Researchers at Children’s Hospital of Philadelphia (CHOP) identified promising methods to enhance the effectiveness of chimeric antigen receptor (CAR) T cell therapy in neuroblastoma, a deadly pediatric cancer. The findings were published in the journal Science Translational Medicine.
High-risk neuroblastoma is a severe form of cancer that affects children, with a long-term survival rate of less than 50%, even after aggressive treatments like chemotherapy and radiation. This highlights a crucial need for new and innovative treatment options.
Kristopher Bosse, MD, the senior study author and attending physician at CHOP’s Cancer Center, and his team have focused their research on a protein called glypican-2 (GPC2), which is found on high-risk neuroblastomas and other deadly cancers, but not on vital normal tissues. This makes GPC2 an ideal target for new cancer therapies.
In Bosse’s lab, researchers have developed therapies that specifically target GPC2. These include GPC2 CAR-T cells, which are a type of treatment where a patient's T cells are modified to better attack cancer cells. One of the researchers’ GPC2 CAR-T cell therapies is currently being tested in a first-in-human clinical trial. Additionally, other clinical trials are examining the effectiveness of GD2 CAR-T cells for treating neuroblastoma and other GD2-positive tumors. These trials have shown promising results, providing the first strong evidence that CAR-T cells can be effective against this type of childhood cancer.
However, there are challenges. Like many other cancer treatments, CAR-T cells can lose effectiveness over time due to the cancer's ability to adapt and the harsh tumor environment that suppresses immune responses, including the effectiveness of CAR-T cells.
One innovative strategy to improve the persistence and effectiveness of CAR-T cells in the body is “CAR vaccination.” In this preclinical study, led by first author and research collaborator at CHOP, Anna Maria Giudice, PhD, researchers did not use messenger RNA (mRNA) or traditional vaccines; instead, they employed engineered extracellular vesicles (EVs) or synthetic SyntEVs containing and, in some cases, also binding to specific tumor antigens. For example, GPC2+ SyntEVs stimulated GPC2 CAR T cells in preclinical neuroblastoma models, inducing their persistence and antitumor efficacy. Additionally, by administering GD2-binding SyntEVs, the researchers increased GPC2 antigen levels on tumor cells, enhancing CAR-T cell infiltration and their ability to control tumors. This method also shows promise in restimulating CAR-T cells in vivo and maintaining their therapeutic effects.
“While early, our findings mark a step forward in the battle against neuroblastoma, offering better understanding of how to potentially enhance the efficacy of CAR-T," said Bosse.
Moving forward, the researchers are also looking into using specialized nanoparticles, known as lipid nanoparticles (LNPs), to deliver mRNA vaccines that can help improve CAR-T cell therapy for cancer treatment. The idea is that after a patient receives CAR-T cell therapy, they could periodically receive these mRNA vaccines to maintain and boost the activity of the CAR-T cells. This is particularly important for solid tumors, which have targeted antigens hidden in these harsh tumor environments making them hard for CAR-T cells to access.
This work was supported by the Rally Foundation for Childhood Cancer Research, an Alex’s Lemonade Stand Foundation (ALSF) ‘A’ Award, NCI R37 CA282041, NCI K08 CA230223, (RP210154) from the Cancer Prevention & Research Institute of Texas, Burroughs Welcome Fund and a Children’s Hospital of Philadelphia Cell and Gene Therapy Collaborative Seed Grant. The ALSF also provides support for the COG Childhood Cancer Repository (www.cccells.org).
Giudice et al. “Antigen-displaying extracellular vesicles boost CAR-T cell efficacy in cell and mouse models of neuroblastoma.” Sci Trans Medicine. Online. November 19, 2025. DOI: 10.1126/scitranslmed.ads4214.
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Researchers at Children’s Hospital of Philadelphia (CHOP) identified promising methods to enhance the effectiveness of chimeric antigen receptor (CAR) T cell therapy in neuroblastoma, a deadly pediatric cancer. The findings were published in the journal Science Translational Medicine.
High-risk neuroblastoma is a severe form of cancer that affects children, with a long-term survival rate of less than 50%, even after aggressive treatments like chemotherapy and radiation. This highlights a crucial need for new and innovative treatment options.
Kristopher Bosse, MD, the senior study author and attending physician at CHOP’s Cancer Center, and his team have focused their research on a protein called glypican-2 (GPC2), which is found on high-risk neuroblastomas and other deadly cancers, but not on vital normal tissues. This makes GPC2 an ideal target for new cancer therapies.
In Bosse’s lab, researchers have developed therapies that specifically target GPC2. These include GPC2 CAR-T cells, which are a type of treatment where a patient's T cells are modified to better attack cancer cells. One of the researchers’ GPC2 CAR-T cell therapies is currently being tested in a first-in-human clinical trial. Additionally, other clinical trials are examining the effectiveness of GD2 CAR-T cells for treating neuroblastoma and other GD2-positive tumors. These trials have shown promising results, providing the first strong evidence that CAR-T cells can be effective against this type of childhood cancer.
However, there are challenges. Like many other cancer treatments, CAR-T cells can lose effectiveness over time due to the cancer's ability to adapt and the harsh tumor environment that suppresses immune responses, including the effectiveness of CAR-T cells.
One innovative strategy to improve the persistence and effectiveness of CAR-T cells in the body is “CAR vaccination.” In this preclinical study, led by first author and research collaborator at CHOP, Anna Maria Giudice, PhD, researchers did not use messenger RNA (mRNA) or traditional vaccines; instead, they employed engineered extracellular vesicles (EVs) or synthetic SyntEVs containing and, in some cases, also binding to specific tumor antigens. For example, GPC2+ SyntEVs stimulated GPC2 CAR T cells in preclinical neuroblastoma models, inducing their persistence and antitumor efficacy. Additionally, by administering GD2-binding SyntEVs, the researchers increased GPC2 antigen levels on tumor cells, enhancing CAR-T cell infiltration and their ability to control tumors. This method also shows promise in restimulating CAR-T cells in vivo and maintaining their therapeutic effects.
“While early, our findings mark a step forward in the battle against neuroblastoma, offering better understanding of how to potentially enhance the efficacy of CAR-T," said Bosse.
Moving forward, the researchers are also looking into using specialized nanoparticles, known as lipid nanoparticles (LNPs), to deliver mRNA vaccines that can help improve CAR-T cell therapy for cancer treatment. The idea is that after a patient receives CAR-T cell therapy, they could periodically receive these mRNA vaccines to maintain and boost the activity of the CAR-T cells. This is particularly important for solid tumors, which have targeted antigens hidden in these harsh tumor environments making them hard for CAR-T cells to access.
This work was supported by the Rally Foundation for Childhood Cancer Research, an Alex’s Lemonade Stand Foundation (ALSF) ‘A’ Award, NCI R37 CA282041, NCI K08 CA230223, (RP210154) from the Cancer Prevention & Research Institute of Texas, Burroughs Welcome Fund and a Children’s Hospital of Philadelphia Cell and Gene Therapy Collaborative Seed Grant. The ALSF also provides support for the COG Childhood Cancer Repository (www.cccells.org).
Giudice et al. “Antigen-displaying extracellular vesicles boost CAR-T cell efficacy in cell and mouse models of neuroblastoma.” Sci Trans Medicine. Online. November 19, 2025. DOI: 10.1126/scitranslmed.ads4214.
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