Abstract Background Relapsed or refractory (RR) pediatric CNS embryonal tumors, including medulloblastoma (MB), embryonal tumor with multilayered rosettes (ETMR), atypical teratoid/rhabdoid tumor (AT/RT), and pineoblastoma, have dismal outcomes with 5-year overall survival ranging from ∼10% in RR-MB to 1% in ETMR and AT/RT. Glypican-2 (GPC2) is an oncofetal antigen and promising immunotherapeutic target expressed in pediatric cancers including CNS embryonal tumors. Preclinical studies demonstrating potent antitumor activity of GPC2-CAR T cells in MB models prompted initiation of a first-in-human Phase I clinical trial (NCT07087002) evaluating their feasibility and safety using intracerebroventricular administration in children and young adults with RR-CNS embryonal tumors. Methods Because antigen density is critical for GPC2-CAR T-cell potency, enrollment is restricted to GPC2-positive disease, predicted to exceed CAR detection thresholds using an H-score of 100 as surrogate eligibility cut-off. Tumor specimens undergo CLIA-certified GPC2 immunohistochemistry (IHC) and are scored using a standard H-score (0–300) derived from staining intensity (0–3+) and percentage of GPC2-positive tumor cells. In parallel, an advanced scoring method segmenting intratumoral intensity differences (formula = (1 × % weak) + (2 × % moderate) + (3 × % strong)) is performed to assess potential clinical utility. Results To date, twelve patients were screened; 75% met eligibility by standard H-score, and two patients have enrolled. Screened tumors include MB (n = 2/median H-score 190), ETMR (n = 4/median 170), pineoblastoma (n = 2/median 200), and AT/RT (n = 3/median 2). Except for AT/RT, all tumors exceeded the enrollment threshold by either scoring method, with advanced H-scores trending higher than standard scores (p = 0.0977). Conclusion These findings demonstrate feasibility of GPC2 antigen prescreening using archival tumor tissue to support early-phase trial enrollment, enabling coherent safety and early efficacy assessment of GPC2-CAR T-cells in pediatric CNS Embryonal tumors. Larger cohorts are needed to determine whether advanced scoring provides added benefit in borderline cases.
Ryan et al. (Tue,) studied this question.