New Funding Supports Researchers’ Search for Neurofibromatosis Type 1 Therapies

The Gilbert Family Foundation will support CHOP researchers focused on understanding the biology and discovery of new immunotherapy targets for NF1-associated brain tumors.

By Lauren Ingeno

The Gilbert Family Foundation has invested $10 million in funding to researchers at Children's Hospital of Philadelphia, which houses one of the oldest and foremost neurofibromatosis clinics in the United States, to accelerate scientific understanding and development of therapies for tumors associated with neurofibromatosis type 1 (NF1). Affecting one in every 3,000 people, NF1 is one of the most common cancer predisposition syndromes that you've likely never heard of.

Usually diagnosed during childhood, a change in the NF1 gene causes the disease and can lead to the formation of both benign and malignant tumors throughout the body. Though often benign, tumors that develop in the brain and body in the setting of NF1 can lead to serious complications, including vision loss and severe pain.

Sometimes, an NF1-associated glioma — a type of brain tumor — can turn malignant. Since malignant and highly aggressive brain tumors in NF1 are rare, research on this group of patients and their treatment options is scarce.

CHOP has a longstanding research program focused on optic pathway and other low-grade brain tumors, including a project funded with $5.4 million from the Gilbert Family Foundation that was awarded in 2021. Robert Avery, DO, MSCE, a pediatric neuro-ophthalmologist in the Division of Ophthalmology at CHOP, and Michael Fisher, MD, chief of Neuro-Oncology and director of CHOP's Neurofibromatosis Program, are also leading a natural history study that is tracking 250 NF1 patients with optic pathway tumors across 25 clinics to understand their natural progression.

Now, the Gilbert Family Foundation established by Dan and Jennifer Gilbert, has committed $5 million to fund three new CHOP projects focused on understanding the biology and discovery of new immunotherapy targets for NF1-associated brain tumors. The projects will be led by Chelsea Kotch, MD, MSCE, a pediatric neuro-oncologist; John M. Maris, MD, a pediatric oncologist and Giulio D'Angio Chair in Neuroblastoma Research; and Thomas De Raedt, PhD, a research scientist.

"The support from the Gilbert Family Foundation to undertake these new research projects will enable us to make new discoveries that may lead to breakthroughs in the management of patients with NF1 and gliomas," Dr. Fisher said.

Understanding Risk Factors for Better Outcomes

As a clinician and a parent, Dr. Kotch said she faces an "emotional and personal challenge" each time she speaks with the family of an NF1 patient who has been newly diagnosed with a brain tumor. She's unable to give them a definitive outline of what the next few years of their child's life will look like.

"It's hard to say to a family, 'We think half of children will need treatment, but we don't know who those kids are and when they will need it,'" Dr. Kotch said.

For some other types of childhood cancers, clinicians can identify subgroups of patients and individualize their level of care, based on factors such as their age and characteristics of their tumor. It's a process called risk stratification, and it enables medical teams to make important decisions tailored to a patient's specific disease, rather than using a "one-size-fits-all" approach.

Contrary to other childhood cancers, there is not enough large-scale, quality data available for researchers to develop risk stratification schema for NF1-associated glioma, Dr. Kotch said. Funding from the Gilbert Family Foundation will allow Dr. Kotch to lead two studies that will do just that.

Dr. Kotch's second project is a prospective study that will enroll 270 children from multiple clinical sites with NF1-associated brain tumors — both benign and malignant — occurring outside of the optic pathway.

Rather than assigning or testing specific treatments on this group of patients, each enrolled child's clinician will decide if or when a child receives treatment for the glioma. Each clinic will gather imaging, physical, behavioral, quality-of-life, and other information to see which children require treatment for their tumors and how different therapies affect outcomes.

"Especially for patients with low-grade tumors, we expect these children to live a long and healthy life, and so, measuring their functional and quality of life outcomes matters most," Dr. Kotch said. "We really want them to be able to keep up with their peers on the playground."

Capturing that data, Dr. Kotch said, will help to establish standard-of-care guidelines and to inform further epidemiological studies.

"This research will help tell us whether patients need MRIs every three months, or maybe that imaging can be spaced out to every six months, or even a year," Dr. Kotch said. "Are we doing too much surveillance, or too little? How is that impacting patients' quality of life? I really think those are the most important questions to focus on."

Harnessing CAR T-Cell Therapy to Treat NF1 Gliomas

In 2021, a team of researchers led by CHOP's Dr. Maris announced a breakthrough in the treatment of aggressive solid cancers. Published in Nature, the researchers showed that they had developed a novel CAR T-cell therapy that could target and kill neuroblastoma tumor cells.

With funding from the Gilbert Family Foundation, Dr. Maris and colleagues are aiming to replicate that success story to develop a similar CAR T therapy for NF1.

CAR T is a type of immunotherapy in which clinicians re-engineer a patient's own immune system (T cells) to recognize and kill cancer. For CAR T therapy to work effectively, the CAR T cells must be programmed so that they can find a unique target (a protein) that is expressed only by the tumor. Otherwise, the therapy will target healthy cells.

"If you teach the immune system to attack something that is expressed in your lungs, then it will start attacking your lungs," said Dr. Raedt, a co-principal investigator on the NF1 CAR T project.

CAR T cells also do not have the ability to see inside of a tumor cell, so the unique target must be displayed on the tumor surface. One of the main limitations in targeting solid tumors with CAR T, Dr. De Raedt said, is that most of the proteins on the surface of tumor cells are not unique to the tumor and can be found on normal cells.

To overcome this challenge, Dr. Maris developed a method that gives CAR T cells the ability to "see inside" of a tumor cell and identify it as cancerous or abnormal.

"Your immune system continuously checks up on cells to make sure they are 'safe' and not infected by a pathogen. As part of that system, every cell displays short fragments of internal proteins, called peptides, on their cell surface to the immune system," Dr. De Raedt said.

He likened the system to showing your passport at border control.

In the context of neuroblastoma, Dr. Maris and his research team used various computational and genomic approaches to identify tumor-specific internal peptides, which they could then use to engineer and teach CAR T cells to eliminate tumors.

Now, Dr. Maris is collaborating with Dr. De Raedt and others to repeat this approach for high-grade brain tumors in patients with NF1.

"We're extracting and analyzing all of those displayed peptides from NF1 high-grade gliomas," Dr. De Raedt said. "By knowing what they're displaying, we can identify tumor unique peptides that we can potentially target with CAR T."

CHOP is well positioned to discover a new immunotherapy to treat high-grade NF1-associated gliomas, for which there is currently no cure, Dr. De Raedt said.

"Not only do we have the help of the NF1 patient community, but we have the knowledge, support, and infrastructure of the wider research community at CHOP and Penn," he said, "and I think that's really what makes us unique."