Eine erhöhte GD2-Expression in Oligodendrogliomen bietet eine grundlegende Voraussetzung für die Immuntherapie mit CAR T-Zellen

Gliomas, the most prevalent malignant brain tumors, present with limited treatment options and often dismal prognoses. Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic approach that requires a careful selection of tumor-associated antigens (TAAs). GD2, a well-explored TAA in neuroblastoma, is currently under investigation in four clinical CAR T-cell trials for gliomas. This study aims to assess GD2 expression in glioma entities, correlating findings with survival outcomes and target safety.

A retrospective cohort of 198 adult glioblastoma (GBM) (n=145), astrocytoma WHO grade 1-4 (n=31), oligodendroglioma WHO grade 2 (n=12) and 3 (n=10), and 5 pediatric-type diffuse high grade glioma patients was included. Formalin-fixed paraffin-embedded tumor samples underwent immunohistochemical staining for GD2. Staining intensity of each sample was quantified into an H-score (range 0-300) using QuantCenter. Analysis of overall (OS) and progression-free survival (PFS) of GBM patients was analyzed with Kaplan-Meier curves and Cox regression, considering clinical data. GD2 safety as a target was evaluated in healthy FDA-approved tissue microarrays.

High GD2 expression was detected in 10 of 12 oligodendroglioma WHO grade 2 (median H-score 259) and 9 of 10 WHO grade 3 patients (median H-score 250.5) with a narrow interquartile range. GBM and astrocytoma WHO grade 1, 2, 3, or 4 displayed moderate to weak GD2 expression (median H-score of 95, 61, 169, 134, 90, respectively). All pediatric-type diffuse high-grade gliomas moderately expressed GD2. Survival analysis revealed that GD2 high GBM patients had shorter OS (log rank p=0.057) and PFS (log rank p=0.073). Multivariate analysis identified GD2 as a significant negative prognostic factor for PFS (HR=1.004, 95% CI=1.000–1.008, p=0.008). Furthermore, we found elevated levels of GD2 in healthy colon, kidney, and liver.

This study marks the inaugural characterization of GD2 expression in oligodendroglioma, unveiling elevated GD2 levels primarily affecting younger patients with an unfavorable outcome. Target expression analysis in healthy tissues provides valuable insights into potential on-target off-tumor toxicity, although such effects have not been observed in clinical trials. Further research and validation studies are warranted to confirm the clinical utility of GD2 as a prognostic marker and to explore its potential as a therapeutic target in gliomas.