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Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells

Researchers at the Children's Hospital of Philadelphia have developed a new strategy to improve the effectiveness of GPC2-directed CAR T cell therapy in neuroblastoma by reprogramming the tumor immune microenvironment. Published in Molecular Therapy, the study addresses a major obstacle in treating solid tumors with CAR T cells: poor infiltration and suppression by tumor-associated immune cells. The team engineered murine CAR T cells using the clinically utilized D3-GPC2 single-chain variable fragment and tested them in immunocompetent mouse models of neuroblastoma, mimicking the human immune context more accurately than previous xenograft studies.

Using syngeneic allograft models, the researchers observed that although GPC2 CAR T cells initially infiltrated the tumor, they failed to persist and were functionally suppressed. Immune profiling revealed a robust recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), driven by high levels of chemokines CXCL1 and CXCL2. Ex vivo assays confirmed that these MDSCs directly inhibited CAR T cell proliferation, activation, and cytotoxic function. To counter this, the team genetically modified the CAR T cells to express CXCR2 — the receptor for CXCL1/2 — enabling them to exploit the chemokine gradient for enhanced tumor trafficking. These "CXCR2-armored" CAR T cells demonstrated improved migration toward tumor sites, superior anti-tumor activity, and a reduction in intratumoral MDSCs. Importantly, this modification not only enhanced therapeutic efficacy but also reshaped the TME in a way that favored sustained CAR T cell activity.

This study is one of the first to evaluate GPC2 CAR T cells in an immunocompetent setting and highlights the importance of designing context-specific armoring strategies to overcome immune suppression in solid tumors. The CXCR2-engineered CAR T cells represent a promising advancement toward durable and effective CAR T therapy for pediatric neuroblastoma, with implications for broader applications in solid tumor immunotherapy.

Reference:

Giudice AM, Roth SL, Matlaga S, et al. Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells. Mol Ther. Published online May 27, 2025. http://doi.org/10.1016/j.ymthe.2025.05.025