Hyundai Hope On Wheels Supports Neuroblastoma Research at CHOP

By Lauren Ingeno

Emerging immunotherapies like Chimeric Antigen Receptor (CAR) T-cell therapy — which re-programs a patient’s own immune cells to find and kill cancer cells — have revolutionized treatment for some cancers. However, they don’t work well in every disease, including high-risk neuroblastoma. 

With the support of two grants from Hyundai Hope On Wheels, Children’s Hospital of Philadelphia researchers are improving immunotherapies to increase survival rates and minimize treatment-related toxicity for patients with this rare and aggressive cancer, which starts in nerve tissue and can spread throughout the body. 

“I find it incredibly meaningful and a privilege to take care of patients and their families who have cancer,” said Adam Wolpaw, MD, PhD, an Assistant Professor of Pediatrics and attending physician, who received a Scholar Hope award from the Hope On Wheels program this year. “When we have therapies that are toxic or don’t work well for some patients, that always motivates me to come back to the lab and think about the questions we need to ask to make those therapies better.” 

With his award, Dr. Wolpaw is creating new models to better understand how to enhance immunotherapies in solid tumors. 

Timothy Spear, MD, PhD, a fourth-year Hematology/Oncology Fellow, received a 2024 Hope On Wheels Young Investigator award to design and test a vaccine that would boost anti-tumor activity in CAR T cells.

“Our group will be the first to test the vaccine strategy in a pediatric cancer model,” Dr. Spear said.

Enhancing the ‘Bystander Effect’

One of the challenges in curing neuroblastoma is the diverse cell types within a child’s tumor. While most cells in a neuroblastoma tumor are in an “adrenergic” state, there are also “mesenchymal” cells that are less differentiated, and therefore are more resistant to therapy.

Dr. Wolpaw’s past research has shown that cells in a mesenchymal state are more easily killed by immune cells, revealing their potential vulnerability to immunotherapy. However, most forms of immunotherapy currently in clinical use for neuroblastoma patients target GD2 or GPC2 molecules, both of which are found on the surface of adrenergic cells, but not on mesenchymal cells.

Rather than developing new drugs — a process that can take decades — Dr. Wolpaw and colleagues hypothesized that they could enhance two existing immunotherapies, including CAR T, to destroy mesenchymal cells.

“By taking advantage of what the therapies are doing to target the adrenergic cells, we thought we could trick them into targeting the other cells as well,” Dr. Wolpaw said.

This strategy is what Dr. Wolpaw refers to as the “bystander effect.”

“Part of this project is building models to test that effect,” Dr. Wolpaw said. “We take small numbers of mesenchymal cells, put them into tumors, and treat them with immunotherapy to see if those cells survive or not. Then we want to know whether we can enhance that effect to make existing therapies kill more cancer cells.”

GD2 antibody and CAR T treatments recruit natural killer cells and T cells, respectively, to kill neuroblastoma. To enhance the bystander effect, the CHOP research team will identify changes they can make to mesenchymal neuroblastoma cells that increase natural killer and T-cell recruitment, boosting their ability to kill cancer.

“Engineering the tumor cell is a scientific tool to understand the biology of a system, which is what we’re going to do first,” Dr. Wolpaw said. “Once we understand this biology better, the therapeutic potential is that you could engineer a CAR T cell to enhance this bystander effect.” 

Designing a Vaccine to Boost CAR T

Another barrier to the effectiveness of CAR T-cell therapy in solid tumors is their low persistence. 

To effectively treat cancer, CAR T cells must engraft and persist in the body over a long period of time. Many factors affect CAR T cells’ longevity, including an immunosuppressive tumor microenvironment, exhaustion when trying to penetrate solid tumors, and immune system rejection. 

To overcome these challenges, Dr. Spear and his team are working with Nobel Prize-winning Drew Weissman, MD, PhD, the Roberts Family Professor in Vaccine Research at the University of Pennsylvania’s Perelman School of Medicine, best known for his scientific contributions to the development of COVID-19 vaccines. The research team is designing a CAR-enhancing vaccine that will use messenger RNA (mRNA) to trigger an immune response in the CAR T cells, increasing their numbers and longevity.

“As we're learning more about checkpoint inhibitors, CAR T cells, and the basics of cancer immunology, we're reevaluating and reinforcing how we design cancer vaccines,” Dr. Spear said.

Hyundai Hope On Wheels is a nonprofit established by Hyundai Motor America that funds innovative research with the hope of finding a cure for pediatric cancer.

With these latest grant awards, Hyundai Hope On Wheels has provided more than $7.2 million to CHOP, aiding critical pediatric cancer research. Dr. Wolpaw and Dr. Spear were recognized as 2024 grant recipients during a Hope On Wheels ceremony in September.