Cancer

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.

Dr. Javad Nazarian

Q&A with Dr. Javad Nazarian on his upcoming work on low-grade gliomas

Dr. Javad Nazarian

Supported by the Gilbert Family Foundation, Dr. Nazarian’s return is part of a special research program within the Gilbert Family Neurofibromatosis Institute that focuses on NF1 research.

Javad Nazarian, Ph.D., M.Sc., associate professor of Pediatrics at George Washington University and professor at the University of Zurich, has expanded his research group at Children’s National to focus on Neurofibromatosis type 1 (NF1) transformed low-grade gliomas (LGGs). Dr. Nazarian will apply his expertise from establishing a successful DIPG (diffuse intrinsic pontine glioma) and DMG (diffuse midline glioma) program in Zurich Switzerland and previously at Children’s National.

In addition to his continued research in Zurich, as a principal investigator at the Department of Genomics and Precision Medicine at Children’s National Dr. Nazarian plans on aggregating his knowledge to the new research and work spearheaded at Children’s National. As one of the first research teams to move to the Children’s National Research & Innovation Campus, Dr. Nazarian’s group is excited to use the opportunity to establish cutting-edge and clinically translational platforms.

Supported by the Gilbert Family Foundation, Dr. Nazarian’s return is part of a special research program within the Gilbert Family Neurofibromatosis Institute that focuses on NF1 research. This research includes associated gliomas with a special emphasis on NF1-associated transformed anaplastic LGGs. His team will develop new avenues of research into childhood and young adult NF-associated LGGs with a special emphasis on transformed high-grade gliomas.

Dr. Nazarian is excited for what’s to come and his goals are clear and set. Here, Dr. Nazarian tells us more about his main objectives and what it means for the future of pediatric neuro-oncology care at Children’s National.

  1. What excites you most about being back at Children’s National?

I have received most of my training at Children’s National, so this is home for me. Being one of the nation’s top children’s hospitals gives a unique advantage and ability to advocate for childhood diseases and cancers. It is always exciting to play a part in the vision of Children’s National.

  1. What are some of the lessons learned during your time working in Zurich? And how do you think these will compliment your work at Children’s National?

We developed a focused group with basic research activities intertwined with clinical needs.  The result was the launch of two clinical trials. I also helped in developing the Diffuse Midline Glioma-Adaptive Combinatory Trial (DMG-ACT) working group that spans across the world with over 18-member institutions that will help to design the next generation clinical trials. I will continue leading the research component of these efforts, which will have a positive impact on our research activities at Children’s National.

  1. How does your work focusing on low-grade gliomas formulating into high-grade gliomas expand and place Children’s National as a leader in the field?

Scientifically speaking, transformed LLGs are very intriguing. I became interested in the field because these tumors share molecular signatures similar to high-grade gliomas (HGGs). Our team has done a great job at Children’s National to develop tools – including biorepositories, avatar models, drug screening platforms, focused working groups, etc. – for HGGs. We will apply the same model to transformed LGGs with the goal of developing biology-derived clinical therapeutics for this patient population.

  1. How will this work support families and patients seeking specific neuro-oncology care?

We will develop new and high thruput tools so that we can better study cancer formation or transformation. These tools and platforms will allow us to screen candidate drugs that will be clinically effective. The main focus is to accelerate discovery, push drugs to the clinic, feed information back to the lab from clinical and subsequently design better therapies.

  1. You are one of the first scientists to move to the Children’s National Research & Innovation Campus. What are some of the valuable changes or advancements you hope to see as a result of the move?

The campus will provide high-end facilities, including cutting-edge preclinical space, and allow for team expansion. The close proximity to Virginia Tech will also provide an environment for cross-discipline interactions.

  1. Anything else you think peers in your field should know about you, the field or our program?

The team at Children’s National includes Drs. Roger Packer and Miriam Bornhorst. Both have provided constant clinical support, innovation and clinical translation of our findings. I look forward to working with them.

Jeffrey Dome

Q&A with Dr. Jeffrey Dome on his new role as Continental President of SIOP-North America

Jeffrey Dome

In March 2021, Jeffrey Dome, M.D., Ph.D., senior vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, was elected as the International Society of Paediatric Oncology’s (SIOP) Continental President of North America.

In March 2021, Jeffrey Dome, M.D., Ph.D., senior vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, was elected as the International Society of Paediatric Oncology’s (SIOP) Continental President of North America.

On October 21-24, the society will hold its 53rd SIOP Annual Congress virtually. During the congress, Dr. Dome will begin his 3-year term as SIOP continental president of North America and will also chair and speak at an educational symposium on current approaches to the treatment of recurrent Wilms tumor.

Dr. Dome attended his very first SIOP meeting in 2005 and was captivated by how regional context influences pediatric cancer treatment. In 2017, he was chair of the local organizing committee for the 49th annual congress in Washington, D.C., and served on the SIOP Board of Directors.  After 15 years of involvement and attending many of the annual meetings, Dr. Dome shares what he looks forward to while serving as continental president of SIOP North America and the legacy he hopes to leave behind.

  1. What does it mean to you to be elected SIOP continental president of North America?

I’m very excited about this role. There are several important societies and organizations in North America that have made a mark on the field of pediatric oncology, but SIOP is unique in its sole focus on childhood cancer and global approach to improving outcomes, as encapsulated by its vision statement: No child should die of cancer: cure for more, care for all.

  1. What excites you most about this role?

In an eye-opening statistic, North America has only about 10% of the global burden of childhood cancer and less than 2% of worldwide childhood cancer deaths.  Although we relentlessly strive to improve childhood cancer outcomes in the United States, what we experience here is just the tip of the iceberg of the worldwide problem. SIOP seeks to make a difference on the international level by improving education, research and access to care for children with cancer around the world. And I’m excited to have a platform to lead North American ambassadors to do that.

Even though North America has a relatively small fraction of the overall childhood cancer cases, we are one of the most well-resourced continents. The question is, how can we use our knowledge, technology and resources to help the rest of the world.  A big part of this role is to make connections and liaisons to move the needle on improving outcomes.

The other thing we’ve learned from a research standpoint is that pediatric cancers are relatively uncommon and are becoming even rarer through molecular classification, which divides cancers into small genetically defined subgroups.  While these advances are tremendously exciting, they require international collaboration to amass a sufficient number of patients to evaluate novel treatment strategies.  My vision for SIOP North America is to be a convener of researchers and connect people around the world to facilitate that work.

  1. What are some of your goals while serving as continental president?

We recently sent a survey to more than 450 SIOP North America members and had a nearly 45% response rate, which I’m told is superb.  This speaks to an excellent level of engagement in SIOP’s mission, with many members volunteering to participate in committees related to research, advocacy and global health. The majority of the respondents to the survey were physicians but improving childhood cancer treatment takes a holistic approach.  One of my main goals is to increase SIOP North American membership to grow the number of nurses, pharmacists, scientists, psychologists, other behavioral health specialists and clinical research coordinators onboard.

I’d like to also identify two to three very specific projects that will impact pediatric cancer care on a global level. There are different ways to do that. We could improve education in different areas around the world (nursing education that we provide to areas that are lacking nursing support, for example). It could be research education and database education for regions of the world that would like to develop more robust research programs. It can also be medical support and developing medical guidelines for oncologists around the world that are adjusted to different levels of resources that are available.

The other goal would be to enhance supportive care and education for cancer care delivery on the global level.

  1. Why is this work important for you?

One of my mentors from when I was a junior faculty member advised me that to be a well-rounded oncologist, one must be familiar with how childhood cancer is treated around the world because different regions have different approaches. There is something to be learned from everyone.  I took that advice to heart and have tried to look beyond the North American approaches.  I think it’s very important to have a global exchange of ideas and serving as continental president of SIOP-North America will enable more to facilitate this dialogue.

  1. What’s the legacy or impact you hope to leave behind?

SIOP North America has a strong and devoted membership but has largely functioned at the level of the individual members.  I hope to bring more structure to the organization to tackle the global challenges of childhood cancer treatment.

Once this structure is in place, I hope to complete two or three SIOP-North America initiatives that have a measurable impact on improving childhood cancer care delivery or outcomes.  The specific projects have yet to be defined but will likely be in the categories of enhancing education, supportive care and facilitating research infrastructure. There’s so much to tackle that if you just look at the overall problem of childhood cancer, it’s overwhelming.  We’re not going to be able to solve everything in three years, but if we could have a few victories and be able to move the needle in some areas, I think that would be a huge success.

close-up of two people holding hands

Effective palliative end-of-life care for Spanish-speaking teens with cancer

close-up of two people holding hands

Despite research showing how vital advance care planning conversations are between adolescents with cancer and their families, the efficacy of pediatric advance care planning has not been studied in Hispanic adolescents living with cancer.

Pediatric advance care planning has positively impacted English-speaking adolescents with cancer and HIV, but it has not been studied in other populations — exacerbating health disparities. In a new study published in Clinical Practice in Pediatric Psychology, Maureen E. Lyon, Ph.D., lead author and clinical health psychologist at Children’s National Hospital, and other experts look to adapt and refine the evidence-based Family-Centered Advance Care Planning for Teens with Cancer (FACE®-TC) for Spanish-speaking adolescents with cancer. Using a community-based participatory approach and key informant interviews with patients and families, the experts identified important themes and outcomes.

Despite research showing how vital advance care planning conversations are between adolescents with cancer and their families, the efficacy of pediatric advance care planning has not been studied in Hispanic adolescents living with cancer. According to the authors, this creates a health disparity as Hispanic adolescents with cancer and their families do not have access to or provision of this potentially beneficial service.

“If successfully adapted, FACE-TC Spanish would benefit patient’s communication with their families about their end-of-life treatment preferences if the worse were to happen and they could not communicate,” Dr. Lyon said. “It could also increase families’ positive appraisal of their caregiving and increase communication about goals of care with treating physicians, so the first conversation about goals of care is not in the intensive care unit.”

The study’s findings showed that first-generation Spanish-speaking individuals living in the Washington D.C., Maryland and Virginia area wanted community education about advance care planning for Spanish-speaking adults, many of whom were unfamiliar with the concept.

These findings, in turn, showed the need for future research to include informational messages on Hispanic radio stations, educational workshops or radionovelas.

“We learned that fear of deportation meant that potential participants only felt safe to participate while at the hospital,” Dr. Lyon added. “Because of COVID-19, this was not feasible during the study period. There was consensus that families should be involved in the conversations and that the goals of care conversations and advance directives should be communicated to the physician.”

While this is the first study to adapt a family-centered approach to pediatric advance care planning for Spanish-speaking teens with cancer and their families, it is consistent with cultural values of ‘familismo’ (family) and ‘respecto’ (respect).

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.”

Sickle-Cell-Blood-Cells

Children’s National joins ASH RC Sickle Cell Disease Clinical Trials Network

Sickle-Cell-Blood-Cells

The American Society of Hematology Research Collaborative (ASH RC) has announced the first 10 clinical research consortia to join the ASH RC Sickle Cell Disease Clinical Trials Network. Children’s National Hospital will be one of the clinical trials units to serve in the DMV Sickle Cell Disease Consortium (DMVSCDC).

The sites will be able to enroll children and adults living with sickle cell disease (SCD) within their patient populations in clinical trials as part of an unprecedented national effort to streamline operations and facilitate data sharing to expedite the development of new treatments for this disease.

“As part of the ASH RC SCD clinical trials network, we will learn regionally and nationally how sickle cell patients respond differently to therapies, hopefully giving us clues to provide more successful targeted and individualized treatments that will improve the morbidity and mortality in sickle cell disease patients,” said Andrew Campbell, M.D., director of Comprehensive Sickle Cell Disease Program at Children’s National.

SCD is a chronic, progressive, life-threatening, inherited blood disorder that affects more than 100,000 Americans and an estimated 100 million persons worldwide. Clinical trials hold incredible promise for the development of much-needed new treatments, and possibly even a cure. While there are currently only four U.S. Food and Drug Administration (FDA)-approved drugs to treat the disease, there is a robust SCD drug development pipeline that will drive demand for clinical trials to a new level, providing a prime opportunity to advance treatment and care of those affected by SCD.

“We are proud that the DMV Sickle Cell Disease Consortium will contribute regionally, allowing our patients and families to benefit from new clinical trials investigating new therapies that may improve the clinical course and quality of life of patients living with sickle cell disease in the DMV region,” Dr. Campbell added. “We will also have an integrated Community Advisory Board who will continue to provide guidance and expertise for our consortium including patients, families and caregivers.”

Read the full list of other hospitals joining the network.

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation

Using targeted signaling pathway therapy to prevent pediatric glioma formation

Researchers at Children’s National Hospital identified a vulnerability in a developmental signaling pathway that can be hijacked to drive pediatric low-grade glioma (pLGG) formation, according to a pre-clinical study published in Developmental Cell. The study demonstrated that targeted treatment prevents tumor formation, long before irreversible damage to the optic nerve can cause permanent loss of vision. This finding will inform chemo-prevention therapeutic trials in the future.

Brain tumors are the most common solid tumors in children, the most prevalent of which are pLGGs. Approximately 10% to 15% of pLGGs arise in patients with the familial cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This is a genetic condition that increases risks of developing tumors along the nerves and in the brain.

Nearly 20% of children with NF1 develop pLGGs along the optic pathway, also known as NF1-associated optic pathway glioma (NF1-OPG). Despite many advances in cancer therapy, there are no definitive therapies available that prevent or alleviate the neurological deficits (i.e. vision loss) and that could improve the quality of life.

“The evidence presented can inform chemoprevention therapeutic trials for children with NF1-OPG,” said Yuan Zhu, Ph.D., scientific director and Gilbert Family Endowed professor at the Gilbert Family Neurofibromatosis Institute and associate director of the Center for Cancer and Immunology Research, both part of Children’s National. “This therapeutic strategy may also be applicable to children with the developmental disorders that are at high risk of developing pediatric tumors, such as other RASopathies.”

The mechanism of vulnerability to pLGGs during development is not fully understood. It has been implied that the cell population of origin for this debilitating tumor is transiently proliferative during development. The NF1 gene produces a protein that helps regulate normal cell proliferation, survival and differentiation by inhibiting MEK/ERK signaling. When there is loss of function in NF1, it abnormally activates the MEK/ERK signaling pathway and leads to tumor formation.

Certain cells that exist transiently during the normal development of the brain and optic nerve are vulnerable to tumor formation because they depend on the MEK/ERK signaling. In this study, researchers in Zhu’s lab identified cells that were MEK/ERK pathway dependent and grew during a transient developmental window as the lineage-of-origin for NF1-OPG in the optic nerve. The researchers used a genetically engineered pre-clinical model to design a transient, low-dose chemo-preventative strategy, which prevented these tumors entirely.

“When we provided a dose-dependent inhibition of MEK/ERK signaling, it rescued the emergence and increase of brain lipid binding protein-expressing (BLBP+) migrating GPs glial progenitors, preventing NF1-OPG formation,” wrote Jecrois et al. “Equally importantly, the degree of ERK inhibition required for preventing NF1-OPG formation also greatly improved the health and survival of the NF1-deficient model.”

Ongoing clinical trials using MEK inhibitors (MEKi) are being performed for children as young as 1 month old. Thus, it becomes increasingly feasible to design a chemo-preventative trial using a MEKi to treat children with NF1. These treatment paradigms may have the potential to not only prevent OPG formation, but also other NF1-associated and RASopathies-associated developmental defects and tumors.

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation

A transient low-dose MEKi treatment in a pre-clinical model prevents NF1-OPG formation. The middle panels highlighted by a red dashed box show an OPG in the optic nerve (arrows, top), exhibiting abnormal triply-labeled tumor cells, inflammation and nerve damage (the bottom three panels), which are absent in the normal (left panels) or MEKi-treated Nf1-deficient optic nerves (right panels). [Credit: Jecrois et al., Developmental Cell, (2021)]

Yuan Zhu

Yuan Zhu, Ph.D., receives Outstanding Scientist Award

Yuan Zhu

The George Washington University (GW) Cancer Center recently announced the selection of the 2021 GW Cancer Center Awards, recognizing excellence in research, mentorship and early career contributions.

The GW Cancer Center Outstanding Scientist Award was presented to Yuan Zhu, Ph.D., professor of pediatrics at the GW School of Medicine and Health Sciences (SMHS) and Children’s National Hospital. The award is presented to faculty members who make a noteworthy contribution in the areas of basic science, clinical science, translational science or population science.

In his nomination, Dr. Zhu was cited for his contributions to the understanding of the mechanisms underlying the development of tumors and altered brain development arising in the setting of the inherited condition neurofibromatosis type 1 (NF1). “Throughout his career, Dr. Zhu has had a remarkable consistency of focus in his scholarly work, where he has sought to advance new molecular and mechanistic insights to understand the biological basis of NF1 and the cancers arising in individuals affected by this genetic disease.”

You can find a full list of award winners here.

Jia-Ray Yu

Virginia Tech announces cancer biologist to launch lab at Children’s National Research & Innovation Campus

Jia-Ray Yu

Jia-Ray Yu, Ph.D., will be an assistant professor at Virginia Tech’s Fralin Biomedical Research Institute at Virginia Tech Carilion and in the Department of Biomedical Sciences and Pathobiology in the Virginia-Maryland College of Veterinary Medicine, as well as an adjunct assistant professor at Children’s National Hospital starting Sept. 1.

Every year, 790 Americans are diagnosed with a rare and deadly form of brain cancer called a diffuse midline glioma, according to the National Cancer Institute. Tragically, only 2% of children with this disease will survive five years.

Jia-Ray Yu, Ph.D., a new assistant professor joining the Fralin Biomedical Research Institute at Virginia Tech Carilion and the Department of Biomedical Sciences and Pathobiology on Sept. 1, studies these fast-growing, treatment-resistant brain tumors, which commonly affect children, with hopes of identifying new therapeutic approaches. Yu will be the first of several cancer researchers to work in Virginia Tech’s brand-new research facility on the Children’s National Research & Innovation Campus in Washington, D.C.

“This disease is fatal and there is no cure. Any hint at a potential therapeutic pathway could be helpful,” said Yu, who will also hold an adjunct faculty position in the Children’s National Hospital Center for Cancer and Immunology Research.

Michael Friedlander, Virginia Tech’s vice president for health sciences and technology, and executive director of the Fralin Biomedical Research Institute, led Yu’s recruitment.

“Jia-Ray Yu is one of the rising leaders in understanding the molecular substrates of aggressive forms of pediatric brain cancer that can contribute to the identification of innovative therapeutic approaches. Moreover, his fundamental research into chromatin remodeling is at the very forefront of this area of emerging area importance in molecular biology,” Friedlander said. “We are very fortunate to have been able to attract Dr. Yu to Virginia Tech as we grow our greater cancer research community and our partnership with one of the nation’s pre-eminent children’s health care delivery and research systems, Children’s National Hospital.”

Yu studies how genes change when an ordinary brain cell develops malignant traits.

In particular, he examines changes in proteins called histones that spool strands of DNA molecules into a substance called chromatin, which forms chromosomes. In addition to packing genetic material into cells, these structures also play a key role in telling genes when to turn on or off.

Faulty histone proteins alter the chromatin’s structure, which in turn garbles the genetic instructions that regulate a cell’s behavior, growth rate, and identity. Furthermore, when this defective cell divides, its two daughter cells inherit the original cell’s chromatin, the malignant traits are passed on, and the cancer grows.

“These epigenetic features of chromatin are distinct from the DNA itself, yet they are inherited during cellular division,” said Yu.

Yu said 80% of tumors from diffuse midline gliomas begin with one cell that has a histone gene defect. He found when this tiny piece of a specific histone, called H3K27, stops working properly, it creates a series of domino-like reactions that cause normal cells to become cancerous.

Yu recently examined this molecular cascade as a postdoctoral fellow in the lab of Danny Reinberg, Terry and Mel Karmazin Professor in the NYU Grossman School of Medicine Department of Biochemistry and Molecular Pharmacology, and senior Howard Hughes Medical Institute Investigator.

The research team identified two genes, NSD1 and NSD2, appear to be the molecular fingers that tap the histone domino. When these genes are disabled, diffuse midline gliomas stop growing in a cultured lab dish, and in animal models. They also identified signaling pathways that could be targets for new drug therapies. Their findings are available in pre-print and will be published this summer in Science Advances.

Yu’s laboratory at the new Children’s National Research & Innovation Campus in Washington, D.C., will build on this fundamental question: How can chromatin-associated molecules be targeted to stop aggressive cancers?

Yu says that as he studies the molecular genesis of diffuse midline glioma, he may also identify therapeutic approaches for other diseases, such as leukemia and Sotos syndrome, that involve mutations in these chromatin-associated molecules.

His research team will combine biochemistry, single-molecule imaging, next-generation sequencing, biophysics, and preclinical research to develop and test new pharmaceutical alternatives to chemotherapy and radiation.

Yu was awarded a three-year American Cancer Society Postdoctoral Fellowship while working in Reinberg’s laboratory.

He completed a bachelor’s degree in biological science and technology at National Chiao Tung University in Taiwan, and his doctoral degree in genetics at Stony Brook University and Cold Spring Harbor Laboratory, where he studied signaling pathways in lung adenocarcinoma metastasis.

Recruitment for research positions in the Yu lab begins this summer.

Deepika Darbari

Deepika Darbari, M.D., receives the 2021 ASH Award for leadership in promoting diversity

Deepika Darbari

Deepika Darbari, M.D., hematologist at Children’s National Hospital, is being honored by the American Society of Hematology (ASH) for her significant contributions to the mentorship and training of underrepresented minority researchers and for advancing the care for underrepresented patient populations, primarily individuals living with sickle cell disease (SCD). Dr. Darbari started studying and treating SCD at Howard University, where she also saw firsthand the many disparity issues surrounding the condition, such as inadequate funding, limited treatment options and biases and stigma. She also learned about barriers to career development that minority students faced. She worked to address those issues through her mentorship.

Dr. Darbari has mentored many medical students, residents and fellows whose research projects focused on improving care for individuals living with SCD. She has also fostered the careers of junior investigators of underrepresented minorities as well as served as a member of the ASH Minority Medical Student Award Program, the ASH Committee on Promoting Diversity and the ASH Women in Hematology working group, all in her continued efforts to increase diversity, equity and inclusion at ASH and in the health care community at large.

cancer cell

Muller Fabbri, M.D., Ph.D.: The microRNA journey and the future of cancer therapy

cancer cell

Children’s National Hospital welcomes Muller Fabbri, M.D. Ph.D., as associate director for the Center for Cancer and Immunology Research at the Children’s National Research Institute. In this role, he will build and lead the Cancer Biology Program while developing and conducting basic and translational research. Dr. Fabbri will also develop multidisciplinary research projects with various clinical divisions, including oncology, blood and marrow transplantation, pathology and hematology.

Dr. Fabbri shares his journey working with microRNAs, how his work is advancing the field and his vision for the Center for Cancer and Immunology Research at Children’s National.

Q: You have been working with microRNAs for quite some time. How are you exploring the role of microRNAs in cancer?

A: It was well established within the scientific community that a gene, which is a piece of DNA, becomes a piece of RNA and then becomes a protein. This thought process was pretty much a one-way flow of information that we had, going from DNA to protein as part of a cell function. But, almost 30 years ago, it was discovered that this is not entirely true because what happens is that some of these genes that are transcribed into RNA do not become a protein. Instead, they stay as RNA. Some of these RNAs are tiny and have short sequences, which is why they are called microRNAs.

I work primarily on microRNAs and non-coding RNAs and my research studies focus on the role that microRNAs play in cancer. I can take a cancer cell and a healthy cell and observe how these microRNAs are expressed in the two different cell populations. In this way, the microRNAs expressed in cancer cells are profoundly different from the microRNAs expressed in healthy cells.

We conducted a series of studies to observe what happens to a cancer cell if we restore normal levels of certain microRNAs like the ones you would see in a normal cell. We discovered that by restoring some of these microRNAs levels it led to the death of the cancer cells, suggesting that this approach may be used as a cancer treatment. This is one of the research areas that I will further develop at Children’s National as I seek to understand the mechanisms that control microRNA expression and subsequently affect cancer cell proliferation. With this information, we can target these mechanisms and create drugs that interfere with this function and, hopefully, stop cancer cell growth.

Q: Can you tell us about that eureka moment with your best friend during a lunch break?

A: This was a bit of a crazy idea. I will never forget. I shared a theory during a lunch break with a friend. I dared to ask, what if microRNAs worked like hormones? MicroRNAs can be detected in the blood of patients with cancer, and they can be transferred from one cell to another inside of little vesicles called exosomes. If you think about it, I further asked, what other molecules in our body behave like that — i.e. are secreted, circulate in the blood and then transferred to a target cell? My friend replied, “well, those would be hormones.” To which, I added, yes, exactly! Then, why do we not think of RNAs as hormones? And I quote him now, “you are crazy, but if it works it is huge.”

I felt that I had some validation from my best friend, so I decided to invest in this crazy idea, carving extra time on the side while working on my “safe” projects. It was one of those rare cases in science, where in a little over a year, we showed for the first time that microRNAs do not only work the traditional way, but they can also work as hormones. They do have a receptor protein to attach to, and by binding to this protein, they trigger a response in a cell that can be pro-tumoral or anti-tumoral.

Even today, if you open a textbook of endocrinology, under the chapter of hormones, it mentions that there are only two categories, proteins and lipids. Well, it turns out there is a third category, which is nucleic acids because of RNAs.

Q: You mentioned other research areas of interest as it relates to cancer cell biology. What are they?

A: The other line of research that I am developing stems from the original observation that I made in 2012. Cancer cells release tiny vesicles that I like to compare to envelopes containing a written message — the RNA and microRNA. These vesicles released in the surrounding environment contain a message captured by immune cells, known as macrophages. Macrophages act as scavengers in our bodies. In cancer, macrophages are supposed to digest and destroy the cancer cell. However, it turns out that they also have the proper receptor to receive and read the message enclosed in the vesicles. Then, something shocking happens. The macrophage stops fighting the cancer cell and starts producing proteins called cytokines that promote cancer growth. This finding means that we are 180 degrees apart from what we thought at the beginning. A lot of macrophages in the cancer are good news for the patient because they are supposed to kill cancer cells, but because of this mechanism, a lot of macrophages can be bad news since they can also help the cancer cell grow.

My contribution to this discovery was to investigate how the macrophage response is mediated. I discovered that macrophages operate, at least in part, by expressing receptors that bind to microRNAs released by the cancer cell, thereby favoring cancer growth. In the pediatric cancer field we discovered that because of this microRNA–receptor interaction, the pediatric tumor neuroblastoma becomes resistant to chemotherapy. Therefore, one of the strategies we are working on now is to interfere or impair these negative communications between the cancer cell and immune cell. We want to disrupt these communications so the macrophage cannot read the message from the cancer cell anymore and instead keeps doing its job to fight the cancer. We hope that we can leverage this approach to develop novel cancer treatments or create strategies that improves immune cell function in the presence of the patient’s current therapy to enhance an anti-cancer treatment response.

Q: What is your vision for the Center of Cancer and Immunology Research?

A: I am very excited about what I saw at Children’s NationalI was delighted to talk to many faculty members, and I recognized the immense talent within the Center. I would like to help elevate and enhance the cancer biology program focused on solid tumors, and augment the work being done in this space by the cell therapy program. The clinicians are clearly eager to collaborate with the basic scientists including the sharing of samples and ideas, which is not typical of many scientific environments. My other goal is to ensure that the Cancer Biology Program plays a central role in acquiring an NCI-Designated Cancer Center recognition often given to institutions that stand out in scientific leadership and clinical research. Finally, I want to create the first national center that develops extracellular vesicles as an innovative treatment strategy for cancer. Importantly, I think that we have all the resources and connections at Children’s National that are necessary to realize this vision!

 

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.

US News badges

For fifth year in a row, Children’s National Hospital nationally ranked a top 10 children’s hospital

US News badges

Children’s National Hospital in Washington, D.C., was ranked in the top 10 nationally in the U.S. News & World Report 2021-22 Best Children’s Hospitals annual rankings. This marks the fifth straight year Children’s National has made the Honor Roll list, which ranks the top 10 children’s hospitals nationwide. In addition, its neonatology program, which provides newborn intensive care, ranked No.1 among all children’s hospitals for the fifth year in a row.

For the eleventh straight year, Children’s National also ranked in all 10 specialty services, with seven specialties ranked in the top 10.

“It is always spectacular to be named one of the nation’s best children’s hospitals, but this year more than ever,” says Kurt Newman, M.D., president and CEO of Children’s National. “Every member of our organization helped us achieve this level of excellence, and they did it while sacrificing so much in order to help our country respond to and recover from the COVID-19 pandemic.”

“When choosing a hospital for a sick child, many parents want specialized expertise, convenience and caring medical professionals,” said Ben Harder, chief of health analysis and managing editor at U.S. News. “The Best Children’s Hospitals rankings have always highlighted hospitals that excel in specialized care. As the pandemic continues to affect travel, finding high-quality care close to home has never been more important.”

The annual rankings are the most comprehensive source of quality-related information on U.S. pediatric hospitals. The rankings recognize the nation’s top 50 pediatric hospitals based on a scoring system developed by U.S. News. The top 10 scorers are awarded a distinction called the Honor Roll.

The bulk of the score for each specialty service is based on quality and outcomes data. The process includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with the most complex conditions.

Below are links to the seven Children’s National specialty services that U.S. News ranked in the top 10 nationally:

The other three specialties ranked among the top 50 were cardiology and heart surgerygastroenterology and gastro-intestinal surgery, and urology.

Muller Fabbri

Children’s National Hospital welcomes Muller Fabbri, M.D., Ph.D.

Muller Fabbri

Dr. Fabbri joins Children’s National from the University of Hawaii Cancer Center, where he was a tenured associate professor and leader of the Cancer Biology Program. He received his medical degree at the University of Pisa in Italy and his Ph.D. degree at the Second University of Naples in Italy.

Children’s National Hospital is pleased to announce it has selected Muller Fabbri, M.D. Ph.D., as associate director for the Center for Cancer and Immunology Research at the Children’s National Research Institute. In this role, he will build and lead the Cancer Biology Program while developing and conducting basic and translational research. Dr. Fabbri will also develop multidisciplinary research projects with various clinical divisions, including oncology, blood and marrow transplantation, pathology and hematology.

A distinguished lecturer, instructor, researcher, public speaker and mentor, Dr. Fabbri’s research interest focuses on decoding cancer cellular biology riddles that lead to personalized medicine. He has pioneered a theory that explains non-coding RNAs’ functioning in intercellular communication that promotes cancer cell growth, dissemination and drug resistance. To better understand the immune response against cancer cells, he has investigated the role of exosomes and other extracellular vesicles. Inflammation, tumor microenvironment and immunity, as it relates to cancer, are other research areas of interest.

“I feel fortunate to be working with Dr. Catherine Bollard and her team at an extraordinary research center,” said Dr. Fabbri. “I am eager to join Children’s National, and I look forward to learning from this leadership team, which also includes Dr. Vittorio Gallo, Dr. Mark Batshaw and Dr. Jeffery Dome.”

Dr. Fabbri was drawn to Children’s National because of its proximity to partners like the National Institute of Health (NIH), the Food Drug Administration (FDA), various universities and the private sector, fostering a rich scientific environment. One of Dr. Fabbri’s many goals, is to make sure that the Cancer Biology Program plays a central role in the acquisition of an NCI-Designated Cancer Center recognition often given to institutions that stand out in scientific leadership and clinical research.

Dr. Fabbri joins Children’s National from the University of Hawaii Cancer Center, where he was a tenured associate professor and leader of the Cancer Biology Program. He received his medical degree at the University of Pisa in Italy and his Ph.D. degree at the Second University of Naples in Italy.

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.

little girl with cancer

Pediatric advance care planning linked to families’ positive caregiving appraisals

little girl with cancer

In a first-of-its-kind clinical trial, experts directly measured families’ appraisals of caregiving as one potential benefit to pediatric advance care planning.

Little is known about how families respond to pediatric advance care planning. Physicians often are concerned that initiating pediatric advance care planning conversations with families is too distressing for them.

But a first-of-its-kind clinical trial led by Maureen E. Lyon, Ph.D., F.A.B.P.P., principal investigator, and Jessica Thompkins, B.S.N, R.N., C.P.N., research nurse coordinator, both at Children’s National Hospital, directly measured families’ appraisals of caregiving as one potential benefit to pediatric advance care planning.

The clinical trial, summarized in a video abstract,  shows that compared to controls, families’ participation in Family-Centered Advance Care Planning for Teens with Cancer (FACE®-TC) resulted in positive appraisals of their caregiving for their child with cancer while not significantly burdening them with distress or strain.

“Clinicians can be assured of the benefit and tolerability of this person-centered/family-supported model of pediatric advance care planning,” Thompkins says.

Families randomized to the FACE®-TC pediatric advance care planning intervention showed significantly greater positive family appraisals of caregiving and overwhelmingly, families reported the experience as worthwhile without adding undue distress or strain, compared to controls.

“This evidence meets practice guidelines for an intervention that could be extended to other adolescents living with serious illnesses and their families,” Dr. Lyon adds.

The clinical trial’s results also showed that FACE®-TC families significantly increased positive caregiving appraisals at three months post-intervention compared to controls. No significant differences were found between groups for strain or distress.

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.

Sickle-Cell-Blood-Cells

Treating neurocognitive difficulties in children with sickle cell disease

Sickle-Cell-Blood-Cells

An adaptive cognitive training program could help treat attention and working memory difficulties in children with sickle cell disease (SCD), a new study published in the of Journal of Pediatric Psychology shows.

An adaptive cognitive training program could help treat attention and working memory difficulties in children with sickle cell disease (SCD), a new study published in the of Journal of Pediatric Psychology shows.

These neurocognitive difficulties have practical implications for the 100,000 individuals in the U.S. with SCD, as 20-40% of youth with SCD repeat a grade in school and fewer than half of adults with SCD are employed. Interventions to prevent and treat neurocognitive difficulties caused by SCD have the potential to significantly improve academic outcomes, vocational attainment and quality of life.

The study, led by Steven Hardy, Ph.D., director of Psychology and Patient Care Services at the Center for Cancer and Blood Disorders at Children’s National Hospital, examined a promising approach using an adaptive cognitive training program (known as Cogmed Working Memory Training) that patients complete at home on an iPad.

Using a randomized controlled trial design, children were asked to complete Cogmed training sessions 3 to 5 times per week for about 30 minutes at a time until they completed 25 sessions. The Cogmed program involves game-like working memory exercises that adapt to the user’s performance, gradually becoming more challenging over time as performance improves. The team found that patients with sickle cell disease (SCD) who completed the cognitive training intervention showed significant improvement in visual working memory compared to a waitlist group that used Cogmed after the waiting period. Treatment effects were especially notable for patients who completed a training “dose” of 10 sessions.

“Patients who completed at least 10 cognitive training sessions showed improved visual working memory, verbal short-term memory and math fluency,” Dr. Hardy said.

SCD increases risk for neurocognitive difficulties because of cerebrovascular complications (such as overt strokes and silent cerebral infarcts) and underlying disease characteristics (such as chronic anemia). Neurocognitive effects of SCD most commonly involve problems with attention, working memory and other executive functions.

“This study demonstrates that digital working memory training is an effective approach to treating neurocognitive deficits in youth with sickle cell disease,” Dr. Hardy added. “We also found that benefits of the training extend to tasks that involve short-term verbal memory and math performance when patients are able to stick with the program and complete at least 10 training sessions. These benefits could have a real impact on daily living, making it easier to remember and follow directions in school and at home, organize tasks or solve math problems that require remembering information for short periods of time.”

To date, there have been few efforts to test interventions that address the neurocognitive issues experienced by many individuals with SCD. These findings show that abilities are modifiable and that a non-pharmacological treatment exists.

The Comprehensive Sickle Cell Disease Program at Children’s National is a leader in pediatric SCD research and clinical innovation. This study was funded by a grant from the Doris Duke Charitable Foundation, which was the only Innovations in Clinical Research Award ever awarded to a psychologist (out of 31 grants totaling over $15 million), since the award established a focus on sickle cell disease in 2009.

Novel cancer vaccine targets oncogenes known to evade immunity in melanoma and neuroblastoma models

"Neuroblastoma of the Adrenal Gland (2)" by euthman is licensed under CC BY 2.0

Neuroblastoma of the Adrenal Gland (2)” by euthman is licensed under CC BY 2.0.

A personalized tumor cell vaccine strategy targeting Myc oncogenes combined with checkpoint therapy creates an effective immune response that bypasses antigen selection and immune privilege, according to a pre-clinical study for neuroblastoma and melanoma. The neuroblastoma model showed a 75% cure with long-term survival, researchers at Children’s National Hospital found.

Myc is a family of regulator genes and proto-oncogenes that help manage cell growth and differentiation in the body. When Myc mutates to an oncogene, it can promote cancer cell growth. The Myc oncogenes are deregulated in 70% of all human cancers.

Myc mutations, like the amplification of c-MYC and MYCN, are associated with host immune suppression in melanoma and neuroblastoma tumors, according to the study published in The Journal for Immunotherapy of Cancer.

“Paradoxically, from an immunotherapeutic perspective, a lack of an immune response may offer an opportunity to target those tumors [melanoma and neuroblastoma] that would be less resistant to host immunity assuming potent cellular immunity can be generated against the tumor,” said the authors.

The findings suggest that small molecule inhibitors — I-BET726 and JQ1 — suppress Myc’s uncontrolled cellular proliferation and enhance the immune response against tumor cells themselves, enabling their use as a tumor cell vaccine. The combination of cell vaccine and available therapies that keep the immune responses in check, also known as checkpoint inhibitor therapy, can help inform a personalized therapeutic tumor vaccine in the future.

“The work is pre-clinical and although we have seen excellent responses in these models, we need to determine whether this will also be effective in humans,” said Xiaofang Wu, staff scientist III at Sheikh Zayed Institute for Pediatric Surgical Innovation and lead author.  “For this purpose we have started laboratory testing in human cells. Our eventual hope is to translate these basic science findings to clinical application.”

There is a need for more effective therapies for neuroblastoma and melanoma, given the poor outcome of patients experiencing high-risk or advanced disease through traditional chemotherapy methods.  While the field has developed tumor vaccines and immune-based therapies, c-MYC and MYCN seem to protect the tumor against an immune response, so they often evade cure.

The researchers cautioned that both models induced potent immunity but draw different results, which means that this novel therapeutic vaccine is more effective in the neuroblastoma model than in the melanoma model. The neuroblastoma model resulted in a remarkable 75% cure and significantly improved long-term survival despite a larger initial tumor challenge.

“In contrast, the melanoma tumor gained adaptive resistance that is associated with an imbalance between tumor cell growth and cytotoxic killing and thus the vaccine failed to eradicate the tumor,” said the authors. “Despite potent immune effects from the vaccine, other immunosuppressive molecules will need to be targeted to see the full effects of the vaccine protocol in the melanoma model.”

The study proposes a framework that could be translated for therapeutic patient-specific vaccines for MYCN-amplified neuroblastoma tumors resistant to available therapies.

To understand the exact role of c-Myc and MYCN amplification and their association with immune suppression, the researchers examined 21 human neuroblastoma samples — the majority with metastatic disease — and 324 melanoma samples where only 30 were categorized as MYC amplified. Based on the oncogene’s capability to suppress the immune response, the researchers combined checkpoint inhibitors with pharmacologic molecules — I-BET726 and JQ1 — to target Myc oncogenes in mouse neuroblastoma and melanoma models. They also tested for the effects of different doses, drug combinations and incubation times on tumor cell proliferation, differentiation and gene alteration.

Authors on the study from Children’s National Hospital include: Xiaofang Wu, Ph.D., Marie Nelson, M.D., Mousumi Basu, Priya Srinivasan, Ph.D., Christopher Lazarski, Ph.D., and Anthony Sandler, M.D.