GPC2-CAR T cells have potent preclinical activity against orthotopic medulloblastoma xenografts.
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Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients with group 3 and 4 MB have poor clinical outcomes, underscoring the urgent need for new therapies. Glypican-2 (GPC2) is a recently discovered oncofetal antigen. Given its expression in brain tumors, we evaluated the preclinical activity of our GPC2-chimeric antigen receptor (CAR) against MB and compared it to two existing CARs targeting GD2 and B7-H3. Gene expression analysis of publicly available datasets was performed and validated with immunohistochemistry staining of patient samples. The MB cell line D283 and a newly generated cell line patient-derived xenograft, MAF1433, were used. Cytokine bead assays and single-cell RNA sequencing (scRNA-seq) were used for mechanistic studies. MB patient samples express up to moderate levels of GPC2. GPC2-CARs lead to significant in vivo tumor regression in orthotopic tumor models via intravenous or intraventricular administration route and had equivalent activity to the B7-H3-CAR against D283 and enhanced activity than GD2-CAR in both models in vivo. T cell kinetic studies revealed that GPC2-CAR T cells home to the area of the primary tumor, expand, and upregulate genes critical for cytotoxicity and T cell homing. These results provide a preclinical rationale for including children with GPC2+ MB in our upcoming clinical GPC2-CAR T cell trial.