P08.04.B DLL3 IS EXPRESSED IN GLIOMA AND IS LARGELY RETAINED AT RECURRENCE, MAKING IT A SUITABLE TARGET FOR IMMUNOTHERAPIES

Abstract BACKGROUND Gliomas invariably recur after first-line treatment, and there is a dire need for new therapeutic options at recurrence. Delta-like protein 3 (DLL3) is a ligand in the Notch signalling pathway. It is expressed in several cancers, such as small cell lung cancer (SCLC) and neuro-endocrine carcinoma, but rarely expressed in healthy tissues, making it an attractive therapeutic target. Previous studies have found DLL3 expression in glioma as well, but patient numbers were small. Several immunotherapy constructs targeting DLL3 have been developed, such as antibody-drug conjugates (ADC’s) and bi-specific T cell-engagers (TCE’s), and show promising results in refractory SCLC. Since clinical trials may investigate patients with recurrent glioma based on DLL3 expression in the primary tumor, the aim of this study was to determine if DLL3 expression in glioma persists at recurrence, which would justify selecting patients for clinical trials using primary tumor tissue. MATERIALS AND METHODS 198 FFPE samples of paired primary and recurrent tumors were retrieved from the biobank in the Erasmus MC, Rotterdam, the Netherlands. 190 samples were of sufficient quality for analysis, and 182 samples from n=91 patients could be analysed in matched pairs. Samples were classified as oligodendroglioma, IDHmt and 1p/19q codeleted (n=34), astrocytoma, IDHmt (n=37) and glioblastoma, IDHwt (n=119). Immunohistochemistry for DLL3 was performed using the Ventana kit (Roche, Tucson, AZ, USA). DLL3 expression was defined as the percentage of DLL3-positive cells within areas of vital tumor tissue, as assessed by an experienced neuropathologist. Samples were labelled as DLL3-negative, low, medium or high. RESULTS DLL3 was expressed in the majority of gliomas (86%, 164/190 samples). DLL3 expression was highest in oligodendroglioma (100%; 94% medium or high) and astrocytoma (100%; 78.4 % medium or high) and lowest in glioblastoma (78.2%; 42% medium or high). Only 26/190 samples were DLL3-negative. In the majority of patients, DLL3 expression stayed in the same category or increased at recurrence (oligodendroglioma 87.6%, astrocytoma 66.6%, glioblastoma 77.2%). Initial DLL3-positivity was lost at recurrence in only 7/91 patients (7.7%). CONCLUSION DLL3 is expressed in the majority of gliomas, especially IDHmt tumors, which have a higher proportion of positive cells. In the majority of patients, DLL3 expression level is retained or increased at recurrence. This supports the hypothesis that DLL3 might be a suitable target for (immuno)therapies in recurrent glioma. Trial inclusion based on primary tumor material is justified, but depends on the required level of DLL3 positivity for inclusion.