Researchers at Children’s Hospital of Philadelphia (CHOP) have released new findings that may improve the safety and effectiveness of chimeric antigen receptor T cell (CAR-T) therapy for children with solid tumors. The studies, published in Molecular Therapy and Neuro-Oncology, examine how tumor biology and immune system factors influence CAR-T treatment outcomes for neuroblastoma and diffuse midline glioma (DMG).
In the Molecular Therapy study, CHOP researchers investigated why neuroblastoma often resists CAR-T therapies. Previous attempts using CAR-T cells targeting glypican-2 (GPC2), a protein found in some cancers, were mostly based on models without fully functional immune systems. To address this limitation, the team developed preclinical models with intact immune systems. Their results showed that the tumor environment suppresses CAR-T cell activity by limiting their ability to persist within tumors.
To improve this, scientists engineered GPC2 CAR-T cells to include C-X-C chemokine receptor type 2 (CXCR2). This addition helped guide the modified cells toward tumors and reduce harmful immune cells that interfere with treatment. The enhanced CAR-T cells demonstrated improved tumor targeting and greater cancer-fighting effects.
“The study underscores the critical value of using models with a healthy immune system to pinpoint essential CAR escape mechanisms in solid tumors,” said Kristopher Bosse, MD, an attending physician with the Division of Oncology at Children’s Hospital of Philadelphia. “This approach is vital as we continue to devise biologically balanced enhancements to CAR-T cell therapies.”
The second study, published in Neuro-Oncology, focused on challenges associated with using GD2-targeted CAR-T therapy for high-grade pediatric brain tumors such as DMG. Permanent versions of these engineered cells can cause serious side effects due to prolonged activity in sensitive brain tissues. To address this risk, researchers used mRNA technology to create transient forms of GD2-targeted CAR-T cells that express only temporarily.
Testing these transient cells in lab-grown organoids and live DMG samples revealed they were highly effective at killing tumor cells but naturally reduced their activity after nine days. This allowed for repeated dosing without causing neurological complications—a key consideration when treating tumors near critical brain regions like the pons and thalamus.
“Our findings demonstrate that CAR-T cell therapy is not a one size fits all approach, especially in pediatric oncology where tumor biology and treatment tolerability are uniquely complex,” said Jessica B. Foster, MD, a lead study author and attending physician in the Division of Oncology at Children’s Hospital of Philadelphia. “It’s imperative that we continue to pioneer new ways of making CAR-T therapy safer and more effective for children with aggressive cancers.”
Funding for Dr. Foster’s research came from several sources including the Department of Defense, National Institutes of Health, Matthew Larson Foundation, Liv Like a Unicorn, Greyson Saves Foundation, Kourtney Rose Foundation and October Saves. Dr. Bosse’s work was supported by grants from organizations such as the American Association of Cancer Research (AACR)-AstraZeneca Career Development Award for Physician-Scientists in Honor of José Baselga, Alex’s Lemonade Stand Foundation and National Cancer Institute.
Bosse et al.’s study appears online May 27, 2025: “Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells.” Molecular Therapy. DOI: 1016/j.ymthe.2025.05.025.
Foster et al.’s work was published May 24, 2025: “Transient mRNA CAR T cells targeting GD2 provide dose-adjusted efficacy against diffuse midline glioma and high-grade glioma models.” Neuro-Oncology. DOI: 10.1093/neuonc/noaf115.
