additionally, in 2019, she became a member of the Frederick National Laboratory Advisory Committee (FNLAC) for the NIH and an ad hoc member of the Pediatric Oncologic Drugs Advisory Committee (ODAC) for the FDA. She has been an associate editor for the journal Blood since 2014 and in 2020 was appointed editor-in-chief of Blood Advances (starting Fall 2021). Dr. Bollard has 21 years of cell therapy experience as a physician, sponsor and principal investigator.

Dr. Hanley serves as the commissioning editor of the peer-reviewed journal Cytotherapy, as the vice-president-elect (North America) of the International Society of Cell and Gene Therapy (ISCT), and board of directors member at FACT, which provides him visibility into various cell and gene therapies, manufacturing approaches, and other intangibles that make Children’s National facility one of the leaders in the field.

To find the full research program list and their experts, click here.

GMP group photo

Lab members celebrate the expansion of the GMP Laboratory.

Dr. Catherine Bollard is accompanied by her mentees

Catherine Bollard, M.D., awarded two notable recognitions

Dr. Catherine Bollard is accompanied by her mentees

Dr. Catherine Bollard and some of her mentees.

For her work on developing cell-based therapies and dedication to her trainees, Catherine Bollard, M.D., MBChB, director of the Center for Cancer and Immunology Research at Children’s National hospital, receives two outstanding awards in her field.

Celebrating the minds behind the architecture of modern medicine and influencing the drug industry, The Medicine Maker, through an international panel of judges, added Dr. Bollard to the 2021 Power List in the category of advanced medicine.

Dr. Bollard mentioned that it is encouraging to see mRNA vaccine technology successfully fighting the COVID-19 pandemic because it paves the way for cancer vaccine advancements. Still, there are challenges affecting drug development. The centralized manufacturing hinders the large-scale production of patient-specific products as more cell therapies are getting approval, she added.

“Looking to the future, cell-based therapies will not be sustainable with a purely patient-specific centralized manufacturing model and, therefore, the field must move into the development of off-the-shelf cell therapies,” said Dr. Bollard. “The success of off-the-shelf virus-specific T-cells is especially exciting because it has the potential to be the platform for other antigen-specific and CAR-T cell therapies.”

A global society of clinicians, researchers, regulators, technologists and industry partners, The International Society for Cell & Gene Therapy (ISCT), will bestow Dr. Bollard the 2021 ISCT Darwin J. Prockop Mentoring Award on May 26. Her ongoing commitment to mentorship has advanced the careers of many aspiring professionals that have worked alongside her. The ISCT Award Committee selected someone that can inspire the current and future growing workforce. Dr. Bollard is highly recognized across the industry for her leadership, passion and dedication to her mentees, and her extraordinary efforts to advance their skills, capabilities and opportunities.

Dr. Catherine Bollard is accompanied by her mentees

To Patrick Hanley, Ph.D., chief and director of the Cellular Therapy Program at Children’s National, Dr. Bollard is the most deserving mentor for this award. She has provided advice and guidance to over 93 individuals, including 22 junior faculty, 27 post-doctoral fellows and 12 graduate students. Dr. Bollard also acts as a mentor to other senior investigators at Children’s National, particularly those in the Bone Marrow Transplantation division.

“For the past 15 years, Cath has been a strong mentor, friend, advocate, and voice of reason for me and has been instrumental in my success, both at Baylor College of Medicine and now at Children’s National,” said Hanley. “With her support and mentorship, I have been fortunate to publish high impact papers, earn a number of awards and receive prestigious grants. Without her guidance this wouldn’t have been possible.”

Amy Hont, M.D., oncologist for the Center for Cancer and Immunology Research at Children’s National, mentioned that Dr. Bollard is endlessly dedicated to her mentees and staff. “Dr. Bollard has been incredibly supportive of my research career throughout my training and progression to faculty. I feel very fortunate that I have been able to benefit not only from her unparalleled knowledge and expertise, but also her career advice and resources.”

Dr. Bollard leads clinical and research efforts to fight cancer and other inflammatory diseases by strengthening the immune system using adoptive cell therapy. She is a former president of the International Society of Cellular Therapy, and the current president of the Foundation for the Accreditation for Cellular Therapy (FACT). As a distinguished hematologist, immunologist and immunotherapist, she is working to develop cell and gene therapies for patients with cancer, viral infections and immune mediated diseases. She is especially interested in bone marrow and cord blood transplantation and improving outcomes after such transplant by decreasing infectious complications and preventing relapse. Dr. Bollard also has a specific interest in targeting viral infections in immune-suppressed patient populations, including individuals living with the human immunodeficiency virus.

Wilm's Tumor

PRAME-specific T cell product may facilitate rapid treatment in cancer settings

Wilms Tumor

PRAME is a cancer-testis antigen that plays a role in cancer cell proliferation and survival and is overexpressed in many human malignancies, including Wilms tumor. “Wilms Tumor (Nephroblastoma)” by euthman is licensed under CC BY 2.0.

Generated preferentially expressed antigen in melanoma (PRAME)-specific T cells from healthy donors can kill PRAME-expressing tumor cells in vitro, researchers at Children’s National Hospital found. Several novel epitopes, which are antigens that are recognized by the immune system, were also identified for enhanced matching, making this a potential therapeutic option for a broader patient group, according to a study published in Cytotherapy.

PRAME is a cancer-testis antigen that plays a role in cancer cell proliferation and survival and is overexpressed in many human malignancies, including melanoma, leukemia, sarcoma, renal cell cancer and Wilms tumor. PRAME also acts as a foreign substance in the body that can trigger the immune system by activating T cells, making it a good target for anticancer immunotherapy — especially for immunocompromised patients.

“The development of an effective off-the-shelf adoptive T-cell therapy for patients with relapsed or refractory cancers expressing PRAME antigen requires the identification of epitopes essential to the adaptive immune response, which are presented by major histocompatibility complex (MHC) class I and II, and are then recognized by the manufactured PRAME-specific T cell product,” said Amy Hont, M.D., oncologist for the Center for Cancer and Immunology Research at Children’s National Hospital. “We, therefore, set out to extend the repertoire of HLA-restricted PRAME peptide epitopes beyond the few already characterized and demonstrate the cytotoxic activity of PRAME-specific T cells to tumor cells known to express PRAME.”

Immunotherapy options for pediatric patients with high-risk malignancies, especially solid tumors, are few. Tumor-associated antigen-specific T cells (TAA-T) offer a therapeutic option for these patients, and Children’s National is building upon the success of the ongoing clinical trials to optimize this therapy and improve the treatment of our patients.

“These findings will also benefit patients because it better informs the pre-clinical studies of third party TAA-T to treat high-risk malignancies, so that we can move more quickly and safely to clinical trials,” said Dr. Hont.

Stanojevic et al. describes that the T-cell products killed partially HLA-matched tumors, and that this enhanced disintegration of tumor cells compared with non-specific T cells suggests an anti-tumor potential for a clinical trial evaluation to determine the safety and efficacy. Further research about the PRAME-specific T cells will help inform a treatment alternative for patients with solid tumors in the future.

The researchers generated a PRAME-specific T cell bank from healthy donor cells and demonstrated anti-tumor cytolytic activity against tumor lines partially HLA-matched to the T cells and known to express PRAME. By using epitope mapping, they identified several novel epitopes restricted to MHC class I or MHC class II to further inform HLA matching.

“Defining PRAME-specific T cells beyond HLA epitopes could be useful when developing T-cell therapies for worldwide application,” Stanojevic et al. write. “Moreover, creating off-the-shelf products has many potential advantages since such products are readily available for the treatment of patients with aggressive disease or patients for whom an autologous product cannot be manufactured.”

Additional authors from Children’s National are Maja Stanojevic, M.D., Ashley Geiger, M.S., Samuel O’Brien, Robert Ulrey, M.S., Melanie Grant, Ph.D., Anushree Datar, M.S., Ping-Hsien Lee, Ph.D., Haili Lang, M.D., Conrad R.Y. Cruz, M.D., Ph.D.,  Patrick J. Hanley, Ph.D., A. John Barrett, M.D, Michael D. Keller, M.D., and Catherine M. Bollard, M.D., M.B.Ch.B.

illustration of brain with stem cells

Innovative phase 1 trial to protect brains of infants with CHD during and after surgery

A novel phase 1 trial looking at how best to optimize brain development of babies with congenital heart disease (CHD) is currently underway at Children’s National Hospital.

Children with CHD 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 cardiopulmonary bypass, also known as the heart lung machine.

This phase 1 trial is the first to deliver mesenchymal stromal cells from bone marrow manufactured in a lab (BM-MSC) into infants already undergoing cardiac surgery via cardiopulmonary bypass. The hypothesis is that by directly infusing the MSCs into the blood flow to the brain, more MSCs quickly and efficiently reach the subventricular zone and other areas of the brain that are prone to inflammation. The trial is open to eligible patients ages newborn to six months of age.


Learn more in this overview video.

The trial is part of a $2.5 million, three-year grant from the National Institutes of Health (NIH) led by Richard Jonas, M.D., Catherine Bollard, M.B.Ch.B., M.D., and Nobuyuki Ishibashi, M.D.. The project involves collaboration between the Prenatal Cardiology program of 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.

“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.”

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 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.

For more information about this new treatment, contact the clinical research team: Gil Wernovsky, M.D., Shriprasad Deshpande, M.D., Maria Fortiz.

t-cells attacking cancer cell

Children’s National spin-out cell therapy company receives funding

t-cells attacking cancer cell

Ongoing efforts by researchers at Children’s National Hospital to improve T-cell therapies have led to a spin-out company MANA Therapeutics which has announced a $35 million Series A financing. MANA is a clinical stage company creating nonengineered, allogeneic and off-the-shelf cell therapies that target multiple cancer antigens. Its EDIFY™ platform aims to educate T-cells that target multiple target multiple cell surface and intracellular tumor-associated antigens across a broad range of liquid and solid tumors, with an initial focus on relapsed acute myeloid leukemia (AML).

MANA was founded in 2017, and was based on the research and human proof-of-concept clinical trials conducted by Catherine Bollard, M.D., M.B.Ch.B., Conrad Russell Y. Cruz, M.D., Ph.D., Patrick Hanley, Ph.D. and other investigators at Children’s National along with their colleagues at Johns Hopkins Medical Center. The trials demonstrated safety and anti-tumor activity of MANA’s approach, and Children’s National provided an exclusive license to MANA to further develop this promising technology into commercial products in the field of immuno-oncology.

MANA Therapeutics recruited an experienced leadership team from industry including Martin B. Silverstein, M.D., president and CEO, who is a former senior executive at Gilead Sciences when they acquired Kite Pharma, one of the leading cell therapy companies, as well as Madhusudan V. Peshwa, Ph.D., chief technology officer, who joined from GE Health Care where he had been Chief Technology Officer and Global Head of R&D for Cell and Gene Therapies.

“MANA is building upon the strong foundational science established at Children’s National with a unique approach that promises to produce off-the-shelf allogeneic therapies that do not compromise on safety or efficacy,” said Marc Cohen, co-founder and executive chairman of MANA Therapeutics. “I look forward to continuing to support the MANA team as they advance their internal pipeline for the treatment of AML and select solid tumors, and expand the potential of EDIFY through strategic partnerships focused on new target antigens and cancer types.”

An international leader in the immunotherapy field, Dr. Bollard was an early believer in the potential of immune cell therapies to dramatically improve the treatment of patients with cancer and patients with life-threatening viral infections. Recently, she and her team at the Children’s National Center for Cancer and Immunology Research published findings in Blood showing T-cells taken from the blood of people who recovered from a COVID-19 infection can be successfully multiplied in the lab and maintain the ability to effectively target proteins that are key to the virus’s function.

“Over the past decade we have seen tremendous progress in cancer research and treatment and are beginning to unlock the potential of cell therapy for a variety of tumor types,” said Dr. Bollard. “The human proof-of-concept trials conducted by my team and colleagues showed potential for a nonengineered approach to educating T-cells to attack multiple tumor antigens, which MANA is expanding even further through refinement of the manufacturing process for an allogeneic product and application to a broader set of antigens in a variety of clinical indications and settings.”

Read more about how the Series A funding will enable rapid progress with MANA’s programs.