Umfassende Charakterisierung der B7H3-Expression in erwachsenen und pädiatrischen Hirntumor-Entitäten mit besonderem Fokus auf das Medulloblastom als hoch B7H3-exprimierenden Tumor

Chimeric antigen receptor (CAR) T-cell therapy holds promise as a cancer immunotherapy, necessitating the selection of appropriate tumor-associated antigens (TAAs). The immune checkpoint protein B7H3 is a TAA under evaluation in eight CAR T-cell clinical trials, primarily targeting glioblastoma (GBM). This study assesses B7H3 expression in a diverse spectrum of brain tumors in relation to survival and safety considerations.

Formalin-fixed paraffin-embedded tumor samples from adult (n=199) and pediatric (n=25) patients were subjected to immunohistochemical staining for B7H3. Tumor types included GBM (n=146), astrocytoma WHO grade 1-4 (n=31), oligodendroglioma WHO grade 2 and 3 (n=22), medulloblastoma (n=5), pediatric-type diffuse high-grade glioma (n=5), ependymal tumor (n = 9), circumscribed astrocytic tumor (n = 4), and pediatric astrocytoma (n=2). Staining intensity was quantified with QuantCenter, assigning an H-score (range 0-300) to each sample. Survival analysis for GBM patients was performed using Kaplan-Meier curves and Cox regression, considering relevant clinical factors. B7H3 safety as a target was evaluated in healthy tissue microarrays approved by the FDA.

Medulloblastoma exhibited the highest and uniform B7H3 expression (median H-score 209), presenting a valuable prerequisite for CAR T-cell immunotherapy in this predominantly pediatric tumor. In contrast, other pediatric entities displayed significant heterogeneity in B7H3 expression. Among adult tumors, GBM demonstrated the highest B7H3 expression (median H-score 137), followed by astrocytoma grade 1, 3, and 2. Survival analysis revealed significantly longer overall survival for high B7H3 expressors in GBM (log rank p = 0.049). Healthy liver, lung, and colon exhibited moderate B7H3 levels, providing insights into potential on-target off-tumor toxicity.

This study comprehensively characterized B7H3 expression in diverse adult and pediatric brain tumor entities. The identified high and uniform B7H3 expression in medulloblastoma underscores its potential as a precise target for CAR T-cell immunotherapy, particularly in pediatric cancers. The observation of higher B7H3 expression correlated with longer overall survival in adult GBM patients has implications for prognostication and clinical practice. Insights into B7H3 expression in healthy tissues contribute to the assessment of potential on-target off-tumor toxicity in therapeutic interventions.